Journal Articles

Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy

Spotlight 

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell

Mallard de La Varende et al. showed that gut dysbiosis following treatment with antibiotics or antibiotic-associated species led to loss of secondary bile acids (BAs), increased tauro-conjugated primary BAs, downregulation of MAdCAM-1 in the ilium, and increased γ-glutamyl transferase (γ-GT) in serum, supporting TIME reprogramming, T cell exhaustion, and resistance to anti-PD-1 in tumor-bearing mice. Resistance could be overcome by performing FMT, supplementing secondary BAs, or using an ilium-specific FXR agonist. In patients, resistance was associated with subclinical cholestasis (elevated γ-GT), which predicted poor response.

Contributed by Lauren Hitchings

Anne-Laure Mallard de La Varende (1); Ai-Ling Tian,1 Simon Thomas (1); Imran Lahmar (1); Meriem Messaoudene (2); Sijing Li (3); Omar Motiño (3,4); Hortense Guillaume-dit-Taunière (1); Valerio Iebba (1); Yoan Hurtado (1); Thao-Nguyen Pham (1); Cassandra Thélémaque (1); Miguel Araujo-Voces (1); Deborah Suissa (1); Pierre Ly (1); Ella Reich (1); Giacomo Vitali (5); Bryan Thierry Arlunno (1); Sylvere Durand (6); Fanny Aprahamian (6); Marion Leduc (3,6); Sabrina Forveille (3,6); Oliver Kepp (3,6); Carlos de la Calle-Fabregat (7); Angela Schippers (8); Norbert Wagner (8); Pierre-Edouard Fournier (9); Kenya Honda (10,11,12); Federica Marmorino (13); Chiara Cremolini (13,14); Saman Maleki Vareki (15,16,17,18).

Cancer Cell

Mallard de La Varende et al. showed that gut dysbiosis following treatment with antibiotics or antibiotic-associated species led to loss of secondary bile acids (BAs), increased tauro-conjugated primary BAs, downregulation of MAdCAM-1 in the ilium, and increased γ-glutamyl transferase (γ-GT) in serum, supporting TIME reprogramming, T cell exhaustion, and resistance to anti-PD-1 in tumor-bearing mice. Resistance could be overcome by performing FMT, supplementing secondary BAs, or using an ilium-specific FXR agonist. In patients, resistance was associated with subclinical cholestasis (elevated γ-GT), which predicted poor response.

Contributed by Lauren Hitchings

ABSTRACT: Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compen- sated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased sMAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de rec

Author Info: 1- Université Paris-Saclay, Gustave Roussy (GRCC), ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, 94805 Villejuif, France. 2- Centre de recherche Du CHUM (CRCHUM), Montréal, QC H2W1T8, Canada. 3- Centre de Recherche des Cordeliers, INSERM U1138, Equipe Labellisée – Ligue Nationale Contre le Cancer, Université Paris Cité, Sorbonne Université, 75006 Paris, France. 4- Unidad de Excelencia, Instituto de Biomedicina y Genética Molecular de Valladolid, Consejo Superior de Investigaciones Científicas-Universidad de Valladolid, 47001 Valladolid, Spain. 5- MetaGenoPolis, INRAe, Université Paris-Saclay 78350 Jouy en Josas, France. 6- Université Paris-Saclay, INSERM US23, Analyse moléculaire, modélisation et imagerie de la maladie Cancéreuse, Plateformes de Métabolomique et de Criblage Cellulaire Haut Débit, 94805 Villejuif, France. 7- Université Paris-Saclay, Gustave Roussy, U1356 Next Generation Immuno-Oncology Research, 94805 Villejuif, France

Citation: Cancer Cell July 2026

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    Tryptophan degradation by intestinal Bacteroides induces anti-tumor immunity and limits melanoma growth Spotlight 

    (1) Olea XD (2) Beede K (3) Pereira G (4) Scott D (5) Petucci C (6) Martens E (7) Rodionov D (8) Shah A (9) Martinez MP (10) Kim H (11) Sharma AK (12) Martin A (13) Zhang T (14) Faries MB (15) Hamid O (16) Devkota S (17) Osterman A (18) Knott S (19) Voest EE (20) Ajami NJ (21) Wargo J (22) Ramer-Tait AE (23) Ronai ZA

    Cell reports. Medicine

    Olea and Beede et al. identified Bacteroides rodentium and Bacteroides uniformis (found in mice and humans, respectively) as gut microbes that induced antitumor immunity and inhibited tumor growth in melanoma mouse models. These strains expressed tryptophanase A (TnaA) and aromatic aminotransferases (ArAT) that degraded tryptophan into indoles. TnaA loss in B. uniformis abrogated antitumor activity, whereas indole administration increased CD8+ T cell infiltration and restrained tumor growth, independent of AhR signaling. Elevated levels of ArAT and TnaA were found in patients with melanoma who responded to ICB.

    Contributed by Shishir Pant

    (1) Olea XD (2) Beede K (3) Pereira G (4) Scott D (5) Petucci C (6) Martens E (7) Rodionov D (8) Shah A (9) Martinez MP (10) Kim H (11) Sharma AK (12) Martin A (13) Zhang T (14) Faries MB (15) Hamid O (16) Devkota S (17) Osterman A (18) Knott S (19) Voest EE (20) Ajami NJ (21) Wargo J (22) Ramer-Tait AE (23) Ronai ZA

    Cell reports. Medicine

    Olea and Beede et al. identified Bacteroides rodentium and Bacteroides uniformis (found in mice and humans, respectively) as gut microbes that induced antitumor immunity and inhibited tumor growth in melanoma mouse models. These strains expressed tryptophanase A (TnaA) and aromatic aminotransferases (ArAT) that degraded tryptophan into indoles. TnaA loss in B. uniformis abrogated antitumor activity, whereas indole administration increased CD8+ T cell infiltration and restrained tumor growth, independent of AhR signaling. Elevated levels of ArAT and TnaA were found in patients with melanoma who responded to ICB.

