Journal Articles

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

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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

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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

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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

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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

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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

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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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Extracellular vesicles are key mediators for direct antigen transport to draining lymph nodes Spotlight 

(1) Wang C (2) Cheng X (3) Cheng K (4) Yuan F

Molecular therapy

Wang and Cheng et al. showed that electrotransfection activated the HSP90–p53–TSAP6 signaling pathway to enhance extracellular vesicle (EV) biogenesis, facilitating antigen transport from muscles to draining lymph nodes during DNA vaccination. Vaccine-encoded transmembrane antigen (hemagglutinin) was enriched in the secreted EVs, trafficked through lymphatic vessels, and reached draining lymph nodes within hours. Direct visualization confirmed passive extracellular vesicle transport through lymphatic vasculature. Pharmacologic inhibition of vesicle biogenesis reduced EV concentration in the muscle, and impaired immune responses.

Contributed by Shishir Pant

(1) Wang C (2) Cheng X (3) Cheng K (4) Yuan F

Molecular therapy

Wang and Cheng et al. showed that electrotransfection activated the HSP90–p53–TSAP6 signaling pathway to enhance extracellular vesicle (EV) biogenesis, facilitating antigen transport from muscles to draining lymph nodes during DNA vaccination. Vaccine-encoded transmembrane antigen (hemagglutinin) was enriched in the secreted EVs, trafficked through lymphatic vessels, and reached draining lymph nodes within hours. Direct visualization confirmed passive extracellular vesicle transport through lymphatic vasculature. Pharmacologic inhibition of vesicle biogenesis reduced EV concentration in the muscle, and impaired immune responses.

Contributed by Shishir Pant

ABSTRACT: DNA vaccines have shown great potential in preclinical and clinical studies. However, it is still unclear how the antigen expressed at the site of vaccination is delivered to draining lymph nodes for activation of the immune system. To address the issue, the current study investigated the role of extracellular vesicles (EVs) in the delivery. Following intramuscular electrotransfection of DNA vaccines encoding a transmembrane antigen, hemagglutinin (HA), EV secretion was significantly increased in the muscle with the peak level being ∼10-fold higher than the unvaccinated control. More importantly, the EVs were highly enriched with HA, and could reach the draining lymph nodes through lymphatic vessels within 4 h. Blocking the EV secretion by systemic treatment with a small molecular inhibitor, GW4869, significantly reduced humoral and cellular responses against the antigen. These findings indicated that the EVs play an important role in the antigen delivery, suggesting that enhancing local EV biogenesis and antigen packaging into EVs can be new avenues for development of next-generation vaccine adjuvants.

Author Info: (1) Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (3) Depart

Author Info: (1) Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (3) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Electronic address: ke.cheng@columbia.edu. (4) Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address: fyuan@duke.edu.

Citation: Mol Ther 2026 Jan 7 34:606-619 Epub10/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41103032

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Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma

Spotlight 

(1) Bachem A (2) Clarke M (3) Kong G (4) Tarasova I (5) Dryburgh L (6) Kosack L (7) Lee AR (8) Newland LD (9) Wagner T (10) Bawden E (11) Yap KM (12) Wilson MD (13) Engel S (14) Wilson KR (15) Russ BE (16) Tandon K (17) Lau PKH (18) McArthur G (19) Marcelino VR (20) Beavis PA (21) Turner SJ (22) Waithman J (23) Stinear TP (24) Sandhu S (25) Schršder J (26) Gebhardt T (27) Bedoui S

Immunity

Bachem, Clarke and Kong et al. studied the role of microbiota-derived short chain fatty acids (SCFAs) in an orthotopic melanoma model, revealing a direct link between melanoma control, CD8+ T cell differentiation and SCFA synthetic pathways. Dietary fiber and the SCFA butyrate reduced melanoma progression, increased tumor specific stem-like CD127+CD8+ T cells in the tdLN and induced a FOXO1-driven stemness program. In melanoma patients, metagenomic modeling of fecal samples revealed that increased butyrate flux correlated positively with ICB outcomes, consistent with previously observed correlations with dietary fiber consumption and fecal butyrate levels.

Contributed by Katherine Turner

(1) Bachem A (2) Clarke M (3) Kong G (4) Tarasova I (5) Dryburgh L (6) Kosack L (7) Lee AR (8) Newland LD (9) Wagner T (10) Bawden E (11) Yap KM (12) Wilson MD (13) Engel S (14) Wilson KR (15) Russ BE (16) Tandon K (17) Lau PKH (18) McArthur G (19) Marcelino VR (20) Beavis PA (21) Turner SJ (22) Waithman J (23) Stinear TP (24) Sandhu S (25) Schršder J (26) Gebhardt T (27) Bedoui S

Immunity

Bachem, Clarke and Kong et al. studied the role of microbiota-derived short chain fatty acids (SCFAs) in an orthotopic melanoma model, revealing a direct link between melanoma control, CD8+ T cell differentiation and SCFA synthetic pathways. Dietary fiber and the SCFA butyrate reduced melanoma progression, increased tumor specific stem-like CD127+CD8+ T cells in the tdLN and induced a FOXO1-driven stemness program. In melanoma patients, metagenomic modeling of fecal samples revealed that increased butyrate flux correlated positively with ICB outcomes, consistent with previously observed correlations with dietary fiber consumption and fecal butyrate levels.

