Journal Articles

Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome

(1) Vendramin R (2) Fu H (3) Fernandez Patel S (4) Zhao Y (5) Qian D (6) Ligammari L (7) Bartok O (8) Greenberg P (9) Levy R (10) Castro A (11) Thakkar K (12) Murai J (13) Lu WT (14) Sng CCT (15) Weller C (16) Beattie G (17) Bhamra A (18) Farriol-Duran R (19) Karagianni D (20) Augustine M (21) Dijkstra KK (22) Pinder CL (23) Simpson BS (24) Cheung GW (25) Galvez-Cancino F (26) Vlckova P (27) Surinova S (28) Rodriguez-Justo M (29) Shah M (30) McGranahan N (31) Carlton JG (32) Gršnroos E (33) Reading JL (34) Samuels Y (35) Swanton C (36) Quezada SA (37) Litchfield K

Immunity

Vendramin, Fu, Fernandez Patel, Zhao, et al. investigated nonsense-mediated mRNA decay (NMD) in cancer, and detected high activity of this pathway in tumors, with lower scores associated with better ICB responses in clinical data. Inhibition of SMG1 reduced NMD activity and resulted in significant increases in immunogenic MHC-I-presented neoantigens. This resulted in improved antitumor immune responses and synergized with ICB in vivo.

(1) Vendramin R (2) Fu H (3) Fernandez Patel S (4) Zhao Y (5) Qian D (6) Ligammari L (7) Bartok O (8) Greenberg P (9) Levy R (10) Castro A (11) Thakkar K (12) Murai J (13) Lu WT (14) Sng CCT (15) Weller C (16) Beattie G (17) Bhamra A (18) Farriol-Duran R (19) Karagianni D (20) Augustine M (21) Dijkstra KK (22) Pinder CL (23) Simpson BS (24) Cheung GW (25) Galvez-Cancino F (26) Vlckova P (27) Surinova S (28) Rodriguez-Justo M (29) Shah M (30) McGranahan N (31) Carlton JG (32) Gršnroos E (33) Reading JL (34) Samuels Y (35) Swanton C (36) Quezada SA (37) Litchfield K

Immunity

Vendramin, Fu, Fernandez Patel, Zhao, et al. investigated nonsense-mediated mRNA decay (NMD) in cancer, and detected high activity of this pathway in tumors, with lower scores associated with better ICB responses in clinical data. Inhibition of SMG1 reduced NMD activity and resulted in significant increases in immunogenic MHC-I-presented neoantigens. This resulted in improved antitumor immune responses and synergized with ICB in vivo.

ABSTRACT: DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

Author Info: (1) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Inst

Author Info: (1) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: r.vendramin@ucl.ac.uk. (2) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Pre-Cancer Immunology Lab, University College London Cancer Institute, London, UK. (3) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Organelle Dynamics Lab, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK; Organelle Dynamics Lab, the Francis Crick Institute, London, UK. (4) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (5) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (6) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (7) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (10) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (11) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (12) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Drug Discovery Technology Laboratories, Ono Pharmaceutical Co. Ltd., Osaka, Japan. (13) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK. (14) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (16) CRUK City of London Centre Single Cell Genomics Facility, University College London Cancer Institute, London, UK; Bioinformatics Hub, University College London Cancer Institute, London, UK. (17) Proteomics Research Translational Technology Platform, University College London Cancer Institute, London, UK. (18) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Barcelona Supercomputing Center (BSC), Barcelona, Spain; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK. (19) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK. (20) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Division of Medicine, University College London, London, UK. (21) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (22) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (23) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (24) Research Department of Haematology, University College London Cancer Institute, London, UK. (25) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK; Immune Regulation Lab, Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (26) Organoid Translational Technology Platform, University College London Cancer Institute, London, UK. (27) Proteomics Research Translational Technology Platform, University College London Cancer Institute, London, UK. (28) Department of Research Pathology, University College London Cancer Institute, London, UK. (29) CRUK City of London Explant and Patient-Derived Xenograft Core, London, UK. (30) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK. (31) Organelle Dynamics Lab, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK; Organelle Dynamics Lab, the Francis Crick Institute, London, UK. (32) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK. (33) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Pre-Cancer Immunology Lab, University College London Cancer Institute, London, UK. (34) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (35) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: charles.swanton@crick.ac.uk. (36) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK. Electronic address: s.quezada@ucl.ac.uk. (37) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: k.litchfield@ucl.ac.uk.