    Contributed by Shishir Pant

    ABSTRACT: Study of gut microbiota control of anti-tumor immunity (ATI) identifies Bacteroides rodentium and the human-related Bacteroides uniformis species to be capable of inducing ATI and limiting melanoma development in germ-free (GF), complex microbiome, or wild-type (WT) mice. Enhanced CD8(+) T cell infiltration within tumors of mice harboring B. rodentium coincides with increased expression of immune-stimulating pathways. Metabolomic analyses identify lower tryptophan levels in the cecal samples of GF mice harboring B. rodentium. In silico genomic reconstruction reveals that B. rodentium and B. uniformis harbor tryptophanase A (TnaA) and aromatic aminotransferase genes, which degrade tryptophan to indoles. Administration of B. uniformis harboring TnaA mutant fails to inhibit melanoma growth. Notably, administration of indoles effectively induces ATI and inhibits melanoma development. Correspondingly, the levels of bacterially encoded tryptophan-degrading enzymes are higher in cohorts of patients with melanoma responding to immunotherapy. These findings identify indoles as tryptophan breakdown products capable of inducing ATI resulting in melanoma inhibition.

    Author Info: (1) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars S

    Author Info: (1) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (2) Department of Food Science and Technology, Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. (3) Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (4) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (5) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Department of Microbiology & Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. (7) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (8) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (9) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (10) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (11) Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (12) Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (13) Division of Cancer Epidemiology & Genetics, National Cancer Institute, Rockville, MD 20892, USA. (14) The Angeles Clinic and Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90025, USA. (15) The Angeles Clinic and Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90025, USA. (16) Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Human Microbiome Research Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (17) Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. (18) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. (19) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (20) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Food Science and Technology, Nebraska Food for Health Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address: aramer-tai2@unl.edu. (23) Translational Research Institute, Elinor and Rendall Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: zeev.ronai@csmc.edu.

    Citation: Cell Rep Med 2026 Jul 14 102921 Epub07/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42447866

    Tags:

    Metabolic determinants of cancer immunotherapy outcomes identified by plasma profiling Spotlight 

    (1) Suissa D (2) Fidelle M (3) Reich E (4) Pham TN (5) Thomas S (6) Bjšrk JR (7) Liu P (8) Zhao L (9) Kitaoka K (10) Piard E (11) Lebhar I (12) Tian AL (13) Thelemaque C (14) Alves Costa Silva C (15) Deutsch E (16) Loriot Y (17) Segata N (18) Piccinno G (19) Hospers GAP (20) Maleki Vareki S (21) Silverman MS (22) Lenehan JG (23) Bataille V (24) Boulate D (25) Kuznetsova T (26) Weersma RK (27) Messaoudene M (28) Durand S (29) van der Aalst CM (30) de Koning HJ (31) Schuler-Thurner B (32) de Vries IJM (33) Rafie E (34) Saliby RM (35) Machaalani M (36) Haferkamp S (37) Schilling B (38) Porcari S (39) Ciccarese C (40) Iacovelli R (41) Cremolini C (42) Choueiri TK (43) Elkrief A (44) Kroemer G (45) Heinzerling L (46) Chamoto K (47) Ianiro G (48) Routy B (49) Derosa L (50) Paragios N (51) Zitvogel L

    Nature medicine

    Suissa and Fidelle et al. performed targeted metabolomics to 4,336 plasma samples from 1,714 ICI-treated patients across 16 cohorts and trained an ML model that predicted 12‑month PFS, with histidine as a favorable marker and long-chain fatty acids and succinate associated with poor outcome. Histidine supplementation promoted mitochondrial FAO and regulated T cell exhaustion, enhancing ICI-induced antitumor immunity in fibrosarcoma and melanoma models. Histidine-rich diet was associated with favorable PFS in patients without dysbiosis-associated histidine catabolism, and fecal histidine levels inversely correlated with severe irAEs.

    Contributed by Shishir Pant

    (1) Suissa D (2) Fidelle M (3) Reich E (4) Pham TN (5) Thomas S (6) Bjšrk JR (7) Liu P (8) Zhao L (9) Kitaoka K (10) Piard E (11) Lebhar I (12) Tian AL (13) Thelemaque C (14) Alves Costa Silva C (15) Deutsch E (16) Loriot Y (17) Segata N (18) Piccinno G (19) Hospers GAP (20) Maleki Vareki S (21) Silverman MS (22) Lenehan JG (23) Bataille V (24) Boulate D (25) Kuznetsova T (26) Weersma RK (27) Messaoudene M (28) Durand S (29) van der Aalst CM (30) de Koning HJ (31) Schuler-Thurner B (32) de Vries IJM (33) Rafie E (34) Saliby RM (35) Machaalani M (36) Haferkamp S (37) Schilling B (38) Porcari S (39) Ciccarese C (40) Iacovelli R (41) Cremolini C (42) Choueiri TK (43) Elkrief A (44) Kroemer G (45) Heinzerling L (46) Chamoto K (47) Ianiro G (48) Routy B (49) Derosa L (50) Paragios N (51) Zitvogel L

    Nature medicine

    Suissa and Fidelle et al. performed targeted metabolomics to 4,336 plasma samples from 1,714 ICI-treated patients across 16 cohorts and trained an ML model that predicted 12‑month PFS, with histidine as a favorable marker and long-chain fatty acids and succinate associated with poor outcome. Histidine supplementation promoted mitochondrial FAO and regulated T cell exhaustion, enhancing ICI-induced antitumor immunity in fibrosarcoma and melanoma models. Histidine-rich diet was associated with favorable PFS in patients without dysbiosis-associated histidine catabolism, and fecal histidine levels inversely correlated with severe irAEs.

