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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    A Patient-Derived Screen Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Immunotherapy Partners Spotlight 

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    (1) Khalaj M (2) Burden AT (3) Gutierrez ML (4) Hoonsbeen SC (5) Nejad P (6) Raveh T (7) Young JS (8) Fattahi F (9) Weissman IL

    Cancer immunology research

    Khalaj et al. performed a small molecule screen of FDA-approved compounds on CD11b+ tumor-associated microglia/macrophages isolated from patient GBM, and identified histone deacetylase (HDAC) inhibitors as enhancers of TAM phagocytosis. HDAC inhibitors increased phagocytosis across multiple TAM-GBM pairs, and showed synergy with CD47 blockade ex vivo. In an orthotopic patient-derived GBM xenograft model, Pracinostat combined with anti-CD47 slowed tumor growth and extended survival. Pracinostat reprogrammed TAMs toward an NF-κB-driven inflammatory state, and epigenetically primed FcγR-mediated phagocytic machinery.

    Contributed by Shishir Pant

    ABSTRACT: Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAMs) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted a large-scale small molecule screen on primary TAMs isolated directly from GBM patient tumors, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. This screen revealed enrichment for histone deacetylase (HDAC)-targeting drugs among the top hits. HDAC inhibitors enhanced phagocytosis of cancer cells across multiple primary human TAM-GBM combinations, and synergized with CD47 blockade ex vivo. In a xenograft GBM model, Pracinostat suppressed tumor growth and extended survival, with additive benefit when combined with CD47 antibodies. RNA-sequencing and H3K27Ac CUT&Tag profiling of Pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a pro-inflammatory state via NF-κB activation, and epigenetic priming of FcγR-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade. Our findings establish a patient-first functional screening platform for identifying TAM-reprogramming therapeutics in GBM, validate HDAC inhibitors as a lead class that potentiates innate checkpoint immunotherapy, and provide additional candidate compounds for clinical investigation.

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San F

    Author Info: (1) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (2) Stanford Medicine United States. ROR: https://ror.org/03mtd9a03 (3) University of California, San Francisco San Francisco United States. ROR: https://ror.org/043mz5j54 (4) University of California San Francisco Medical Center San Francisco United States. ROR: https://ror.org/01t8svj65 (5) Stanford Medicine Stanford United States. ROR: https://ror.org/03mtd9a03 (6) Stanford University California 94305-5439, CA United States. ROR: https://ror.org/00f54p054 (7) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (8) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (9) Stanford University Stanford University, CA United States. ROR: https://ror.org/00f54p054

    Citation: Cancer Immunol Res 2026 Jul 14 Epub07/14/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42446904

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    Dendritic cells control tertiary lymphoid structure development and maintenance in cancer Featured  

    (1) Mattiuz R (2) Boumelha J (3) Aerakis E (4) Le Berichel J (5) Hamon P (6) Halasz L (7) Vaidya A (8) Soong BY (9) Radkevich E (10) Kim HM (11) Park MD (12) Donne R (13) Troncoso L (14) Kaplan RA (15) Hennequin C (16) Hern‡ndez-Verdin I (17) L—pez L (18) Rentzeperis F (19) D'Souza D (20) Kaiza ME (21) MacFawn IP (22) Belabed M (23) Mestrallet G (24) Humblin E (25) Merand R (26) Hegde S (27) Lone JC (28) Ioannou G (29) Ozbey S (30) Figueiredo I (31) Tepper A (32) Merarda H (33) Serhan N (34) Schaefer MM (35) An J (36) Ohara RA (37) Nemeth E (38) Goldstein S (39) Reid AM (40) Noureddine M (41) Tabachnikova A (42) Piperno GM (43) Tsoumakidou M (44) Ahmed J (45) Polydorides AD (46) Bhardwaj N (47) Lujambio A (48) Chen Z (49) Gonzalez Kozlova E (50) Kim-Schulze S (51) Brody JD (52) Schotsaert M (53) Moussion C (54) Gnjatic S (55) Roudko V (56) Ginhoux F (57) Murphy KM (58) Sauts-Fridman C (59) Fridman WH (60) Brown BD (61) Marron TU (62) Benvenuti F (63) Cyster JG (64) Salmon H (65) Bruno TC (66) Joshi NS (67) Kamphorst AO (68) Merad M

    Science

    Mattiuz et al. assessed the role of dendritic cells in TLS formation and maintenance. Mature cDC1s were found to play essential roles, with TLS formation being dependent on maturation of cDC1s and their cross-presentation to T cells in the TDLN, followed by T cell recruitment to the tumor. Over time, maintenance of TLSs required the presence of cDC1s and cDC1 migration to CCR7 ligand-enriched stromal hubs, MHC-I and MHC-II antigen presentation to T cells, and CD40 signaling.