Citation: Immunity 2026 Apr 8 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41956098

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    The CD4+ T cell population partners with Tpex CD8+ T cells to mediate antitumor immunity in the tumor microenvironment

    (1) Takei S (2) Yamasaki S (3) Yamaguchi O (4) Mouri A (5) Shiono A (6) Miura Y (7) Hashimoto K (8) Imai H (9) Kaira K (10) Ichiki Y (11) Nitanda H (12) Sakaguchi H (13) Hishida T (14) Horimoto K (15) Kagamu H

    Nature communications

    Takei et al. identified IL-7Rhi CCR6+ Th1-like CD4+ T cells (Th7R) that were distinct from Th1 and Th17 states. Th7R cells expressed CXCL13 and lymphotoxin-β, localized to TLSs, and associated with high endothelial venules. Th7R abundance correlated with GZMK+GZMB- progenitor exhausted CD8+ T cells (Tpex) across tumors and lymph nodes. Adoptive transfer of Th7R cells into mice bearing MCA205 skin tumors expanded Tpex and Tex populations, supported Tpex maintenance and differentiation, and enhanced tumor control. Intratumoral and circulating Th7R correlated with response to PD-1 blockade, and improved clinical outcomes in patients with lung cancer.

    Contributed by Shishir Pant

    (1) Takei S (2) Yamasaki S (3) Yamaguchi O (4) Mouri A (5) Shiono A (6) Miura Y (7) Hashimoto K (8) Imai H (9) Kaira K (10) Ichiki Y (11) Nitanda H (12) Sakaguchi H (13) Hishida T (14) Horimoto K (15) Kagamu H

    Nature communications

    Takei et al. identified IL-7Rhi CCR6+ Th1-like CD4+ T cells (Th7R) that were distinct from Th1 and Th17 states. Th7R cells expressed CXCL13 and lymphotoxin-β, localized to TLSs, and associated with high endothelial venules. Th7R abundance correlated with GZMK+GZMB- progenitor exhausted CD8+ T cells (Tpex) across tumors and lymph nodes. Adoptive transfer of Th7R cells into mice bearing MCA205 skin tumors expanded Tpex and Tex populations, supported Tpex maintenance and differentiation, and enhanced tumor control. Intratumoral and circulating Th7R correlated with response to PD-1 blockade, and improved clinical outcomes in patients with lung cancer.

    Contributed by Shishir Pant

    ABSTRACT: CD4⁺ T cells support the priming, expansion, and function of CD8⁺ T cells through dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but the identity of their CD4⁺ T-cell partners remains unclear. Here, we perform scRNA-seq, scTCR-seq, and mass cytometry analysis on peripheral blood, tumor, and lymph nodes primarily from lung cancer patients and, in part, renal cell carcinoma. We identify an IL-7Rhigh CCR6⁺ Th1-like CD4⁺ T cell-population, named Th7R, that is numerically and spatially partnered with Tpex. Th7R cells express lymphotoxin-β and CXCL13, correlate with high endothelial venules, and co-localize with Tpex in tertiary lymphoid structures. Th7R cell abundance correlates with Tpex numbers in the TME and lymph nodes, and adoptive transfer of Th7R increases Tpex in a preclinical mouse model. Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.

    Author Info: (1) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. Department of Respiratory Medicine, Kyoto Pr

    Author Info: (1) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. Department of Respiratory Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan. (2) Department of Clinical Cancer Genomics, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (3) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (4) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (5) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (6) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (7) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (8) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (9) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (10) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (11) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (12) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (13) Department of General Thoracic Surgery, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (14) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. (15) Department of Respiratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama, Japan. kagamu19@saitama-med.ac.jp.

    Citation: Nat Commun 2026 Mar 28 Epub03/28/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41904165

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    Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models

    (1) Figueroa D (2) Vega JP (3) Hernández-Oliveras A (4) Ardiles F (5) Hidalgo S (6) López X (7) Saavedra V (8) Bustamante C (9) Malavó D (10) Flores F (11) Gálvez-Cancino F (12) Gonzalez H (13) Varas-Godoy M (14) Bono MR (15) Osorio F (16) Borgna V (17) Lladser A

    Nature communications

    Figueroa et al. demonstrated that lasting efficacy of adoptive T cell therapy (ACT) against solid tumors relied not only on the antitumor activity of transferred T cells, but also on their ability to expand host CD8+ T cells in a TNF- and cDC1-dependent manner. Host CD8+ T cells protected against rechallenge with ACT-resistant antigen-negative tumor cells. Lymphodepleting preconditioning promoted transferred T cell expansion, but impaired host immunity against antigen-loss variants. In patients with melanoma, enrichment of cDC1, TNF signaling, Tpex and Tex gene signatures correlated with clinical responses to ACT and better overall survival.