    Contributed by Shishir Pant

    ABSTRACT: Immune-checkpoint inhibitors benefit a subset of patients with advanced cancer, and the metabolic determinants of response remain unclear. Here, using targeted metabolomics and metagenomics, we profiled 4,336 plasma samples from 1,714 patients across five tumor types and 16 cohorts spanning Europe and North America, longitudinally sampled during five immune-checkpoint inhibitor-based treatment modalities, including fecal microbiota transplantation. A multimodal machine-learning framework integrating 154 metabolites with clinical variables identified five metabolites, age, body mass index and renal function as predictors of 12-month progression-free survival. The model achieved areas under the curve of 0.88 in training and 0.73 in validation cohorts of 105 and 30 patients, respectively and generalized across seven external cohorts. Histidine was a favorable prognostic feature of survival, whereas long-chain fatty acids and succinate were negatively associated with outcome. Histidine supplementation enhanced antitumor immunity in mice. Histidine-rich diets improved progression-free survival in patients lacking dysbiotic microbiome signatures associated with histidine catabolism.

    Author Info: (1) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (2) UniversitŽ Paris-Saclay,

    Author Info: (1) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (2) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (3) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (4) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (5) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (6) Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. (7) INSERM U1138 - Metabolism, Cancer & Immunity, ƒquipe LabellisŽe par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. (8) INSERM U1138 - Metabolism, Cancer & Immunity, ƒquipe LabellisŽe par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. (9) Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto, Japan. (10) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (11) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (12) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (13) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. (14) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. Oncoclinicas&Co - Medica Scientia Innovation Research (MEDSIR), Sao Paulo, Brazil. Gonalo Moniz Institute, Fiocruz, Salvador, Brazil. Federal University of Bahia, Salvador, Brazil. (15) Department of Radiation Oncology, Gustave Roussy, UniversitŽ Paris-Saclay, INSERM U1355, RHU LySAIRI, Villejuif, France. (16) Department of Therapeutic Innovation and Early Trials (DITEP), INSERM U981, Gustave Roussy, Villejuif, France. (17) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (18) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (19) Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. (20) Verspeeten Family Cancer Centre, London Health Sciences Research Institute, London, Ontario, Canada. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Department of Oncology, Division of Experimental Oncology, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada. (21) Lawson Health Research Institute, London, Ontario, Canada. Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St Joseph's Health Care, London, Ontario, Canada. (22) Verspeeten Family Cancer Centre, London Health Sciences Research Institute, London, Ontario, Canada. Department of Oncology, Western University, London, Ontario, Canada. (23) Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. Department of Dermatology, Mount Vernon Cancer Centre, Northwood, UK. Department of Dermatology, Hemel Hempstead Hospital, West Hertfordshire NHS Trust, Hemel Hempstead, UK. (24) Department of Thoracic Surgery, H™pital-Nord-APHM, Aix-Marseille University, Marseille, France. H™pital Marie Lannelongue, GHPSJ, Le Plessis-Robinson, France. (25) Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. (26) Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands. (27) Centre de Recherche du Centre Hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. (28) INSERM U1138 - Metabolism, Cancer & Immunity, ƒquipe LabellisŽe par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. (29) Department of Public Health, Erasmus Medical Centre - University Medical Centre Rotterdam, Rotterdam, The Netherlands. (30) Department of Public Health, Erasmus Medical Centre - University Medical Centre Rotterdam, Rotterdam, The Netherlands. (31) Department of Dermatology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), UniversitŠtsklinikum Erlangen, Erlangen, Germany. Bavarian Cancer Research Center (BZKF), Erlangen, Germany. (32) Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands. (33) Centre de Recherche du Centre Hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. Hemato-Oncology Division, Centre Hospitalier de l'UniversitŽ de MontrŽal (CHUM), Montreal, Quebec, Canada. (34) Dana-Farber Cancer Institute, Boston, MA, USA. Yale School of Medicine, New Haven, CT, USA. (35) Dana-Farber Cancer Institute, Boston, MA, USA. (36) Bavarian Cancer Research Center (BZKF), Erlangen, Germany. Department of Dermatology, University Hospital Regensburg, Regensburg, Germany. (37) Department of Dermatology, Goethe University Frankfurt, University Hospital, Frankfurt am Main, Germany. (38) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore, Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (39) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore, Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (40) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore, Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (41) Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. (42) Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (43) Centre de Recherche du Centre Hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. Hemato-Oncology Division, Centre Hospitalier de l'UniversitŽ de MontrŽal (CHUM), Montreal, Quebec, Canada. (44) INSERM U1138 - Metabolism, Cancer & Immunity, ƒquipe LabellisŽe par la Ligue Contre le Cancer, Centre de Recherche des Cordeliers, UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 AMMICa, Metabolomic Platform, Gustave Roussy, Villejuif, France. Institut du Cancer Paris CARPEM, Department of Biology, H™pital EuropŽen Georges Pompidou, AP-HP, Paris, France. (45) Department of Dermatology, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), UniversitŠtsklinikum Erlangen, Erlangen, Germany. Bavarian Cancer Research Center (BZKF), Erlangen, Germany. Department of Dermatology and Allergy, LMU University Hospital LMU Munich, Munich, Germany. (46) Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto, Japan. Division of Cancer Immune Regulation, Center for Cancer Immunotherapy and Immunobiology (CCII), Graduate School of Medicine, Kyoto University, Kyoto, Japan. (47) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore, Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (48) Centre de Recherche du Centre Hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), Axe Cancer, Montreal, Quebec, Canada. Hemato-Oncology Division, Centre Hospitalier de l'UniversitŽ de MontrŽal (CHUM), Montreal, Quebec, Canada. (49) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. Department of Medical Oncology, Gustave Roussy, Villejuif, France. (50) MICS Laboratory, CentraleSupŽlec, UniversitŽ Paris-Saclay, Gif-sur-Yvette, France. nikos.paragios@centralesupelec.fr. TheraPanacea, Paris, France. nikos.paragios@centralesupelec.fr. (51) UniversitŽ Paris-Saclay, Gustave Roussy, ClinicObiome, Inserm UMR1367, Microbiota and Mucosal Immunity for Cancer Immunotherapy, Villejuif, France. Laurence.zitvogel@gustaveroussy.fr.