    (1) Mattiuz R (2) Boumelha J (3) Aerakis E (4) Le Berichel J (5) Hamon P (6) Halasz L (7) Vaidya A (8) Soong BY (9) Radkevich E (10) Kim HM (11) Park MD (12) Donne R (13) Troncoso L (14) Kaplan RA (15) Hennequin C (16) Hern‡ndez-Verdin I (17) L—pez L (18) Rentzeperis F (19) D'Souza D (20) Kaiza ME (21) MacFawn IP (22) Belabed M (23) Mestrallet G (24) Humblin E (25) Merand R (26) Hegde S (27) Lone JC (28) Ioannou G (29) Ozbey S (30) Figueiredo I (31) Tepper A (32) Merarda H (33) Serhan N (34) Schaefer MM (35) An J (36) Ohara RA (37) Nemeth E (38) Goldstein S (39) Reid AM (40) Noureddine M (41) Tabachnikova A (42) Piperno GM (43) Tsoumakidou M (44) Ahmed J (45) Polydorides AD (46) Bhardwaj N (47) Lujambio A (48) Chen Z (49) Gonzalez Kozlova E (50) Kim-Schulze S (51) Brody JD (52) Schotsaert M (53) Moussion C (54) Gnjatic S (55) Roudko V (56) Ginhoux F (57) Murphy KM (58) Sauts-Fridman C (59) Fridman WH (60) Brown BD (61) Marron TU (62) Benvenuti F (63) Cyster JG (64) Salmon H (65) Bruno TC (66) Joshi NS (67) Kamphorst AO (68) Merad M

    Science

    Mattiuz et al. assessed the role of dendritic cells in TLS formation and maintenance. Mature cDC1s were found to play essential roles, with TLS formation being dependent on maturation of cDC1s and their cross-presentation to T cells in the TDLN, followed by T cell recruitment to the tumor. Over time, maintenance of TLSs required the presence of cDC1s and cDC1 migration to CCR7 ligand-enriched stromal hubs, MHC-I and MHC-II antigen presentation to T cells, and CD40 signaling.

    ABSTRACT: Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7+ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (TFH) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

    Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn Schoo

    Author Info: (1) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Institute for Bioinnovation, "Alexander Fleming" Biomedical Sciences Research Center, Vari, Greece. (4) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (11) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, Paris, France. (17) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (18) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (20) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (21) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. Department of Biology, Grove City College, Grove City, PA, USA. (22) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (23) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (24) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (25) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (26) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (27) GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. (28) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (29) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (30) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (31) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (32) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (33) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (34) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (35) Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (36) Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. (37) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (38) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (39) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (40) Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (41) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (42) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (43) Institute for Bioinnovation, "Alexander Fleming" Biomedical Sciences Research Center, Vari, Greece. (44) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (45) Henry D. Janowitz Division of Gastroenterology, Department of Medicine, and Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (46) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (47) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (48) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (49) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (50) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (51) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (52) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal. Global Health and Emerging Pathogens Institute and Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (53) Genentech, South San Francisco, CA, USA. (54) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (55) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (56) Paris-Saclay University, Gustave Roussy, INSERM U1015, Villejuif, France. (57) Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA. (58) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, Paris, France. (59) Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, Paris, France. (60) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (61) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Institute for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (62) Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy. (63) Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (64) Institut Curie, Paris, France. (65) Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (66) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (67) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Graduate Education, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (68) Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

    Citation: Science 2026 Jul 16 393:eady1678 Epub07/16/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42462020

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    The efficacy of immunotherapy in glioma requires distal B cell responses in tumor-draining lymph nodes Spotlight 

    (1) Kim Y (2) Kang I (3) Kang BH (4) Park WH (5) Kim CW (6) Kim HJ (7) La J (8) Kwon MS (9) Park SH (10) Im SH (11) Kim HC (12) Ku KB (13) Kim M (14) Oh JE (15) Lee HK

    Science immunology

    Kim et al. showed that anti-CTLA-4 efficacy in orthotopic murine glioblastoma (GBM) models was abolished by B cell deficiency and tdLN removal. In WT mice, anti-CTLA-4 increased B cell numbers and GC reactions in tdLNs, but not in the TIME, and therapeutic efficacy required CD4+ T cell help to B cells. While maintaining tumor-reactive CD4+ T cell function in the TIME, in tdLNs, anti-CTLA-4 therapy boosted TFH cell differentiation to support GC B cell clonal expansion and generation of antibody-secreting cells producing tumor-binding class-switched IgG1 antibodies that promoted macrophage-mediated phagocytosis of glioma cells via Fc receptor signaling.