    Contributed by Ute Burkhardt

    (1) Figueroa D (2) Vega JP (3) Hernández-Oliveras A (4) Ardiles F (5) Hidalgo S (6) López X (7) Saavedra V (8) Bustamante C (9) Malavó D (10) Flores F (11) Gálvez-Cancino F (12) Gonzalez H (13) Varas-Godoy M (14) Bono MR (15) Osorio F (16) Borgna V (17) Lladser A

    Nature communications

    Figueroa et al. demonstrated that lasting efficacy of adoptive T cell therapy (ACT) against solid tumors relied not only on the antitumor activity of transferred T cells, but also on their ability to expand host CD8+ T cells in a TNF- and cDC1-dependent manner. Host CD8+ T cells protected against rechallenge with ACT-resistant antigen-negative tumor cells. Lymphodepleting preconditioning promoted transferred T cell expansion, but impaired host immunity against antigen-loss variants. In patients with melanoma, enrichment of cDC1, TNF signaling, Tpex and Tex gene signatures correlated with clinical responses to ACT and better overall survival.

    Contributed by Ute Burkhardt

    ABSTRACT: Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8(+) T cells that eradicate established murine tumors promote expansion of host CD8(+) T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8(+) T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8(+) T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8(+) T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.

    Author Info: (1) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (2) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (3) Centro Basal Ciencia & V

    Author Info: (1) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (2) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (3) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Centro de Investigaci—n e Innovaci—n en C‡ncer, Fundaci—n Arturo L—pez PŽrez OECI Cancer Center, Santiago, Chile. (4) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (5) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Centro de Investigaci—n e Innovaci—n en C‡ncer, Fundaci—n Arturo L—pez PŽrez OECI Cancer Center, Santiago, Chile. (6) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (7) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (8) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (9) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (10) Laboratory of Immunology and Cellular Stress, Facultad de Medicina, Universidad de Chile, Santiago, Chile. (11) Laboratory of Immune Regulation, NDM Centre for Immuno-Oncology, University of Oxford, Oxford, UK. (12) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. (13) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Centro de Biolog’a Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebasti‡n, Santiago, Chile. (14) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Laboratory of Immunology, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. (15) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Laboratory of Immunology and Cellular Stress, Facultad de Medicina, Universidad de Chile, Santiago, Chile. (16) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. vincenzo.borgna@uss.cl. Servicio de Urolog’a, Hospital Barros Luco Trudeau, Santiago, Chile. vincenzo.borgna@uss.cl. Facultad de Medicina, Universidad San Sebasti‡n, Santiago, Chile. vincenzo.borgna@uss.cl. (17) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. alladser@cienciavida.org. Facultad de Medicina, Universidad San Sebasti‡n, Santiago, Chile. alladser@cienciavida.org.

    Citation: Nat Commun 2026 Mar 31 Epub03/31/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41912536

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    Acute and chronic infections drive distinct trajectories in human memory CD4+ T cell formation

    (1) Reinscheid M (2) Weisser J (3) Pascual Maier N (4) Reeg DB (5) Hafkemeyer PL (6) Kelsch L (7) Rusignuolo G (8) Arnold J (9) Emmerich F (10) Walker A (11) Froehlich Y (12) Cherukunnath A (13) Timm J (14) Picelli S (15) Bengsch B (16) Sagar (17) Thimme R (18) Boettler T (19) Hofmann M

    Immunity

    Comparing CD4+ T cells generated during acute or chronic hepatitis C virus (HCV) infection, Reinscheid and Weisser et al. evaluated patient samples and found that acute infection generated various subsets of progenitor CD4+ T cells, including subsets also observed in chronic infection. In chronic infection, a subset of stem-like/resting Bcl-2+ CD4+ T cells likely gave rise to a subset of T-bet+ effector CD4+ T cells. In patients treated with DAA to clear the virus, the effector subset essentially disappeared, while the stem-like subset formed a functional long-term memory pool that was distinct from the memory pools that formed after spontaneous HCV clearance.

    Contributed by Lauren Hitchings

    (1) Reinscheid M (2) Weisser J (3) Pascual Maier N (4) Reeg DB (5) Hafkemeyer PL (6) Kelsch L (7) Rusignuolo G (8) Arnold J (9) Emmerich F (10) Walker A (11) Froehlich Y (12) Cherukunnath A (13) Timm J (14) Picelli S (15) Bengsch B (16) Sagar (17) Thimme R (18) Boettler T (19) Hofmann M

    Immunity

    Comparing CD4+ T cells generated during acute or chronic hepatitis C virus (HCV) infection, Reinscheid and Weisser et al. evaluated patient samples and found that acute infection generated various subsets of progenitor CD4+ T cells, including subsets also observed in chronic infection. In chronic infection, a subset of stem-like/resting Bcl-2+ CD4+ T cells likely gave rise to a subset of T-bet+ effector CD4+ T cells. In patients treated with DAA to clear the virus, the effector subset essentially disappeared, while the stem-like subset formed a functional long-term memory pool that was distinct from the memory pools that formed after spontaneous HCV clearance.