    Citation: Nat Med 2026 Jun 25 Epub06/25/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350644

    Tags:

    Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity Spotlight 

    (1) You Z (2) Kim J (3) Guo C (4) Hu H (5) Chapman NM (6) Meng X (7) Shi H (8) Wang Y (9) Guy C (10) Kc A (11) Li J (12) Saravia J (13) Palacios G (14) Rankin S (15) Robinson CG (16) Chi H

    Science

    You and Kim et al. identified discrete mitochondrial states in intratumoral cDC1s, wherein cDC1s with polarized mitochondria more effectively primed CD8+ T cells than depolarized cDC1s. OPA1 regulated mitochondrial fusion and membrane potential, sustaining NRF1 expression, OXPHOS, and NAD+/NADH balance to support cDC1 functional fitness. The OPA1-NRF1 axis suppressed autophagy- and lysosome-mediated degradation of MHC-I and antigens to support cDC1 immunogenic function. OPA1 loss impaired antigen presentation and promoted tumor growth, while whole-tumor-cell-pulsed polarized cDC1 administration synergized with ICB in solid tumor models.

    Contributed by Shishir Pant

    (1) You Z (2) Kim J (3) Guo C (4) Hu H (5) Chapman NM (6) Meng X (7) Shi H (8) Wang Y (9) Guy C (10) Kc A (11) Li J (12) Saravia J (13) Palacios G (14) Rankin S (15) Robinson CG (16) Chi H

    Science

    You and Kim et al. identified discrete mitochondrial states in intratumoral cDC1s, wherein cDC1s with polarized mitochondria more effectively primed CD8+ T cells than depolarized cDC1s. OPA1 regulated mitochondrial fusion and membrane potential, sustaining NRF1 expression, OXPHOS, and NAD+/NADH balance to support cDC1 functional fitness. The OPA1-NRF1 axis suppressed autophagy- and lysosome-mediated degradation of MHC-I and antigens to support cDC1 immunogenic function. OPA1 loss impaired antigen presentation and promoted tumor growth, while whole-tumor-cell-pulsed polarized cDC1 administration synergized with ICB in solid tumor models.

    Contributed by Shishir Pant

    ABSTRACT: Antitumor immunity requires conventional type 1 dendritic cells (cDC1s). How cDC1s maintain functional fitness in the tumor microenvironment remains unclear. In this study, we established that intratumoral cDC1s exhibited discrete mitochondrial states and that OPA1-mediated mitochondrial energy and redox metabolism dictated cDC1 antitumor responses. Mechanistically, OPA1 orchestrated antigen presentation and the CD8(+) T cell priming function of cDC1s by promoting nuclear respiratory factor 1 (NRF1) expression and electron transport chain integrity, thereby supporting bioenergetics and NAD(+)/NADH balance. During tumor progression, mitochondrial membrane potential and volume, as well as OPA1-NRF1 signaling, declined in intratumoral cDC1s. Furthermore, intratumoral administration of cDC1s with polarized mitochondria showed immunotherapeutic benefits in mice, particularly in combination with immune checkpoint blockade. Collectively, our findings reveal mitochondrial metabolism and signaling as putative targets to reinvigorate cDC1 function for cancer immunotherapy.

    Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (3) De

    Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (3) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (4) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (5) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (6) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (7) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (8) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (9) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (10) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (11) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (12) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (13) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (14) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA. (15) Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, Memphis, TN, USA. (16) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.

    Citation: Science 2026 Apr 2 392:eadv6582 Epub04/02/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41926583

    Tags:

    16-h fasting optimizes cancer immunotherapy in mice and humans Spotlight 

    (1) Chen S (2) Hu T (3) Zhu K (4) Liu Y (5) Yang Y (6) Li X (7) He J (8) Cui W (9) Chi Z (10) Yu W (11) Chen D (12) Wang Z (13) Zhang J (14) Sun R (15) Yang D (16) Dai S (17) Yu Q (18) Wang Q (19) Xiao Q (20) Qian J (21) Ding K (22) Wang D

    Cell metabolism

    Chen et al. designed an overnight 16h fasting regimen that augmented ICB efficacy in mice and patients with colorectal cancer. Fasting reprogrammed tumor cell nutrient preferences, triggering a metabolic trade-off that enriched intratumoral isoleucine (Ile). Ile fueled the acetyl-CoA pool in CD8+ T cells, which coordinated the epigenetic landscape and membrane lipid dynamics required for CD8+ T cell effector functions. Fasting reduced exhausted T cell populations, increased TEMRA and TRM effector functions, augmented the clonal expansion and cytotoxic activity of CD8+ T cells, and enhanced anti-PD-1 efficacy in preclinical models and patients with CRC.

    Contributed by Shishir Pant

    (1) Chen S (2) Hu T (3) Zhu K (4) Liu Y (5) Yang Y (6) Li X (7) He J (8) Cui W (9) Chi Z (10) Yu W (11) Chen D (12) Wang Z (13) Zhang J (14) Sun R (15) Yang D (16) Dai S (17) Yu Q (18) Wang Q (19) Xiao Q (20) Qian J (21) Ding K (22) Wang D

    Cell metabolism

    Chen et al. designed an overnight 16h fasting regimen that augmented ICB efficacy in mice and patients with colorectal cancer. Fasting reprogrammed tumor cell nutrient preferences, triggering a metabolic trade-off that enriched intratumoral isoleucine (Ile). Ile fueled the acetyl-CoA pool in CD8+ T cells, which coordinated the epigenetic landscape and membrane lipid dynamics required for CD8+ T cell effector functions. Fasting reduced exhausted T cell populations, increased TEMRA and TRM effector functions, augmented the clonal expansion and cytotoxic activity of CD8+ T cells, and enhanced anti-PD-1 efficacy in preclinical models and patients with CRC.