    Contributed by Paula Hochman

    (1) Kim Y (2) Kang I (3) Kang BH (4) Park WH (5) Kim CW (6) Kim HJ (7) La J (8) Kwon MS (9) Park SH (10) Im SH (11) Kim HC (12) Ku KB (13) Kim M (14) Oh JE (15) Lee HK

    Science immunology

    Kim et al. showed that anti-CTLA-4 efficacy in orthotopic murine glioblastoma (GBM) models was abolished by B cell deficiency and tdLN removal. In WT mice, anti-CTLA-4 increased B cell numbers and GC reactions in tdLNs, but not in the TIME, and therapeutic efficacy required CD4+ T cell help to B cells. While maintaining tumor-reactive CD4+ T cell function in the TIME, in tdLNs, anti-CTLA-4 therapy boosted TFH cell differentiation to support GC B cell clonal expansion and generation of antibody-secreting cells producing tumor-binding class-switched IgG1 antibodies that promoted macrophage-mediated phagocytosis of glioma cells via Fc receptor signaling.

    Contributed by Paula Hochman

    ABSTRACT: Humoral immunity, mediated by B cells that mature in germinal centers in lymph nodes (LNs), is essential for adaptive immune responses, but its role in antitumor immunity and responses to immunotherapy remain unclear. Here, we show that activation of B cells in tumor-draining deep cervical LNs (dcLNs) is necessary for the efficacy of CTLA-4 (cytotoxic T lymphocyte-associated protein 4) immune checkpoint blockade in glioma in vivo. Anti-CTLA-4 therapy enhanced T follicular helper cell (T(FH) cell) expansion in dcLNs, leading to germinal center B cell responses, immunoglobulin G (IgG) class switching, and the generation of glioma-reactive antibodies. Glioma-bearing mice lacking antibody-secreting cells did not benefit from CTLA-4 blockade. Distally secreted IgG accumulated in the tumor microenvironment and promoted glioma cell phagocytosis in vivo. These findings define a B cell-dependent mechanism underlying CTLA-4-mediated control of glioma and provide a conceptual framework for future therapeutic strategies in tumor.

    Author Info: (1) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (2) Laboratory of Host D

    Author Info: (1) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (2) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (3) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (4) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (5) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (6) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (7) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (8) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (9) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (10) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (11) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (12) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Department of Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea. (13) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (14) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. (15) Laboratory of Host Defenses, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Regenerative Medical Research Institute (reMRI) for Aging-Related Diseases, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

    Citation: Sci Immunol 2026 Jul 10 11:eadz2494 Epub07/10/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42430444

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    Generalizable AI predicts immunotherapy outcomes across cancers and treatments Spotlight 

    (1) Shen W (2) Moon I (3) Nguyen TH (4) Li MM (5) Huang Y (6) Nair N (7) Marbach D (8) Zitnik M

    Nature medicine

    Shen et al. developed COMPASS, an AI model that interprets pre-treatment tumor RNAseq data in the context of tumor-immune gene expression modules and maps them to predict ICB response. Trained on TCGA and cohort data, COMPASS was applicable across cohorts, indications, ICB drugs, and targets, with superior response prediction compared to established models or correlates (TMB, PD-L1). COMPASS also generated personalized “response maps” identifying potential resistance mechanisms; unexpected nonresponders (i.e. patients with an inflammatory TME) often had gene expression associated with angiogenesis, TGFβ, and B cell deficiency.

    Contributed by Alex Najibi

    (1) Shen W (2) Moon I (3) Nguyen TH (4) Li MM (5) Huang Y (6) Nair N (7) Marbach D (8) Zitnik M

    Nature medicine

    Shen et al. developed COMPASS, an AI model that interprets pre-treatment tumor RNAseq data in the context of tumor-immune gene expression modules and maps them to predict ICB response. Trained on TCGA and cohort data, COMPASS was applicable across cohorts, indications, ICB drugs, and targets, with superior response prediction compared to established models or correlates (TMB, PD-L1). COMPASS also generated personalized “response maps” identifying potential resistance mechanisms; unexpected nonresponders (i.e. patients with an inflammatory TME) often had gene expression associated with angiogenesis, TGFβ, and B cell deficiency.