    Contributed by Lauren Hitchings

    ABSTRACT: Virus-specific CD4(+) T cells are essential for coordinating adaptive immunity during infection, but their differentiation and maintenance in chronic infection remain unclear. Using human hepatitis C virus (HCV) infection as a model, we assessed the determinants of virus-specific CD4(+) T cell immunity in acute, spontaneously cleared, chronic, and therapeutically cured infections. During acute infection, multiple subsets of progenitor CD4(+) T cells emerged, including subsets that are also found in chronic infection. In chronic infection, stem-like Bcl-2(+) CD4(+) T cells and T-bet(+) effector CD4(+) T cells existed in a progenitor/progeny relationship. Following therapy-mediated HCV cure, these cells retained their chronic signature but formed a stable memory pool that persisted for years and was distinct from HCV-specific CD4(+) T cell memory after spontaneous clearance. Collectively, our findings highlight differences in CD4(+) T cell fates that depend on infection outcomes and reveal common principles of CD4(+) and exhausted CD8(+) T cell maintenance during and after chronic infection.

    Author Info: (1) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany

    Author Info: (1) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. (2) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. (3) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. (4) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. (5) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. (6) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. (7) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. (8) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. (9) Institute for Transfusion Medicine and Gene Therapy, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. (10) Institute of Virology, Medical Faculty and University Hospital DŸsseldorf, Heinrich Heine University DŸsseldorf, DŸsseldorf, Germany. (11) Institute of Virology, Medical Faculty and University Hospital DŸsseldorf, Heinrich Heine University DŸsseldorf, DŸsseldorf, Germany. (12) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. (13) Institute of Virology, Medical Faculty and University Hospital DŸsseldorf, Heinrich Heine University DŸsseldorf, DŸsseldorf, Germany. (14) Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland. (15) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany, partner site Freiburg, Freiburg, Germany; Signaling Research Centers BIOSS and CIBSS, Freiburg, Germany. (16) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. (17) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: robert.thimme@uniklinik-freiburg.de. (18) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: tobias.boettler@uniklinik-freiburg.de. (19) Department of Medicine II, Medical Center - University of Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address: maike.hofmann@uniklinik-freiburg.de.

    Citation: Immunity 2026 Apr 1 Epub04/01/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41928520

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    In vivo generation of CAR myeloid cells through erythrocyte-mediated mRNA delivery for cancer immunotherapy

    (1) Nie X (2) Liu Y (3) Song Y (4) Yao X (5) Chen Y (6) Lee HY (7) Gao X

    Science translational medicine

    Nie, Liu, Song, and Yao et al. developed a spleen delivery platform of mRNA-loaded lipid nanoparticles (LNPs) covalently bound to erythrocytes (mRNA-LNP-Ery), which naturally target splenic CD11b+ myeloid cells. Unlike conventional LNPs, mRNA-LNP-Ery entered cells via phagocytosis, avoiding lysosomal degradation and efficiently delivering mRNA. CAR myeloid cells (HER2 or CD19) adopted a proinflammatory antigen-presenting phenotype, migrated to tumors, and stimulated T and NK cell influx, potent antitumor activity, and systemic immunity, which was spleen-dependent. Repeated doses of mRNA-LNP-Ery resulted in superior efficacy at 1/10 the dose of LNPs.

    Contributed by Katherine Turner

    (1) Nie X (2) Liu Y (3) Song Y (4) Yao X (5) Chen Y (6) Lee HY (7) Gao X

    Science translational medicine

    Nie, Liu, Song, and Yao et al. developed a spleen delivery platform of mRNA-loaded lipid nanoparticles (LNPs) covalently bound to erythrocytes (mRNA-LNP-Ery), which naturally target splenic CD11b+ myeloid cells. Unlike conventional LNPs, mRNA-LNP-Ery entered cells via phagocytosis, avoiding lysosomal degradation and efficiently delivering mRNA. CAR myeloid cells (HER2 or CD19) adopted a proinflammatory antigen-presenting phenotype, migrated to tumors, and stimulated T and NK cell influx, potent antitumor activity, and systemic immunity, which was spleen-dependent. Repeated doses of mRNA-LNP-Ery resulted in superior efficacy at 1/10 the dose of LNPs.