    Contributed by Shishir Pant

    ABSTRACT: Dietary interventions hold promise for cancer therapy but often require prolonged, poorly tolerated regimens. Furthermore, how transient nutrient deprivation affects the metabolic interplay between tumor and immune cells within the tumor microenvironment (TME) remains unknown. Here, we introduce a brief, 16-h fasting regimen that enhances immunotherapy efficacy in both mice and humans. We found that this transient nutrient stress alters tumor-cell nutrient preferences, creating a metabolic window that can be leveraged to augment treatment. Mechanistically, short-term fasting induces intratumoral accumulation of isoleucine, which reconfigures CD8(+) T cell epigenetic programs and phospholipid remodeling, thereby licensing enhanced anti-tumor capacity. In patients receiving neoadjuvant immunotherapy, short-term fasting was able to enhance CD8(+) clonal expansion and cytotoxic programs. These findings establish a clinically feasible, well-tolerated dietary regimen that counters nutrient competition in the TME and that provides a tractable path to strengthen existing immunotherapy regimens.

    Author Info: (1) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University

    Author Info: (1) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (2) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (3) Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. (4) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (5) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (6) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (7) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (8) Eye Center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (9) Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, International School of Medicine, International Institutes of Medicine, Yiwu 322000, P.R. China. (10) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (11) Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (12) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (13) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China. (14) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (15) Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China. (16) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (17) Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (18) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (19) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. (20) Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. (21) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China; Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou 310020, P.R. China; Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou 310009, P.R. China. Electronic address: dingkefeng@zju.edu.cn. (22) Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310017, P.R. China; Institute of Immunology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311113, P.R. China; Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China. Electronic address: diwang@zju.edu.cn.

    Citation: Cell Metab 2026 Feb 19 Epub02/19/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41720105

    Tags:

    Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial Featured  

    (1) Porcari S (2) Ciccarese C (3) Heidrich V (4) Rondinella D (5) Quaranta G (6) Severino A (7) Arduini D (8) Buti S (9) Fornarini G (10) Primi F (11) Stumbo L (12) Giannarelli D (13) Giudice GC (14) Damassi A (15) Giron Berr’os JR (16) Pun_och‡_ M (17) Barbazuk TB (18) Piccinno G (19) Pinto F (20) Armanini F (21) Asnicar F (22) Schinzari G (23) Derosa L (24) Kroemer G (25) Sanguinetti M (26) Masucci L (27) Gasbarrini A (28) Tortora G (29) Cammarota G (30) Zitvogel L (31) Segata N (32) Iacovelli R (33) Ianiro G

    Nature medicine

    Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

    (1) Porcari S (2) Ciccarese C (3) Heidrich V (4) Rondinella D (5) Quaranta G (6) Severino A (7) Arduini D (8) Buti S (9) Fornarini G (10) Primi F (11) Stumbo L (12) Giannarelli D (13) Giudice GC (14) Damassi A (15) Giron Berr’os JR (16) Pun_och‡_ M (17) Barbazuk TB (18) Piccinno G (19) Pinto F (20) Armanini F (21) Asnicar F (22) Schinzari G (23) Derosa L (24) Kroemer G (25) Sanguinetti M (26) Masucci L (27) Gasbarrini A (28) Tortora G (29) Cammarota G (30) Zitvogel L (31) Segata N (32) Iacovelli R (33) Ianiro G

    Nature medicine

    Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

    ABSTRACT: Renal cell carcinoma (RCC) is a common malignancy with limited durable responses to first-line immune checkpoint inhibitor (ICI)-based therapies. Emerging evidence implicates the gut microbiome in modulating ICI efficacy. In the investigator-initiated, randomized, double-blind placebo-controlled phase 2a TACITO trial, we evaluated whether fecal microbiota transplantation (FMT) from complete ICI responders enhances clinical outcomes in treatment-naive patients with metastatic RCC (mRCC) receiving pembrolizumab + axitinib. The primary endpoint was the rate of patients free from disease progression at 12 months after randomization (12-month progression-free survival (PFS)). Secondary endpoints were median PFS and median overall survival, objective response rate (ORR), safety and microbiome changes, after randomization. Forty-five patients randomly received donor FMT (d-FMT) or placebo FMT (p-FMT). Although the primary endpoint was not met (70% versus 41% for d-FMT versus p-FMT, respectively, P = 0.053), the secondary endpoint of median PFS was significantly longer with d-FMT (24.0 months in the d-FMT arm versus 9.0 months in the p-FMT arm; hazard ratio = 0.50, P = 0.035). The ORR was 52% of patients in the d-FMT arm and 32% of patients receiving placebo. Microbiome analysis confirmed donor strain engraftment and increased α-diversity and larger microbiome shifts (β-diversity) compared with baseline composition in the d-FMT treatment group. Acquisition or loss of specific strains, but not total engraftment, was associated with the primary endpoint. Our findings support the safety and potential efficacy of selected donor FMT to enhance ICI-based treatment in mRCC, which deserves further investigations. ClinicalTrials.gov identifier: NCT04758507 .

