Journal Articles

In situ reprogramming of glioma stem cells into dendritic cell-like cells for glioblastoma immunotherapy

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Chunwei Tang (1,4), Weiyi Sun (1,4), Zhenmei Yang (1,4), Xiaotian Zhao (1), Jian Gao (1), Kun Han (1), Zichao Yao (1), Xianghui Dong (1), Miaoyan Liu (1), Jing Zhang (1), Zhaoyu Chen (2), Xiao Yue (1), Zhipeng Fu (1), Yan Wang (1), Maosen Han (1), Ying Liu (1), Jinxin Gao (1), Yulin Zhang (3), Xinyi Jiang (1), Chen Chen (1), Xin Wen (1), Kun Zhao (1) & Jingyi Han (1).

Nature communications

Tang, Sun, Yang, et al. reprogrammed glioma stem cells (GSCs) into cDC1-like cells in situ by administering a hydrogel to the post-op tumor cavity for slow and local delivery of CD133-targeting LNPs carrying plasmids encoding PIB (PU.1, IRF8, BATF3) and costimulatory TNFSF9. In vivo, GSCs were preferentially targeted and acquired a cDC1-like phenotype with increased antigen presentation, costimulatory signaling, and proinflammatory cytokine secretion, supporting enhanced antigen-specific effector and memory T cell responses that cleared tumor cells, improved survival and neurological outcomes, and protected against relapse and rechallenge.

Contributed by Lauren Hitchings

Chunwei Tang (1,4), Weiyi Sun (1,4), Zhenmei Yang (1,4), Xiaotian Zhao (1), Jian Gao (1), Kun Han (1), Zichao Yao (1), Xianghui Dong (1), Miaoyan Liu (1), Jing Zhang (1), Zhaoyu Chen (2), Xiao Yue (1), Zhipeng Fu (1), Yan Wang (1), Maosen Han (1), Ying Liu (1), Jinxin Gao (1), Yulin Zhang (3), Xinyi Jiang (1), Chen Chen (1), Xin Wen (1), Kun Zhao (1) & Jingyi Han (1).

Nature communications

Tang, Sun, Yang, et al. reprogrammed glioma stem cells (GSCs) into cDC1-like cells in situ by administering a hydrogel to the post-op tumor cavity for slow and local delivery of CD133-targeting LNPs carrying plasmids encoding PIB (PU.1, IRF8, BATF3) and costimulatory TNFSF9. In vivo, GSCs were preferentially targeted and acquired a cDC1-like phenotype with increased antigen presentation, costimulatory signaling, and proinflammatory cytokine secretion, supporting enhanced antigen-specific effector and memory T cell responses that cleared tumor cells, improved survival and neurological outcomes, and protected against relapse and rechallenge.

Contributed by Lauren Hitchings

ABSTRACT: Immunotherapy has revolutionized the treatment landscape for many cancers, but fails to improve the outcomes of glioblastoma multiforme (GBM), in which low tumor antigen presentation restricts the recognition and eradication of cancerous cells by immunocytes. We here report an approach to in situ reprogramming hypoimmunogenic glioblastoma stem cells (GSCs) into type 1 conventional dendritic cell (cDC1)-like cells for presenting endogenous tumor antigens and priming sustained tumoricidal T-cell responses. Specifically, our cavity-injectable nucleobase-derived lipid nanoparticle (LNP)-hydrogel superstructure efficiently delivers transcription factors (PU.1, IRF8, BATF3) and the costimulatory molecule (TNFSF9) into GSCs to induce cDC1-like reprogramming. These cDC1-like cells potentiate GBM immunogenicity, elicit robust adaptive immunity and long-term antitumor memory, thereby inhibiting tumor growth and preventing postoperative GBM relapse in mice. Collectively, this work establishes in situ tumor cell reprogramming into licensed cDC1-like cells as a therapeutic paradigm for converting immunologically “cold” tumors into a self-vaccinating immune niche with broad translational potential for hypoimmunogenic malignancy treatment.

Author Info: (1) Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory fo

Author Info: (1) Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.(2) Shandong University of Traditional Chinese Medicine, Jinan, China. (3) Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China. (4)These authors contributed equally: Chunwei Tang, Weiyi Sun, Zhenmei Yang. e-mail: xinyijiang@sdu.edu.cn; chenchen27@sdu.edu.cn; wxzbc@mail.sdu.edu.cn; kzhao2013@sdu.edu.cn; jyhantw@email.sdu.edu.cn

Citation: nat com 2026

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    Bridging innate and adaptive immunity- A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance

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    (1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

    Cell reports. Medicine

    Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

    Contributed by Katherine Turner

    (1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

    Cell reports. Medicine

    Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

    Contributed by Katherine Turner

    ABSTRACT: Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming-thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.

    Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue,

    Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (2) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (3) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (4) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (5) Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China. (6) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (7) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (8) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (9) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (10) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (11) Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: huax@pennmedicine.upenn.edu. (12) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: dianwenju@fudan.edu.cn. (13) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: xuyaozhang@fudan.edu.cn.

    Citation: Cell Rep Med 2026 Oct 5 103087 Epub10/05/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42833217

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    Tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity while minimizing immune-related adverse events

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    Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

    Nature communications

    By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

    Contributed by Paula Hochman

    Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

    Nature communications

    By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

    Contributed by Paula Hochman

    ABSTRACT: Tumor-targeting cytokines have emerged as a promising strategy for cancer immunotherapy, although their mechanisms of action often remain complex. In this study, we develop an approach by combining tumor-targeted IL-10 (CmAb-(IL10)2) with IL-2 (CmAb-IL2) to enhance antitumor immunity while minimizing immune-related adverse events (irAEs). We demonstrate that endogenous IL-10 plays a critical role in IL-2-mediated antitumor effects, and that the combination of CmAb-(IL10)2 and CmAb-IL2 preferentially expands less-exhausted CD8+ T cells within tumors. Mechanistically, we identify that the IL-10/IL-10 receptor (IL-10R) axis in dendritic cells (DCs) is critical for mediating the efficacy of this combination therapy by promoting intratumoral DC function. Furthermore, we show that this combination enhances antitumor immune responses in humanized female mice and ex vivo patient-derived tumor fragments models. Our findings reveal that tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity through the IL-10/IL-10R/DC axis within tumors, while mitigating IL-2-associated irAEs through the IL-10/IL-10R/macrophage axis. This approach offers an IL-10 based strategy to improve the efficacy of immunotherapy while reducing irAEs.

    Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Hea

    Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3 - Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, USA. 4 - Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 5 - Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. 6 - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. e-mail: Jian.Qiao@UTSouthwestern.edu

    Citation: Nat com 2026

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      Metastasis enables immunogenicity through migrasome-mediated antigen release Spotlight 

      (1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L

      Nature immunology | Free PMC Article

      Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.

      Contributed by Shishir Pant

      (1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L

      Nature immunology | Free PMC Article

      Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.

      Contributed by Shishir Pant

      ABSTRACT: Antigen release is a critical step in initiating antitumor immune responses, yet its regulation during metastasis is not well understood. Here we show that circulating tumor cells undergoing vascular migration produce migrasomes that serve as a metastasis-specific mechanism of antigen release. These migrasomes are enriched in tumor-associated antigens, including cancer-testis and mutated antigens, and are captured efficiently by antigen-presenting cells in secondary lymphoid organs, where they undergo cross-presentation to elicit CD8(+) T cell-mediated immune responses that constrain metastatic progression. Genetic inhibition of migrasome formation enhances metastasis, while administration of purified cancer-derived migrasomes restores immune-mediated suppression of metastatic growth. These findings show paradoxically that metastasis can enhance tumor immunogenicity through migrasome-mediated antigen release, highlighting a link between cancer dissemination and immune activation and establishing migrasomes as a distinct and potent platform for endogenous tumor antigen delivery.

      Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantat

      Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. jiang-dong@zju.edu.cn. (2) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (3) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (4) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (5) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (6) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (7) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (8) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (9) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (10) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (11) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (12) Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. (13) Beijing Stomatological Hospital, Capital Medical University, Beijing, China. (14) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. liyulab@mail.tsinghua.edu.cn.

      Citation: Nat Immunol 2026 Oct 27:2088-2101 Epub09/22/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42773266

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      Distant lymph nodes compensate for resected tumor-draining lymph nodes during cancer immunotherapy Spotlight 

      (1) Menzel L (2) Zhou H (3) Baish JW (4) O'Melia MJ (5) Darragh LB (6) Effiom DN (7) Specht E (8) Czapla J (9) Lei PJ (10) Rajotte JJ (11) Liu L (12) Nikmaneshi MR (13) Razavi MS (14) Vander Heiden MG (15) Ubellacker JM (16) Munn LL (17) Karam SD (18) Boland GM (19) Cohen S (20) Padera TP

      Immunity

      Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.

      Contributed by Ute Burkhardt

      (1) Menzel L (2) Zhou H (3) Baish JW (4) O'Melia MJ (5) Darragh LB (6) Effiom DN (7) Specht E (8) Czapla J (9) Lei PJ (10) Rajotte JJ (11) Liu L (12) Nikmaneshi MR (13) Razavi MS (14) Vander Heiden MG (15) Ubellacker JM (16) Munn LL (17) Karam SD (18) Boland GM (19) Cohen S (20) Padera TP

      Immunity

      Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.