    Contributed by Katherine Turner

    ABSTRACT: Engineering myeloid cells with chimeric antigen receptors (CARs) holds great therapeutic promise, but their generation in vivo remains challenging. Here, we developed an erythrocyte-mediated messenger RNA (mRNA) delivery platform, termed mRNA-LNP-Ery, in which mRNA-loaded lipid nanoparticles (LNPs) are covalently anchored onto erythrocytes. Exploiting erythrocytes' intrinsic splenic homing capacity and unique biocompatibility, mRNA-LNP-Ery enables highly selective and efficient mRNA delivery to CD11b(+) myeloid cells in the spleen, with minimal uptake by hepatocytes. We also demonstrated that mRNA-LNP-Ery is internalized through phagocytosis and avoids lysosomal degradation, resulting in enhanced cytosolic mRNA translation. Delivery of mRNAs encoding CARs targeting human epidermal growth factor receptor 2 (HER2) or CD19 generated functional CAR myeloid cells in vivo that adopted a proinflammatory, antigen-presenting phenotype. These cells migrated to tumors, eliminated cancer cells, and remodeled the tumor microenvironment, leading to increased infiltration of effector T and natural killer (NK) cells. The antitumor effect was abolished in splenectomized mice and partially diminished in nude mice, indicating that therapeutic activity depends on both CAR myeloid cell formation within the spleen and their cross-talk with adaptive immunity. Furthermore, repeated administration of mRNA-LNP-Ery achieved superior antitumor efficacy to conventional mRNA-LNPs at one-tenth the mRNA dose, with minimal systemic toxicity, underscoring the high efficiency and safety of spleen-targeted delivery. Together, our findings established a clinically translatable erythrocyte-based mRNA platform that enables direct in vivo immune cell programming and advances CAR myeloid therapies for solid tumors.

    Author Info: (1) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake La

    Author Info: (1) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. (2) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Research Center for Industries of the Future and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. (3) Westlake Therapeutics, Hangzhou, Zhejiang 310024, China. (4) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. (5) Westlake Therapeutics, Hangzhou, Zhejiang 310024, China. (6) Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China. (7) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Research Center for Industries of the Future and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China.

    Citation: Sci Transl Med 2026 Mar 25 18:eady6730 Epub03/25/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41880522

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    Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion

    (1) Medina CB (2) Sobierajska E (3) Gong M (4) McManus DT (5) Thapa M (6) Lee J (7) Im SJ (8) Toombs JE (9) Mitchell JM (10) Wang Y (11) Carlisle JW (12) Freeman GJ (13) Master VA (14) Ramalingam SS (15) Kissick HT (16) Li S (17) Brekken RA (18) Ahmed R

    Nature

    In a model of chronic LCMV infection, surface phosphatidylserine (PS) expression increased in virus-specific PD-1+CD8+ T cells over time, relative to naive CD8+ T cells and the setting of acute infection. PS expression increased with T cell differentiation state (stem-like to terminally differentiated). An anti-PS mAb enhanced DC costimulation, splenic PD-1+ stem-like CD8+ T cell proliferation and effector differentiation, and virus-specific CD8+ T cell counts across tissues. Anti-PS synergized with anti-PD-L1 to reduce LCMV burden. PD-1+CD8+ TILs from human renal cancer and NSCLC also expressed surface PS, which increased with T cell differentiation.

    Contributed by Alex Najibi

    (1) Medina CB (2) Sobierajska E (3) Gong M (4) McManus DT (5) Thapa M (6) Lee J (7) Im SJ (8) Toombs JE (9) Mitchell JM (10) Wang Y (11) Carlisle JW (12) Freeman GJ (13) Master VA (14) Ramalingam SS (15) Kissick HT (16) Li S (17) Brekken RA (18) Ahmed R

    Nature

    In a model of chronic LCMV infection, surface phosphatidylserine (PS) expression increased in virus-specific PD-1+CD8+ T cells over time, relative to naive CD8+ T cells and the setting of acute infection. PS expression increased with T cell differentiation state (stem-like to terminally differentiated). An anti-PS mAb enhanced DC costimulation, splenic PD-1+ stem-like CD8+ T cell proliferation and effector differentiation, and virus-specific CD8+ T cell counts across tissues. Anti-PS synergized with anti-PD-L1 to reduce LCMV burden. PD-1+CD8+ TILs from human renal cancer and NSCLC also expressed surface PS, which increased with T cell differentiation.