    Author Info: (1) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences

    Author Info: (1) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (2) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (3) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (4) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (5) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. (6) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (7) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (8) Department of Medicine and Surgery, University of Parma, Parma, Italy. (9) UO Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (10) Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy. (11) Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy. (12) Facility di Epidemiologia e Biostatistica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. (13) Department of Medicine and Surgery, University of Parma, Parma, Italy. (14) UO Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy. (15) Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy. (16) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (17) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (18) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (19) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (20) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (21) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (22) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (23) Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. UniversitŽ Paris-Saclay, _le-de-France, France. Institut National de la SantŽ et de la Recherche MŽdicale (INSERM) U1015, Equipe LabellisŽe-Ligue Nationale contre le Cancer, Villejuif, France. (24) UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Inserm, Centre de Recherche des Cordeliers, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. Institut du Cancer Paris CARPEM, Department of Biology, H™pital EuropŽen Georges Pompidou, AP-HP, Paris, France. Centre de Recherche des Cordeliers, Equipe labellisŽe par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. (25) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Universitˆ Cattolica del Sacro Cuore, Rome, Italy. (26) Department of Laboratory and Hematology Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Universitˆ Cattolica del Sacro Cuore, Rome, Italy. (27) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. (28) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (29) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, Rome, Italy. (30) Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. UniversitŽ Paris-Saclay, _le-de-France, France. Institut National de la SantŽ et de la Recherche MŽdicale (INSERM) U1015, Equipe LabellisŽe-Ligue Nationale contre le Cancer, Villejuif, France. (31) Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy. (32) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. Department of Medical and Surgical Sciences, UOC Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. (33) Department of Translational Medicine and Surgery, Universitˆ Cattolica del Sacro Cuore Facoltˆ di Medicina e Chirurgia, Rome, Italy. gianluca.ianiro@unicatt.it. Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy. gianluca.ianiro@unicatt.it.

    Citation: Nat Med 2026 Jan 28 Epub01/28/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41606119

    Tags:

    Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial Featured  

    (1) Duttagupta S (2) Messaoudene M (3) Hunter S (4) Desilets A (5) Jamal R (6) Mihalcioiu C (7) Belkaid W (8) Marcoux N (9) Fidelle M (10) Suissa D (11) Ponce M (12) Geiger M (13) Malo J (14) Piccinno G (15) Pun_och‡_ M (16) Filin A (17) Heidrich V (18) Rusu D (19) Mbaye B (20) Durand S (21) Ben Aissa I (22) Puller V (23) de Lahonds R (24) Blais N (25) Tehfe M (26) Owen S (27) BŽlanger K (28) Parvathy SN (29) Shieh B (30) Raphael J (31) Lenehan J (32) Breadner D (33) Rothenstein J (34) Rozza N (35) Maillou J (36) Nili S (37) Prifti DK (38) Pinto F (39) Armanini F (40) Kim-Schulze S (41) Marron TU (42) Kroemer G (43) Derosa L (44) Zitvogel L (45) Silverman M (46) Segata N (47) Maleki Vareki S (48) Routy B (49) Elkrief A

    Nature medicine

    Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

    (1) Duttagupta S (2) Messaoudene M (3) Hunter S (4) Desilets A (5) Jamal R (6) Mihalcioiu C (7) Belkaid W (8) Marcoux N (9) Fidelle M (10) Suissa D (11) Ponce M (12) Geiger M (13) Malo J (14) Piccinno G (15) Pun_och‡_ M (16) Filin A (17) Heidrich V (18) Rusu D (19) Mbaye B (20) Durand S (21) Ben Aissa I (22) Puller V (23) de Lahonds R (24) Blais N (25) Tehfe M (26) Owen S (27) BŽlanger K (28) Parvathy SN (29) Shieh B (30) Raphael J (31) Lenehan J (32) Breadner D (33) Rothenstein J (34) Rozza N (35) Maillou J (36) Nili S (37) Prifti DK (38) Pinto F (39) Armanini F (40) Kim-Schulze S (41) Marron TU (42) Kroemer G (43) Derosa L (44) Zitvogel L (45) Silverman M (46) Segata N (47) Maleki Vareki S (48) Routy B (49) Elkrief A

    Nature medicine

    Three clinical trials investigating methods to improve immune checkpoint blockade (ICB) were recently published. Duttagupta, Messaoudene et al. investigated the addition of healthy donor FMT to ICB protocols for NSCLC and melanoma, while Porcari et al. investigated the addition of FMT from patients who had a complete response to ICB to standard-of-care treatment with anti-PD-1 and a VEGFR TKI in patients with metastatic RCC. Finally, Kendra et al. investigated neoadjuvant use of anti-PD-1 in patients with resectable desmoplastic melanoma.

    ABSTRACT: Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor-host microbiome similarity. In NSCLC, the ORR was 80% (16/20), meeting the study primary endpoint. In melanoma, the ORR was 75% (15/20). FMT was deemed safe in both cohorts by an independent data and safety monitoring committee, with no grade 3 or higher adverse events (AEs) in NSCLC and 13 (65%) patients experiencing grade 3 or higher AEs in melanoma. Shotgun metagenomic sequencing revealed that responders developed a distinct post-FMT gut microbiome composition, independent of acquired donor-recipient similarity or strain-level engraftment. Responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. This finding was reproduced across three published FMT oncology trials. We recolonized antibiotic-treated, tumor-bearing mice with post-FMT stool from two responder patients, and reintroduction of the specific bacterial species that were lost after FMT abrogated the antitumor effect of ICI. Taken together, these findings confirm the clinical activity of FMT in combination with ICI and suggest that the elimination of deleterious taxa is required for FMT-mediated therapeutic benefit. ClinicalTrials.gov identifier: NCT04951583 .

    Author Info: (1) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Department of Microbiology & Immunology, Faculty of Medici