    Contributed by Alex Najibi

    ABSTRACT: Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-cancer foundation model that predicts immunotherapy response from bulk tumor transcriptomes using a concept bottleneck transformer. COMPASS encodes gene expression through 44 biologically grounded immune concepts representing immune cell states, tumor-microenvironment interaction and signaling pathways. Trained on 10,184 tumors across 33 cancer types, COMPASS achieves better average performance than 22 methods across 16 clinical cohorts spanning seven cancers and six ICIs, improving accuracy by 8.5% and area under the precision-recall curve by 15.7% on average across cohorts. COMPASS generalizes to cancer types and treatments not represented during fine-tuning and may inform indication selection and patient stratification. In survival analyses, patients classified by COMPASS as responders had longer overall survival (hazard ratio_=_4.7, P_<_0.0001). Personalized response maps connect gene expression to immune concepts, identifying programs associated with response and resistance; in immune-inflamed non-responders, COMPASS highlights programs including TGF_ signaling, endothelial exclusion, CD4(+) T cell dysfunction and B cell deficiency. COMPASS predicts immunotherapy response and provides hypothesis-generating mechanistic insight for trial design and translational studies.

    Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biome

    Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (3) Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. (4) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (5) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (6) Roche Pharma Research and Early Development, Oncology Early Clinical Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland. (7) Computational Sciences Center of Excellence, F. Hoffmann-La Roche Ltd., Basel, Switzerland. daniel.marbach.dm1@roche.com. (8) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. marinka@hms.harvard.edu. Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA. marinka@hms.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. marinka@hms.harvard.edu. Harvard Data Science Initiative, Cambridge, MA, USA. marinka@hms.harvard.edu.

    Citation: Nat Med 2026 Jul 3 Epub07/03/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42399673

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    Single-cell transcriptomic analysis reveals tumor-immune determinants of lymph node colonization and progression in thyroid cancer Spotlight 

    (1) Nguyen AT (2) Viramontes J (3) Vazquez I (4) McWilliam C (5) Devarakonda V (6) Henson R (7) Sacks WL (8) Mallen-St Clair J (9) Chen Y (10) Walgama E (11) Scher KS (12) Moyers J (13) Sandler HM (14) Jang JK (15) Zumsteg ZS (16) Shon W (17) Shiao SL (18) Ho AS

    Science advances | Free PMC Article

    Nguyen et al. used single-cell RNAseq and multiplex IHC on paired primary thyroid carcinomas and metastatic lymph nodes (LNs) to define immune determinants of nodal colonization. In metastatic LNs, thyrocytes and TAMs downregulated inflammatory cytokine receptors. including TNFRSF12A and CX3CR1, and were enriched for Tregs relative to matched primary tumors, which suggests suppression of T cell-mediated cytotoxicity. Tumor-infiltrating lymphocytes in metastatic LNs showed increased IL7R expression, and high IL7R levels within nodal metastases correlated with enhanced immune activation and improved progression-free survival in a validation cohort.

    Contributed by Shishir Pant

    (1) Nguyen AT (2) Viramontes J (3) Vazquez I (4) McWilliam C (5) Devarakonda V (6) Henson R (7) Sacks WL (8) Mallen-St Clair J (9) Chen Y (10) Walgama E (11) Scher KS (12) Moyers J (13) Sandler HM (14) Jang JK (15) Zumsteg ZS (16) Shon W (17) Shiao SL (18) Ho AS

    Science advances | Free PMC Article

    Nguyen et al. used single-cell RNAseq and multiplex IHC on paired primary thyroid carcinomas and metastatic lymph nodes (LNs) to define immune determinants of nodal colonization. In metastatic LNs, thyrocytes and TAMs downregulated inflammatory cytokine receptors. including TNFRSF12A and CX3CR1, and were enriched for Tregs relative to matched primary tumors, which suggests suppression of T cell-mediated cytotoxicity. Tumor-infiltrating lymphocytes in metastatic LNs showed increased IL7R expression, and high IL7R levels within nodal metastases correlated with enhanced immune activation and improved progression-free survival in a validation cohort.