    Contributed by Alex Najibi

    ABSTRACT: In cancer and chronic infection, CD8 T cell exhaustion is hallmarked by expression of inhibitory receptors such as PD1, TIM3, LAG3 and others(1-3). Thus, inhibitory molecule focus has been limited to cell-surface proteins. Here we evaluate the surface lipid metabolite phosphatidylserine (PS) as a regulator of exhaustion. PS primarily localizes to the inner plasma membrane of live cells but is well known to be externalized to the outer membrane during cell death. The role of exposed PS on live immune cells is less clear. We show that viable, antigen-specific CD8 T cells externalize PS during lymphocytic choriomeningitis virus (LCMV) infection. T cell activation induced initial PS exposure, and chronic antigen stimulation sustained externalization. Transcriptomic and lipidomic analyses also identified PS accumulation in exhausted CD8 T cells. To evaluate a role for exposed PS in exhaustion, we treated LCMV chronically infected mice with a PS-targeting antibody (mch1N11)(4) and found that it expanded LCMV-specific CD8 responses. PD1(+)TCF1(+) stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after antibody treatment, highlighting an inhibitory role for PS. Mechanistically, exposed PS on T cells functioned extrinsically to suppress dendritic cell immunostimulatory phenotypes, in turn limiting CD8 T cell responses. PS-targeting antibody with anti-PDL1 synergized to increase CD8 responses and improve viral control. Finally, we show that PD1(+) CD8 T cells from human tumours can also expose PS. In summary, we detail CD8 T cell PS biology and provide insight into a mechanism by which exposed PS functions as a 'non-classical' extrinsic inhibitory molecule in exhaustion.

    Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (

    Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (2) Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (3) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (4) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (5) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. (9) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (10) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (11) Winship Cancer Institute of Emory University, Atlanta, GA, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Harvard Medical School, Boston, MA, USA. (13) Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (14) Winship Cancer Institute of Emory University, Atlanta, GA, USA. (15) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (16) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. Department of Immunology, University of Connecticut, Farmington, CT, USA. (17) Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA. Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. (18) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu.

    Citation: Nature 2026 Mar 25 Epub03/25/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41882354

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    Chemokine-defined macrophage niches establish spatial organization of tumor immunity

    (1) Ghosh S (2) Li X (3) Rawat K (4) Dighal A (5) Kalinowski S (6) Hosseini R (7) Kolling FW (8) Ringelberg CS (9) Jakubzick CV

    Nature immunology | Free PMC Article

    Ghosh et al. demonstrated that tissue-resident interstitial macrophages (IMs) and recruited macrophages (recMacs) showed distinct gene expression profiles in B16F10 lung metastases and KPAR1.3 lung tumor models. CD206hi IM subsets (Cxcl13+, Cxcl9+, Cxcl10+) were localized in bronchovascular regions and promoted TLS formation and lymphocyte recruitment, whereas CD206lo Ccl2+ IMs recruited Ly6c2+Fn1+Vcan+ recMacs with tumor-promoting transcriptional programs. In tdLNs, Ly6C+ monocyte-derived dendritic cells acted as immunosuppressive APCs during neoantigen vaccination, and CCR5 blockade limited their migration, enhancing antitumor immunity.

    Contributed by Shishir Pant

    (1) Ghosh S (2) Li X (3) Rawat K (4) Dighal A (5) Kalinowski S (6) Hosseini R (7) Kolling FW (8) Ringelberg CS (9) Jakubzick CV

    Nature immunology | Free PMC Article

    Ghosh et al. demonstrated that tissue-resident interstitial macrophages (IMs) and recruited macrophages (recMacs) showed distinct gene expression profiles in B16F10 lung metastases and KPAR1.3 lung tumor models. CD206hi IM subsets (Cxcl13+, Cxcl9+, Cxcl10+) were localized in bronchovascular regions and promoted TLS formation and lymphocyte recruitment, whereas CD206lo Ccl2+ IMs recruited Ly6c2+Fn1+Vcan+ recMacs with tumor-promoting transcriptional programs. In tdLNs, Ly6C+ monocyte-derived dendritic cells acted as immunosuppressive APCs during neoantigen vaccination, and CCR5 blockade limited their migration, enhancing antitumor immunity.

    Contributed by Shishir Pant

    ABSTRACT: Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-resident CD206(hi) and CD206(lo) interstitial macrophage (IM) subsets and Ly6c2(+)Fn1(+)Vcan(+) recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial transcriptomics, we identified chemokine-expressing IM subsets with opposing functions. Cxcl13(+)CD206(hi) IMs, Cxcl9(+)CD206(hi) IMs and Cxcl10(+)CD206(hi) IMs positioned along bronchovascular regions drove tertiary lymphoid structure formation, lymphocyte recruitment and tumor control, whereas Ccl2(+) IMs, localized within tumor regions, recruited protumorigenic Ly6c2(+)Fn1(+)Vcan(+) recMacs. In addition, Ly6C(+)CD11b(+) monocyte-derived dendritic cells (moDCs) functioned as immunosuppressive antigen-presenting cells in tumor-draining lymph nodes. During neoantigen vaccination, CCR5 blockade with maraviroc selectively inhibited antigen-bearing moDC migration, enhancing dendritic cell-mediated antitumor immunity. These findings showed how macrophage lineage and spatial compartmentalization govern tumor immunity and identified strategies to preserve protective IM functions, while disrupting macrophage-driven immunosuppression.