    Author Info: (1) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Department of Microbiology & Immunology, Faculty of Medicine, UniversitŽ de MontrŽal, MontrŽal, QuŽbec, Canada. (2) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (3) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (4) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (5) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (6) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (7) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (8) Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de QuŽbec, QuŽbec City, QuŽbec, Canada. (9) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. (10) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. (11) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (12) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (13) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (14) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (15) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (16) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (17) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (18) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (19) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (20) Centre de Recherche des Cordeliers, ƒquipe labellisŽe par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. (21) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (22) GMT Science, Rouen, France. (23) GMT Science, Rouen, France. (24) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (25) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (26) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (27) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (28) Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St. Joseph's Health Care, London, Ontario, Canada. Lawson Research Institute, London, Ontario, Canada. (29) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (30) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Oncology, Division of Medical Oncology, Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada. (31) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Oncology, Division of Medical Oncology, Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada. (32) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Oncology, Division of Medical Oncology, Schulich School of Medicine and Dentistry at Western University, London, Ontario, Canada. (33) R.S. McLaughlin Durham Regional Cancer Center at Lakeridge Health, Oshawa, Ontario, Canada. (34) Departments of Oncology and Medicine, McGill University, Montreal, QuŽbec, Canada. (35) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Department of Microbiology & Immunology, Faculty of Medicine, UniversitŽ de MontrŽal, MontrŽal, QuŽbec, Canada. (36) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (37) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. (38) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (39) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (40) Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (41) Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (42) Centre de Recherche des Cordeliers, ƒquipe labellisŽe par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. UniversitŽ Paris-Saclay, INSERM US23 / CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. UniversitŽ Paris CitŽ, Sorbonne UniversitŽ, Inserm, Centre de Recherche des Cordeliers, Paris, France. Institut du Cancer Paris CARPEM, Department of Biology, H™pital EuropŽen Georges Pompidou, AP-HP, Paris, France. (43) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. Gustave Roussy Cancer Campus (GRCC), ClinicObiome, Villejuif, France. (44) UniversitŽ Paris-Saclay, U1015 INSERM, Gustave Roussy, Ligue LabellisŽe contre le Cancer, Villejuif, France. Gustave Roussy Cancer Campus (GRCC), ClinicObiome, Villejuif, France. (45) Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St. Joseph's Health Care, London, Ontario, Canada. Lawson Research Institute, London, Ontario, Canada. (46) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (47) Verspeeten Family Cancer Centre at London Health Sciences Centre, London, Ontario, Canada. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Division of Experimental Oncology, Department of Oncology, Western University, London, Ontario, Canada. Ontario Institute of Cancer Research, Toronto, Ontario, Canada. (48) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. (49) Axe Cancer, Centre de recherche du Centre hospitalier de l'UniversitŽ de MontrŽal (CRCHUM), MontrŽal, QuŽbec, Canada. arielle.elkrief@umontreal.ca. Hemato-Oncology Division, Centre hospitalier de l'UniversitŽ de MontrŽal (CHUM), MontrŽal, QuŽbec, Canada. arielle.elkrief@umontreal.ca.

    Citation: Nat Med 2026 Jan 28 Epub01/28/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41606121

    Tags:

    DCC-2036 induces repolarization of TAMs to M1 type and enhances CD8+ T cell immunity in TNBC

    Spotlight 

    (1) Liang Y (2) Zeng Q (3) Xiao M (4) Li P (5) He R (6) Chen Z (7) Liu J (8) Cao J (9) Li J (10) Yin L (11) Zhong J (12) Chen X (13) Feng J (14) He J (15) Chen X (16) Zu X (17) Shen Y

    Molecular therapy | Free PMC Article

    Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.

    Contributed by Shishir Pant

    (1) Liang Y (2) Zeng Q (3) Xiao M (4) Li P (5) He R (6) Chen Z (7) Liu J (8) Cao J (9) Li J (10) Yin L (11) Zhong J (12) Chen X (13) Feng J (14) He J (15) Chen X (16) Zu X (17) Shen Y

    Molecular therapy | Free PMC Article

    Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.

    Contributed by Shishir Pant

    ABSTRACT: Therapies for triple-negative breast cancer (TNBC) still need innovative approaches, while repolarizing tumor-associated macrophages (TAMs) may offer a breakthrough in the targeted therapy and immunotherapy of TNBC. In this study, our group found that the small-molecule tyrosine kinase inhibitor DCC-2036 could induce repolarization of TAMs from M2 to M1 type and enhance anti-tumor CD8+ T cell immunity in TNBC. Mechanistically, targeting inhibition of the non-receptor tyrosine kinase hematopoietic cell kinase (HCK) in TAMs regulated the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-glutamine synthetase (GS)-HIF1α signaling pathway, leading to a reprogramming of TAM metabolism from oxidative phosphorylation to glycolysis. This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in interleukin (IL)-10 secretion, which enhanced the immune response of anti-tumor CD8+ T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036 and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy.

    Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of

    Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (2) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (3) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (4) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (5) Department of Pathology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (6) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (7) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (8) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (9) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (10) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (11) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (12) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (13) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (14) Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421002, China. (15) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (16) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: zuxuyu@usc.edu.cn. (17) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: shenyingying1113@usc.edu.cn.

    Citation: Mol Ther 2026 Feb 4 34:985-1008 Epub10/24/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41137391

    Tags:

    Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling

    Spotlight 

    (1) van Haften FJ (2) van der Sluis TC (3) Hepp HS (4) MŸlling N (5) Nadafi R (6) Sampadi B (7) van Duikeren S (8) Mostert JS (9) van der Sterre R (10) van Veelen PA (11) Heieis GA (12) Veerkamp DMB (13) Wesselink TH (14) Vleeshouwers W (15) Beijnes M (16) Pardieck IN (17) van Horssen ELF (18) de Groot AF (19) van der Ploeg M (20) Kroep JR (21) de Miranda NFCC (22) van der Zanden SY (23) Neefjes J (24) Mei H (25) Vertegaal ACO (26) Everts B (27) van der Burg SH (28) Arens R

    Nature immunology

    Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.

    Contributed by Shishir Pant

    (1) van Haften FJ (2) van der Sluis TC (3) Hepp HS (4) MŸlling N (5) Nadafi R (6) Sampadi B (7) van Duikeren S (8) Mostert JS (9) van der Sterre R (10) van Veelen PA (11) Heieis GA (12) Veerkamp DMB (13) Wesselink TH (14) Vleeshouwers W (15) Beijnes M (16) Pardieck IN (17) van Horssen ELF (18) de Groot AF (19) van der Ploeg M (20) Kroep JR (21) de Miranda NFCC (22) van der Zanden SY (23) Neefjes J (24) Mei H (25) Vertegaal ACO (26) Everts B (27) van der Burg SH (28) Arens R

    Nature immunology

    Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.