    Contributed by Shishir Pant

    ABSTRACT: Lymph node (LN) metastases are a major driver of mortality across solid cancers, including thyroid carcinomas, which are known for high rates of nodal colonization. To elucidate the determinants of nodal spread, we isolated tumor-infiltrating leukocytes from primary thyroid tumors and matched metastatic LNs for single-cell RNA sequencing with validation by multiplex immunohistochemistry. Comparing the microenvironmental alterations between primary tumors and their LNs, we found that thyrocytes and tumor-associated macrophages down-regulate the expression of multiple inflammatory cytokine receptors, including TNFRSF12A and CX3CR1, upon LN colonization. LNs were associated with the induction of regulatory T cells to suppress T cell-mediated cytotoxicity compared to matched primary tumors. Notably, tumor-infiltrating lymphocytes within LNs demonstrated increased expression of activation markers, including interleukin-7 receptor (IL7R). High LN expression of IL7R was significantly correlated with improved outcomes and can serve as a biomarker in this heterogeneous disease. Our findings on the dynamic equilibrium within LN metastases may offer conserved mechanisms for nodal colonization across solid tumors.

    Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA,

    Author Info: (1) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (2) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (3) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (4) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (5) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (6) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (7) Division of Endocrinology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (8) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (9) Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (10) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (11) Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (12) Division of Medical Oncology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (13) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (14) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (15) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (16) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (17) Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (18) Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

    Citation: Sci Adv 2026 Jul 3 12:eaea4727 Epub07/03/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397917

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    RIG-I-targeted immunotherapy synergizes with immune checkpoint inhibition in a hepatocellular carcinoma model Spotlight 

    (1) Marx C (2) Teppert J (3) Marisch L (4) Formisano S (5) Senz A (6) Boehmer DFR (7) Metzger P (8) Kechur D (9) Delius L (10) Hoerth C (11) Lauber K (12) Mayr D (13) De Toni EN (14) Helms MW (15) Brunner B (16) Endres S (17) Schnurr M (18) Duewell P (19) Rothenfusser S (20) Koenig LM

    Molecular cancer therapeutics

    Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

    Contributed by Paula Hochman

    (1) Marx C (2) Teppert J (3) Marisch L (4) Formisano S (5) Senz A (6) Boehmer DFR (7) Metzger P (8) Kechur D (9) Delius L (10) Hoerth C (11) Lauber K (12) Mayr D (13) De Toni EN (14) Helms MW (15) Brunner B (16) Endres S (17) Schnurr M (18) Duewell P (19) Rothenfusser S (20) Koenig LM

    Molecular cancer therapeutics

    Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

    Contributed by Paula Hochman

    ABSTRACT: Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic pattern recognition receptor that senses short double-stranded RNA with uncapped 5'-triphosphate (3p-RNA). Upon activation, RIG-I induces type I interferons and proinflammatory cytokines, thereby promoting adaptive immunity. Thus, RIG-I activation is a promising approach for creating a proinflammatory tumor microenvironment. In this study, we investigated its therapeutic potential in hepatocellular carcinoma (HCC). We explored and confirmed RIG-I expression and signaling in human HCC samples and cell lines. The therapeutic potential of RIG-I activation by 3p-RNA for the treatment of HCC was investigated in vitro and in syngeneic murine orthotopic tumor models. In vivo, 3p-RNA treatment significantly reduced the tumor burden, delayed disease progression, and achieved partial complete remission of RIL-175 tumors with durable immune memory. However, no therapeutic effects were observed in the Hep-55.1C model. Tumor clearance depended on CD4⁺ and CD8⁺ T cells, but not NK cells. Additionally, 3p-RNA induced PD-L1 expression on HCC cells, enhancing their sensitivity to anti-PD-1 immune checkpoint therapy in vivo. RIG-I activation via 3p-RNA therapy shows promise as an immunotherapeutic strategy for hepatocellular carcinoma (HCC). Future investigations need to focus on tumor-intrinsic factors to understand heterogeneity between tumors and to overcome resistance mechanisms.

    Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.or

    Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (4) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (5) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (6) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (7) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (8) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (9) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (10) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (11) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (12) Ludwig-Maximilians-UniversitŠt MŸnchen Munich, Bavaria Germany. ROR: https://ror.org/05591te55 (13) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (14) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (15) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (16) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (17) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (18) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (19) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (20) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32

    Citation: Mol Cancer Ther 2026 Jun 25 Epub06/25/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42345470

    Tags:

    Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER+HER2- breast cancer: a randomized phase 2 trial

    Featured  

    (1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

    Nature medicine

    De Caluwé et al. conducted a phase 2 clinical trial in patients with ER+HER2- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