    Author Info: (1) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (2) Department of Microbiology and Immunology, Dartmouth Geisel School of Medi

    Author Info: (1) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (2) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (3) Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (4) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (5) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (6) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (7) Dartmouth Cancer Center, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (8) Dartmouth Cancer Center, Dartmouth Geisel School of Medicine, Hanover, NH, USA. (9) Department of Microbiology and Immunology, Dartmouth Geisel School of Medicine, Hanover, NH, USA. claudia.jakubzick@dartmouth.edu.

    Citation: Nat Immunol 2026 Apr 27:715-724 Epub03/23/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41872505

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    Immunogenic tumor cell death and T-cell-derived IFN-γ elicit tumoricidal macrophages to potentiate OX40 immunotherapy

    Spotlight 

    (1) Liu Y (2) Zhao J (3) Yang K (4) Ma Q (5) Zhang D (6) Xu L (7) Zhang Z (8) Yin Z (9) Chen J (10) Wang Y (11) Wang H (12) Zhou F (13) Han M (14) Wang J (15) Li F (16) Xu Y (17) Yang Y (18) Wang W (19) Huggett S (20) Chung A (21) Gan J (22) Zhang B (23) Zhou Z (24) Cao Y (25) Ding D (26) Wang M (27) Zhang H

    Cell reports. Medicine

    Using a bilateral, humanized OX40 MC38 tumor model, Liu and Zhao et al. demonstrated that OX40 agonist Ab (agOX40) therapy increased infiltration of NOS2+ pro-inflammatory macrophages and effector CD8+ T cells. T cell-derived IFNγ synergized with DAMP-induced TLR4 signaling to reprogram TAMs toward a pro-inflammatory and tumoricidal NOS2+ state. agOX40-mediated depletion of OX40+Foxp3+ Tregs further potentiated NOS2+ TAM polarization. A combination of MPLA, IFNγ, and agOX40 reprogrammed TAMs, promoted DC maturation, and induced durable tumor regression. ICD-inducing cyclophosphamide enhanced agOX40 therapy.

    Contributed by Shishir Pant

    (1) Liu Y (2) Zhao J (3) Yang K (4) Ma Q (5) Zhang D (6) Xu L (7) Zhang Z (8) Yin Z (9) Chen J (10) Wang Y (11) Wang H (12) Zhou F (13) Han M (14) Wang J (15) Li F (16) Xu Y (17) Yang Y (18) Wang W (19) Huggett S (20) Chung A (21) Gan J (22) Zhang B (23) Zhou Z (24) Cao Y (25) Ding D (26) Wang M (27) Zhang H

    Cell reports. Medicine

    Using a bilateral, humanized OX40 MC38 tumor model, Liu and Zhao et al. demonstrated that OX40 agonist Ab (agOX40) therapy increased infiltration of NOS2+ pro-inflammatory macrophages and effector CD8+ T cells. T cell-derived IFNγ synergized with DAMP-induced TLR4 signaling to reprogram TAMs toward a pro-inflammatory and tumoricidal NOS2+ state. agOX40-mediated depletion of OX40+Foxp3+ Tregs further potentiated NOS2+ TAM polarization. A combination of MPLA, IFNγ, and agOX40 reprogrammed TAMs, promoted DC maturation, and induced durable tumor regression. ICD-inducing cyclophosphamide enhanced agOX40 therapy.

    Contributed by Shishir Pant

    ABSTRACT: Understanding the mechanisms limiting OX40 agonist antibody efficacy is critical for developing more effective combination immunotherapies. Tumor microenvironment (TME) analysis revealed that OX40-antibody-responsive mice harbored tumor-associated macrophages (TAMs) with elevated NOS2 expression and heightened pattern recognition receptor (PRR) activation and interferon gamma (IFN-γ) signaling. In addition, patients with more favorable treatment responses to OX40 antibody therapy exhibited increased NOS2 expression. Mechanistically, tumor-infiltrating T-cell-derived IFN-γ synergizes with endogenous ligands of PRR released during immunogenic cell death to drive NOS2+ TAMs reprogramming. Translating these insights into therapeutic strategy, a Combo approach composing of MPLA, IFN-γ, and OX40 agonist antibody is designed to actively polarize TAMs to express NOS2, which mediate tumor clearance through an NOS2-dependent cytotoxicity. Moreover, OX40-antibody-mediated regulatory T cell (Treg) depletion potentiated NOS2+ macrophage induction. This multimodal strategy offers a promising solution to overcome the limitations of OX40 antibody monotherapy and enhance outcomes of the OX40-targeted immunotherapies.