Contributed by Katherine Turner

ABSTRACT: A range of microbiota species correlate with improved cancer outcomes in patients and confer protection in pre-clinical mouse models. Here, we examined how microbiota regulate CD8(+) T cell immunity against melanoma. Spontaneous control of cutaneous melanoma in mice correlated with metabolic pathways required for microbial synthesis of short-chain fatty acids (SCFAs) shared between several microbiota species. Diet-induced enforcement of SCFA production by the gut microbiota reduced melanoma progression and enriched tumor-specific stem-like CD127(+)CD8(+) T cells in the tumor-draining lymph node (tdLN). The SCFA butyrate induced a FOXO1-driven stemness program and directly promoted the differentiation of tumor-specific CD127(+)CD8(+) T cells in the tdLN. Metabolic flux modeling predicted enhanced microbial production of butyrate in melanoma patients with complete therapeutic responses to immune checkpoint blockade (ICB), and butyrate induced transcriptional features of ICB responsiveness in CD8(+) T cells. Our findings suggest a critical role for metabolite production shared across several microbiota species in the preservation of stem-like tumor-specific CD8(+) T cells.

Author Info: (1) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. Electronic add

Author Info: (1) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. Electronic address: abachem@unimelb.edu.au. (2) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (3) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Centre for Pathogen Genomics Innovation Hub, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (4) Computational Science Initiative, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (5) Computational Science Initiative, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (6) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (7) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (8) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, North Rhine-Westphalia 53127, Germany. (9) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (10) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia. (12) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (13) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (14) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (15) Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia. (16) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (17) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia; Melanoma Discovery Laboratory, Harry Perkins Institute of Medical Research, Nedlands, WA 6009, Australia; School of Medicine, University of Western Australia, Crawley, WA 6009, Australia. (18) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (19) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Melbourne Integrative Genomics, School of BioSciences, The University of Melbourne, Melbourne, VIC 3010, Australia. (20) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia. (21) Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia. (22) School of Biomedical Sciences, The University of Western Australia, Perth, WA 6009, Australia; Telethon Kids Institute, The University of Western Australia, Perth, WA 6009, Australia. (23) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Centre for Pathogen Genomics Innovation Hub, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (24) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC 3000, Australia; Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (25) Computational Science Initiative, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (26) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia. (27) Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; Institute of Innate Immunity, University of Bonn, Bonn, North Rhine-Westphalia 53127, Germany. Electronic address: sbedoui@unimelb.edu.au.

Citation: Immunity 2025 Nov 3 Epub11/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41187761

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Oxidative-stress-induced telomere instability drives T cell dysfunction in cancer Featured  

(1) Rivadeneira DB (2) Thosar S (3) Quann K (4) Gunn WG (5) Dean VG (6) Xie B (7) Parise A (8) McGovern AC (9) Spahr K (10) Lontos K (11) Barnes RP (12) Bruchez MP (13) Opresko PL (14) Delgoffe GM

Immunity

Rivadeneira et al. assessed the role of oxidative damage on T cell function in the TME. Oxidative stress in mitochondria resulted in reduced T cell proliferation, terminal differentiation, and dysfunction. DNA damage at telomeres was found to be responsible for these effects. Alleviating oxidative stress at telomeres with a ROS scavenger fusion protein could enhance T cell functionality and prevent formation of dysfunctional phenotype, improving tumor control in vivo.

(1) Rivadeneira DB (2) Thosar S (3) Quann K (4) Gunn WG (5) Dean VG (6) Xie B (7) Parise A (8) McGovern AC (9) Spahr K (10) Lontos K (11) Barnes RP (12) Bruchez MP (13) Opresko PL (14) Delgoffe GM

Immunity

Rivadeneira et al. assessed the role of oxidative damage on T cell function in the TME. Oxidative stress in mitochondria resulted in reduced T cell proliferation, terminal differentiation, and dysfunction. DNA damage at telomeres was found to be responsible for these effects. Alleviating oxidative stress at telomeres with a ROS scavenger fusion protein could enhance T cell functionality and prevent formation of dysfunctional phenotype, improving tumor control in vivo.

ABSTRACT: The tumor microenvironment (TME) imposes immunologic and metabolic stresses sufficient to deviate immune cell differentiation into dysfunctional states. Oxidative stress originating in the mitochondria can induce DNA damage, most notably telomeres. Here, we show that dysfunctional T cells in cancer did not harbor short telomeres indicative of replicative senescence but rather harbored damaged telomeres, which we hypothesized arose from oxidative stress. Chemo-optogenetic induction of highly localized mitochondrial or telomeric reactive oxygen species (ROS) using a photosensitizer caused the accumulation of DNA damage at telomeres, driving telomere fragility. Telomeric damage was sufficient to drive a dysfunctional state in T cells, showing a diminished capability for cytokine production. Localizing the ROS scavenger GPX1 directly to telomeres reduced telomere fragility in tumors and improved the function of therapeutic T cells. Protecting telomeres through expression of a telomere-targeted antioxidant may preserve T cell function in the TME and drive superior responses to cell therapies.

Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: dar177@pitt.edu. (2) Department of Cancer Biology, University of Kansas Medical Cen

Author Info: (1) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: dar177@pitt.edu. (2) Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. (3) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (4) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (5) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (6) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (7) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (9) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (10) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (11) Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. (12) Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA. (13) Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, PA, USA. (14) Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: gdelgoffe@pitt.edu.

Citation: Immunity 2025 Sep 3 Epub09/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40930086

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