    (1) De Caluwé A (2) Desmoulins I (3) Cao K (4) Remouchamps V (5) Baten A (6) Longton E (7) Peignaux K (8) Joaquin Garcia A (9) Venet D (10) Arecco L (11) Agostinetto E (12) Nader-Marta G (13) Denis Z (14) Dhont J (15) Kristanto P (16) Catteau X (17) Larsimont D (18) Salgado R (19) Poortmans P (20) Stagg J (21) Sotiriou C (22) Piccart M (23) Ignatiadis M (24) Romano E (25) Buisseret L

    Nature medicine

    De Caluwé et al. conducted a phase 2 clinical trial in patients with ER+HER2- breast cancer assessing neoadjuvant chemotherapy with immune-modulating stereotactic body radiation therapy (iSBRT) alone or combined with anti-PD-L1 and anti-CD73 ICB. The addition of single or double ICB improved residual cancer burden and complete response rates. Patients with node-positive, PD-L1-negative tumors containing stromal tumor-infiltrating lymphocytes at baseline benefited most, with treatment modulating the tumor immune microenvironment from cold to hot.

    ABSTRACT: Patients with estrogen receptor-positive (ER+), HER2-negative, early breast cancer (BC) have low pathologic complete response (pCR) rates following neoadjuvant chemotherapy. Immune checkpoint inhibitors (ICIs) provide limited benefit in programmed death-ligand 1 (PD-L1)-negative tumors, characterized by an immune-cold tumor microenvironment. Here we hypothesized that immune-modulating stereotactic body radiation therapy (iSBRT; 3 × 8 Gy) could enhance response through tumor microenvironment reprogramming, and that CD73 blockade could further improve efficacy. We conducted a phase 2, randomized, multicenter trial (Neo-CheckRay) in 147 female patients with high-risk, ER+HER2- early BC. Patients received neoadjuvant chemotherapy plus iSBRT alone (No_ICI), with anti-PD-L1 durvalumab (Single_ICI) or with durvalumab plus anti-CD73 oleclumab (Double_ICI). In the intention-to-treat population, the primary endpoint, residual cancer burden 0/1 rate, was 35.4% with No_ICI, 45.1% with Single_ICI and 47.9% with Double_ICI, without statistically significant differences. pCR rates were 16.7%, 29.4% and 33.3%, respectively (P = 0.059). In the per-protocol population (MammaPrint High Risk, n = 131), pCR rates were 16.3%, 32.6% and 35.6%, respectively (P = 0.040). Among PD-L1-negative tumors (n = 91), pCR rates were 3.4%, 28.1% and 30.0%, respectively. No new safety signals were observed. Baseline transcriptomic analysis showed low immune signature expression in PD-L1-negative tumors. Paired baseline and on-treatment biopsies obtained 1 week after iSBRT demonstrated tumor microenvironment reprogramming toward an inflamed phenotype in the iSBRT + anti-PD-L1 arms. These findings suggest that iSBRT + anti-PD-L1 may convert immune-cold ER+HER2- BC into more inflamed tumors and improve response, particularly in PD-L1-negative disease. ClinicalTrials.gov registration: NCT03875573 .

    Author Info: (1) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franoi

    Author Info: (1) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. alex.decaluwe@bordet.be. (2) Centre Georges-Franois Leclerc, UniversitŽ Bourgogne Europe, Dijon, France. (3) Institut Curie, Paris, France. (4) CHU St Elisabeth, Namur, Belgium. (5) Universitaire Ziekenhuizen Leuven, Leuven, Belgium. (6) H™pital Universitaire St Luc, Brussels, Belgium. (7) Centre Georges-Franois Leclerc, UniversitŽ Bourgogne Europe, Dijon, France. (8) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (9) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (10) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (11) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (12) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (13) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (14) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (15) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (16) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (17) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (18) ZAS Hospitals, Antwerp, Belgium. Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia. (19) Iridium Netwerk, Antwerp, Belgium. University of Antwerp, Antwerp, Belgium. (20) Goodman Cancer Institute, McGill University, Montreal, Quebec, Canada. (21) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (22) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (23) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium. (24) Institut Curie, Paris, France. (25) Institut Jules Bordet, H™pitaux Universitaires de Bruxelles (H.U.B), UniversitŽ Libre de Bruxelles (ULB), Brussels, Belgium.