    Contributed by Shishir Pant

    ABSTRACT: Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8(+) T cells that undergo synchronized proliferation and differentiation. How CD8(+) T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8(+) T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8(+) T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8(+) T cells following arrest. Transient arrest in vivo enables superior CD8(+) T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8(+) T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

    Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. De

    Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (4) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (5) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (6) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (7) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (8) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (9) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (10) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (11) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (12) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (13) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (14) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (15) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (16) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (17) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (18) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (19) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (20) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (21) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (22) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (23) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (24) Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands. (25) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (26) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (27) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (28) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. r.arens@lumc.nl.

    Citation: Nat Immunol 2026 Jan 19 Epub01/19/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41555086

    Tags:

    Pan-cancer N-glycoproteomic atlas of patient-derived xenografts uncovers FAT2 as an actionable surface target Spotlight 

    (1) Govindarajan M (2) Mejia-Guerrero S (3) Chafe SC (4) Khan S (5) Shi W (6) Waas M (7) Rossotti MA (8) Khoo A (9) Liu LY (10) Ignatchenko V (11) Principe S (12) Sepiashvili L (13) Hussack G (14) Tatari N (15) Venugopal C (16) Miletic P (17) Topley M (18) Grewal S (19) McKenna D (20) Asselstine LC (21) Sandi MJ (22) Pham NA (23) Casey A (24) Kim H (25) Karamboulas C (26) Meens J (27) Bergqvist P (28) Silva B (29) Chan P (30) Cerna-Portillo L (31) Chin J (32) Rao-Bhatia A (33) Tsao MS (34) Khokha R (35) Su S (36) Xu W (37) Goldstein D (38) Ailles L (39) Stambolic V (40) Liu FF (41) Cummins E (42) Samudio I (43) Singh SK (44) Kislinger T

    Cell reports. Medicine

    Govindarajan and Mejia-Guerrero et al. used enrichment of N-glycosylated surface proteins and mass spectrometry to profile 85 patient-derived xenografts and generated Glyco PDXplorer, an in vivo pan-cancer atlas of tumor cell-surface N-glycoproteins. 290 cancer-enriched surface targets with limited normal tissue expression were identified. FAT2 emerged as a novel HNSC-enriched surface protein, essential for HNSC adhesion, growth, and survival via integrin-PI3K signaling. In the BT530 patient-derived model of brain metastasis with squamous cell histology, intracranial administration of FAT2 CAR-T cells reduced tumor burden and extended survival.

    Contributed by Shishir Pant

    (1) Govindarajan M (2) Mejia-Guerrero S (3) Chafe SC (4) Khan S (5) Shi W (6) Waas M (7) Rossotti MA (8) Khoo A (9) Liu LY (10) Ignatchenko V (11) Principe S (12) Sepiashvili L (13) Hussack G (14) Tatari N (15) Venugopal C (16) Miletic P (17) Topley M (18) Grewal S (19) McKenna D (20) Asselstine LC (21) Sandi MJ (22) Pham NA (23) Casey A (24) Kim H (25) Karamboulas C (26) Meens J (27) Bergqvist P (28) Silva B (29) Chan P (30) Cerna-Portillo L (31) Chin J (32) Rao-Bhatia A (33) Tsao MS (34) Khokha R (35) Su S (36) Xu W (37) Goldstein D (38) Ailles L (39) Stambolic V (40) Liu FF (41) Cummins E (42) Samudio I (43) Singh SK (44) Kislinger T

    Cell reports. Medicine

    Govindarajan and Mejia-Guerrero et al. used enrichment of N-glycosylated surface proteins and mass spectrometry to profile 85 patient-derived xenografts and generated Glyco PDXplorer, an in vivo pan-cancer atlas of tumor cell-surface N-glycoproteins. 290 cancer-enriched surface targets with limited normal tissue expression were identified. FAT2 emerged as a novel HNSC-enriched surface protein, essential for HNSC adhesion, growth, and survival via integrin-PI3K signaling. In the BT530 patient-derived model of brain metastasis with squamous cell histology, intracranial administration of FAT2 CAR-T cells reduced tumor burden and extended survival.

    Contributed by Shishir Pant

    ABSTRACT: Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central roles in cellular signaling, yet their promise remains largely untapped due to technical challenges inherent to profiling them. Here, we employ N-glycoproteomics to analyze 85 patient-derived xenografts (PDXs), constructing Glyco PDXplorer-an in vivo pan-cancer atlas of cancer-derived surface proteins. We develop a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validate FAT2 as a squamous-cancer-enriched surface protein minimally detected in normal tissue. Functional studies reveal that FAT2 is essential for head and neck squamous cancer (HNSC) cell growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR)-T cells targeting FAT2 demonstrate anti-tumor activity. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal platform to inform therapeutic target discovery across cancers.

    Author Info: (1) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (

    Author Info: (1) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (2) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (3) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (4) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (5) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (6) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (7) Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. (8) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (9) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (10) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (11) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (12) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (13) Human Health Therapeutics Research Centre, Life Sciences Division, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. (14) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (15) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (16) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (17) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (18) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (19) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (20) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada. (21) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (22) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (23) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (24) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (25) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (26) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (27) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (28) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (29) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (30) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (31) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (32) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (33) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (34) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (35) Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada. (36) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada. (37) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Otolaryngology-Head & Neck Surgery, University of Toronto, Toronto, ON M5S 3H2, Canada. (38) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (39) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. (40) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada. (41) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (42) adMare BioInnovations, Vancouver, BC V6T 1Z3, Canada. (43) Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON L8S 4M1, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 1C7, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada. (44) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada. Electronic address: thomas.kislinger@utoronto.ca.

    Citation: Cell Rep Med 2026 Jan 23 102578 Epub01/23/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41579862

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