    Author Info: (1) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Na

    Author Info: (1) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou 450003, China; Henan Academy of Sciences, Zhengzhou 450046, China. (2) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; College of Materials Science and Engineering, Shenzhen University, Shenzhen 518071, China. (3) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (4) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (5) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (6) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (7) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (8) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (9) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (10) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (11) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (12) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (13) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (14) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (15) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (16) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (17) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (18) Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. (19) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (20) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (21) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (22) NovelBio Bio-Pharm Technology Co., Ltd., Shanghai 201114, China. (23) Faculty of Life Science, University College London, London WC1E 6BT, UK. (24) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (25) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (26) Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou 450003, China. (27) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: hongkai@nankai.edu.cn.

    Citation: Cell Rep Med 2026 Mar 26 102699 Epub03/26/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41895288

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    Tim-3-targeted vaccines overcome tumor immunosuppression and reduce cDC1 dependence to elicit potent anti-tumor immunity Spotlight 

    (1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

    Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

    Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

    Contributed by Shishir Pant

    (1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

    Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

    Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

    Contributed by Shishir Pant

    ABSTRACT: Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti-DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti-Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-_-catenin(active) mice, which model _-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3(-/-) mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control-albeit both were reduced compared to wild-type mice- demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine-induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3-neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell-dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.

    Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health

    Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824. (2) Department of Computer Science and Engineering, School of Engineering and Computer Science, Oakland University, Rochester, MI 48309. (3) Institute for Molecular Medicine and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany. (4) Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA 94143. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129. (5) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824.

    Citation: Proc Natl Acad Sci U S A 2026 Mar 24 123:e2518080123 Epub03/19/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41855265

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    Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice Spotlight 

    (1) Zhang X (2) Gao Y (3) Hu W (4) Liang Y (5) Yin X (6) Shi X (7) Li H (8) Liao H (9) Guo J (10) Yu X (11) Zhu M (12) Peng H (13) Wang W (14) Fu YX

    Nature communications

    Zhang, Gao, and Hu et al. addressed ways to enhance DC–T cell crosstalk in the TIME. BiDT, a bispecific DC–T cell engager (anti-Tim3–IFNα fusion), simultaneously bound Tim3 on exhausted TILs and activated DCs via the IFNAR receptor. In mouse models, BiDT resulted in potent antitumor activity, robust tumor specific memory, and synergized with anti-PD-L1 in an immune-cold tumor model. Mechanistically, BiDT depended on DCs and intratumoral, not LN, T cells, reactivated exhausted TIM3+ CD8+ TILs via anti-apoptotic Bcl-2 upregulation, and enhanced DC function via increased IL-2 production and B7/CD28 interactions. To address IFNα toxicity, an MMP-cleavable prodrug variant was generated.

    Contributed by Katherine Turner

    (1) Zhang X (2) Gao Y (3) Hu W (4) Liang Y (5) Yin X (6) Shi X (7) Li H (8) Liao H (9) Guo J (10) Yu X (11) Zhu M (12) Peng H (13) Wang W (14) Fu YX

    Nature communications

    Zhang, Gao, and Hu et al. addressed ways to enhance DC–T cell crosstalk in the TIME. BiDT, a bispecific DC–T cell engager (anti-Tim3–IFNα fusion), simultaneously bound Tim3 on exhausted TILs and activated DCs via the IFNAR receptor. In mouse models, BiDT resulted in potent antitumor activity, robust tumor specific memory, and synergized with anti-PD-L1 in an immune-cold tumor model. Mechanistically, BiDT depended on DCs and intratumoral, not LN, T cells, reactivated exhausted TIM3+ CD8+ TILs via anti-apoptotic Bcl-2 upregulation, and enhanced DC function via increased IL-2 production and B7/CD28 interactions. To address IFNα toxicity, an MMP-cleavable prodrug variant was generated.

    Contributed by Katherine Turner

    ABSTRACT: Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3(+)TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFN_-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFN_ and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.

    Author Info: (1) Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. xuhaozhang@cqmu.edu.cn. School of Basic Medical Sciences, Tsinghua University, Beiji

    Author Info: (1) Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. xuhaozhang@cqmu.edu.cn. School of Basic Medical Sciences, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. (2) School of Basic Medical Sciences, Tsinghua University, Beijing, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (3) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (4) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (5) School of Basic Medical Sciences, Tsinghua University, Beijing, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (6) School of Basic Medical Sciences, Tsinghua University, Beijing, China. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (7) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (8) Changping Laboratory, Beijing, China. (9) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (10) Changping Laboratory, Beijing, China. (11) CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. (12) Guangzhou National Laboratory, Bio-Island, Guangzhou, China. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (13) School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. (14) School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. Changping Laboratory, Beijing, China. yangxinfu@tsinghua.edu.cn.

    Citation: Nat Commun 2026 Mar 17 Epub03/17/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41844634

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