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

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350643

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    Addressing Biases in Analysis of Time of Infusion: NCI/SWOG Trial S1404 Among Participants With High-Risk Resectable Melanoma Who Received Adjuvant Anti-PD-1 Therapy Spotlight 

    (1) Othus M (2) Truong TG (3) Sharon E (4) Kendra K (5) Grossmann K (6) Buchbinder E (7) Khushalani NI (8) Eroglu Z (9) Chandra S (10) Doolittle GC (11) Kirkwood JM (12) Ikeguchi A (13) Mihalcioiu C (14) Cowey CL (15) Reddy SA (16) Johnson DB (17) Taylor M (18) Sondak VK (19) Ribas A (20) Patel SP

    JCO oncology practice | Free PMC Article

    In an analysis of a multi-center trial involving 628 patients with high-risk melanoma receiving adjuvant pembrolizumab, Othus et al. identified optimal time cut-points for the first infusion of 1:18 pm for recurrence-free survival and 3:48 pm for overall survival (OS). These findings, however, did not reach statistical significance regarding patient outcomes. Furthermore, the lack of threshold robustness was demonstrated when shifting the OS cut-point 30 minutes earlier, which yielded a hazard ratio of 0.98. Average infusion times trended earlier over the year, while appointments were on average later for patients living further from the treatment center.

    Contributed by Ute Burkhardt

    (1) Othus M (2) Truong TG (3) Sharon E (4) Kendra K (5) Grossmann K (6) Buchbinder E (7) Khushalani NI (8) Eroglu Z (9) Chandra S (10) Doolittle GC (11) Kirkwood JM (12) Ikeguchi A (13) Mihalcioiu C (14) Cowey CL (15) Reddy SA (16) Johnson DB (17) Taylor M (18) Sondak VK (19) Ribas A (20) Patel SP

    JCO oncology practice | Free PMC Article

    In an analysis of a multi-center trial involving 628 patients with high-risk melanoma receiving adjuvant pembrolizumab, Othus et al. identified optimal time cut-points for the first infusion of 1:18 pm for recurrence-free survival and 3:48 pm for overall survival (OS). These findings, however, did not reach statistical significance regarding patient outcomes. Furthermore, the lack of threshold robustness was demonstrated when shifting the OS cut-point 30 minutes earlier, which yielded a hazard ratio of 0.98. Average infusion times trended earlier over the year, while appointments were on average later for patients living further from the treatment center.

    Contributed by Ute Burkhardt

    PURPOSE: Multiple reports have suggested that receiving immunotherapy infusions earlier in the day is associated with improved outcomes, including longer overall survival (OS) and lower toxicity rates. However, the definition of early varies between publications. Reports also fail to account for confounding factors (including distance to infusion center), are subject to survivor bias (analyzing postbaseline factors at baseline), and do not adjust P values for multiple comparisons when evaluating multiple potential thresholds for early versus late time of day of infusion. METHODS: We analyzed a previously reported multicenter clinical trial evaluating pembrolizumab as adjuvant therapy for participants with resectable high-risk melanoma. Standard statistical methodologies that account for potential biasses were used to evaluate the association between time of day of infusion and clinical outcomes. RESULTS: A total of 628 participants received pembrolizumab and had time of first infusion recorded. The median age was 55 years, range, 20-82. Odds of infusion before 11:00 hours increased by 32% over 12 months of therapy (P = .013). Participants living further from their treating institution had later infusion times on average: odds of infusion before 11:00 decreased by 9% for each additional 50 miles (P = .017). The optimal cut point for first infusion time for OS was 15:48 with hazard ratio (HR) = 1.40; changing the cut point by 30 minutes earlier to 15:18 decreased HR to 0.98, indicating lack of robustness of the threshold. No significant association was identified between proportion of early infusions and outcomes in multivariable time-dependent Cox regression models. CONCLUSION: In this multicenter trial of adjuvant pembrolizumab for participants with high-risk melanoma, analyses that account for common sources of bias found no significant association between recurrence-free or OS and time of day of infusion.

    Author Info: (1) Division of Public Health, Fred Hutchinson Cancer Center, Seattle WA. (2) Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3)

    Author Info: (1) Division of Public Health, Fred Hutchinson Cancer Center, Seattle WA. (2) Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3) Department of Medicine, Dana Farber Cancer Institute, Boston, MA. Harvard Medical School, Boston, MA. (4) Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH. (5) Medical Oncology, Providence Cancer Institute, Portland, OR. (6) Medical Oncology, Mass General Brigham Cancer Institute, Boston, MA. (7) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (8) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (9) Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL. (10) Division of Clinical Oncology, University of Kansas Medical Center, Kansas City, KS. (11) Melanoma Program, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA. (12) Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX. (13) Medical Oncology, McGill University Health Centre, Montreal, Canada. (14) Melanoma, Texas Oncology-Baylor Sammons Cancer Center, Dallas, TX. (15) Department of Medical Oncology, Stanford University School of Medicine, Palo Alto, CA. (16) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. (17) Medical Oncology, Providence Cancer Institute, Portland, OR. (18) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (19) Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA. (20) Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO.

    Citation: JCO Oncol Pract 2026 Jun 23 OP2501413 Epub06/23/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42335437

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    FLT3L-secreting cDC1 in situ vaccination enhances antitumor immunity and synergizes with PD-1 blockade in murine non-small cell lung cancer Spotlight 

    (1) Abascal J (2) Dumitras C (3) Tran LM (4) Crosson W (5) Kahangi B (6) Oh M (7) Rennels A (8) Lim RJ (9) Jiang H (10) Reyimjan D (11) Coleman NJ (12) Perez-Reyes E (13) Chin S (14) Krysan K (15) Dubinett SM (16) Liu B (17) Salehi-Rad R

    Journal for immunotherapy of cancer | Free PMC Article

    Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

    Contributed by Paula Hochman

    (1) Abascal J (2) Dumitras C (3) Tran LM (4) Crosson W (5) Kahangi B (6) Oh M (7) Rennels A (8) Lim RJ (9) Jiang H (10) Reyimjan D (11) Coleman NJ (12) Perez-Reyes E (13) Chin S (14) Krysan K (15) Dubinett SM (16) Liu B (17) Salehi-Rad R

    Journal for immunotherapy of cancer | Free PMC Article

    Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

    Contributed by Paula Hochman

    BACKGROUND: Non-small cell lung cancer (NSCLC) frequently evades immune surveillance through defective antigen presentation and a suppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint blockade (ICB). Conventional type 1 dendritic cells (cDC1s) are essential for initiating antitumor CD8(+) T-cell responses; however, their abundance and function are often diminished in NSCLC, contributing to poor outcomes and resistance to immunotherapy. We hypothesized that in situ vaccination (ISV) using gene-modified cDC1s engineered to secrete FMS-like tyrosine kinase 3 ligand (FLT3L) would enhance cDC1 function within the TME, promote antitumor immunity, and improve responses to ICB. METHODS: Syngeneic murine models of NSCLC (Kras(G12D)/P53(-/-)/Lkb1(-/-); Kras(G12D)/P53(-/-) ; and Kras(G12D) ) with varying tumor mutational burden, along with the MC38 model, were used to assess the therapeutic efficacy of FLT3L-cDC1 ISV. Flow cytometry and multiplex immunofluorescence were used to evaluate immune mechanisms of response. To assess translational relevance, immune and tertiary lymphoid structure (TLS) signatures were analyzed in The Cancer Genome Atlas (TCGA) NSCLC datasets, with TLS signatures refined using a retrained xCell2 framework incorporating curated TLS and high endothelial venule (HEV) microdissection datasets. RESULTS: FLT3L-cDC1 ISV remodeled the TME across multiple NSCLC models, inducing T lymphocyte infiltration and expanding cytolytic CD8(+) T cells. FLT3L-cDC1 ISV was associated with increased formation of immature TLS with primary follicle-like features within the TME. TCGA analyses revealed that FLT3L expression correlates with activated DC, T cell, and B cell signatures, as well as HEV-enriched TLS-associated programs. Combination with PD-1 blockade further enhanced the antitumor immunity of FLT3L-cDC1 ISV, resulting in robust local and systemic T-cell activation and the expansion of activated CCR7(+)PD-L1(+) cDC1s and stem-like TCF1(+)PD-1(+) CD8(+) progenitors within the TME. In an LKB1-deficient NSCLC model, FLT3L-cDC1 ISV plus PD-1 blockade induced complete and durable regression in 85% of tumors, leading to long-lasting systemic tumor-specific immune memory, consistent with effective tumor vaccination. CONCLUSIONS: FLT3L-cDC1 ISV represents a rational cytokine-enhanced cellular immunotherapy designed to overcome immunosuppression and restore DC function within the TME, thereby promoting tumor-specific adaptive immune responses and enhancing responsiveness to ICB.

    Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA

    Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (3) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (4) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (5) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (6) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (7) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (8) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (9) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (10) UCLA, Los Angeles, California, USA. (11) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (12) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (13) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (14) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (15) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (16) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. (17) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.

    Citation: J Immunother Cancer 2026 Jun 25 14: Epub06/25/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350046

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