      Contributed by Ute Burkhardt

      ABSTRACT: Surgical removal of tumor-draining lymph nodes (tdLNs) is commonly performed in cancer patients. Here, we investigated whether immune checkpoint blockade (ICB) responses persist after resection of tdLNs, important sites for the initiation and maintenance of anti-cancer immunity. Melanoma patients remained responsive to programmed death 1 (PD-1) blockade after regional LN dissection. Similarly, ICB efficacy persisted after tdLN resection in orthotopic murine melanoma and mammary carcinoma models. Following tdLN removal, interstitial fluid containing soluble antigen was diverted through interstitial spaces across lymphosome boundaries to distant LNs, wherein cancer-derived antigen was acquired and presented to T cells by LN-resident type I conventional dendritic cells. These responses persisted after primary tumor resection and supported ICB-induced systemic immunity. Locoregional delivery of ICB to compensatory LNs enhanced anti-cancer responses after tdLN resection. Consistently, ICB responses in head and neck cancer patients were associated with reactive LNs at distant sites. Thus, antigen rerouting enables distant LNs to compensate for resected tdLNs and sustain anti-cancer immunity, including responses enhanced by immunotherapy.

      Author Info: (1) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Edwin Steele Laboratories, Department of Radiation Oncol

      Author Info: (1) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA; Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (3) Department of Biomedical Engineering, Bucknell University, Lewisburg, PA 17837, USA. (4) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (5) Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (6) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (8) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (10) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. (16) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (17) Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (18) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (19) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (20) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: tpadera@mgh.harvard.edu.

      Citation: Immunity 2026 Oct 1 Epub10/01/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42822444

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      Rejuvenating endogenous antitumor immunity via a chimeric receptor-engineered oncolytic virus targeting tumor-associated macrophages Spotlight 

      (1) Lin C (2) Li S (3) Lou R (4) Teng W (5) Tian Y (6) Feng C (7) Wang N (8) Rao Y (9) Qin Y (10) Li L (11) Huang X (12) Lin Y (13) Zhang J (14) Xia N (15) Huang C

      Science advances | Free PMC Article

      Lin et al. engineered an oncolytic herpesvirus (oHSV) with a PD-L1 nanobody attached to gD on the viral envelope surface (gDαPD- L1), targeting the virus to both tumors and TAMs expressing PD-L1. In addition to its oncolytic activity, this CAR-oHSV also resulted in the presentation of anti-PD-L1 CARs on infected cells, blocking PD-L1 in cis. In TAMs, CAR-oHSV killed a subset of TAMs, while remaining TAMs were reprogrammed via STING activation towards a CXCL9+ antigen-presenting phenotype that supported CD8+ T cell-mediated antitumor immunity. CAR-oHSV was well tolerated and showed synergy with checkpoint blockade and adoptive cell therapy.

      Contributed by Lauren Hitchings

      (1) Lin C (2) Li S (3) Lou R (4) Teng W (5) Tian Y (6) Feng C (7) Wang N (8) Rao Y (9) Qin Y (10) Li L (11) Huang X (12) Lin Y (13) Zhang J (14) Xia N (15) Huang C

      Science advances | Free PMC Article

      Lin et al. engineered an oncolytic herpesvirus (oHSV) with a PD-L1 nanobody attached to gD on the viral envelope surface (gDαPD- L1), targeting the virus to both tumors and TAMs expressing PD-L1. In addition to its oncolytic activity, this CAR-oHSV also resulted in the presentation of anti-PD-L1 CARs on infected cells, blocking PD-L1 in cis. In TAMs, CAR-oHSV killed a subset of TAMs, while remaining TAMs were reprogrammed via STING activation towards a CXCL9+ antigen-presenting phenotype that supported CD8+ T cell-mediated antitumor immunity. CAR-oHSV was well tolerated and showed synergy with checkpoint blockade and adoptive cell therapy.

      Contributed by Lauren Hitchings

      ABSTRACT: Immunosuppressive tumor-associated macrophages (TAMs) create a barrier to effective antitumor immunity and promote therapeutic resistance. Reeducating TAMs to enhance their antitumor capabilities through phenotypic remodeling remains challenging. Here, we report a modular oncolytic herpesvirus platform, engineered with a PD-L1-specific chimeric receptor integrated into the viral envelope protein (CAR-oHSV). This design endows the virus with dual tropism, enabling it to target both tumor cells and TAMs within the tumor microenvironment. In virus-resistant tumor models, CAR-oHSV preferentially targets PD-L1(+) TAMs and triggers a STING-dependent reprogramming into a CXCL9(+) phenotype, enhancing their tumor antigen cross-presentation capability and inducing an endogenous antitumor T cell response. Furthermore, this platform can synergize with adoptive T cell therapy and immune checkpoint blockade therapy to overcome immunotherapy resistance. Collectively, our findings define a precision-oncolytic platform that dismantles TAM-mediated immunosuppression while amplifying adaptive immunity, offering a promising translational avenue for cancer immunotherapy.

      Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institu

      Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (2) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (3) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (4) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (5) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (6) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (7) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (8) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (9) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (10) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (11) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (13) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (14) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. School of Life Sciences, Xiamen University, Xiamen, 361102, China. (15) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China.

      Citation: Sci Adv 2026 Sep 18 12:eaef6767 Epub09/18/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42758830

      Tags:

      Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models Spotlight 

      (1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

      Cancer immunology research

      Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

      Contributed by Lauren Hitchings

      (1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

      Cancer immunology research

      Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

      Contributed by Lauren Hitchings

      ABSTRACT: To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.

      Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4

      Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (5) Hannover Medical School Hannover Germany. (6) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. (7) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (8) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (9) Glycotope GmbH Berlin Germany. (10) Medizinische Hochschule Hannover Hannover, Low Saxony Germany. ROR: https://ror.org/00f2yqf98 (11) Technische UniversitŠt Braunschweig Braunschweig Germany. ROR: https://ror.org/010nsgg66 (12) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (13) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (14) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (15) Leibniz Institute for Immunotherapy and Univ Regensberg Regensburg Germany. (16) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. ROR: https://ror.org/03pvr2g57 (17) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (18) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98

      Citation: Cancer Immunol Res 2026 Sep 22 Epub09/22/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42770707

      Tags:

      Cancers modulate processing and presentation of p53 neoantigens to evade T cell detection Spotlight 

      (1) Haratani K (2) Reinhold B (3) Duke-Cohan JS (4) Fahey CG (5) Tan K (6) Mallis RJ (7) Gusev A (8) Kehl KL (9) Luo J (10) Karmazyn A (11) Holliday EL (12) Masi DJ (13) Zienkiewicz KJ (14) Hennessey CJ (15) Blasco RB (16) Thai TC (17) Gibbons GM (18) Kivlehan S (19) Lizotte P (20) Paweletz CP (21) Aguirre AJ (22) Ligon KL (23) Chiarle R (24) Lang MJ (25) Barbie DA (26) Reinherz EL

      Immunity

      Haratani et al. found that most neoantigens arising from truncal mutations in TP53 were not presented, either because they arose from processing-resistant regions of p53 or because the required HLA allele was absent. Presentable antigens that were immunologically distinct could also be masked in tumors via increased activity of the aminopeptidase ERAP1, which prevented the display of a high-affinity HLA-A*02:01 complex containing a strongly immunogenic 11-mer. Instead, tumors favored the display of low-affinity complexes with a poorly immunogenic 9-mer, resulting in only weak T cell-mediated antitumor immunity, despite high-quality TCRs.

      Contributed by Lauren Hitchings

      (1) Haratani K (2) Reinhold B (3) Duke-Cohan JS (4) Fahey CG (5) Tan K (6) Mallis RJ (7) Gusev A (8) Kehl KL (9) Luo J (10) Karmazyn A (11) Holliday EL (12) Masi DJ (13) Zienkiewicz KJ (14) Hennessey CJ (15) Blasco RB (16) Thai TC (17) Gibbons GM (18) Kivlehan S (19) Lizotte P (20) Paweletz CP (21) Aguirre AJ (22) Ligon KL (23) Chiarle R (24) Lang MJ (25) Barbie DA (26) Reinherz EL

      Immunity

      Haratani et al. found that most neoantigens arising from truncal mutations in TP53 were not presented, either because they arose from processing-resistant regions of p53 or because the required HLA allele was absent. Presentable antigens that were immunologically distinct could also be masked in tumors via increased activity of the aminopeptidase ERAP1, which prevented the display of a high-affinity HLA-A*02:01 complex containing a strongly immunogenic 11-mer. Instead, tumors favored the display of low-affinity complexes with a poorly immunogenic 9-mer, resulting in only weak T cell-mediated antitumor immunity, despite high-quality TCRs.

      Contributed by Lauren Hitchings

      ABSTRACT: TP53 mutations occur early in malignant transformation as truncal events in tumor evolution and are therefore generally present in all descendant tumor cells, creating an immunological vulnerability. Here, we examined the immunogenicity and antigenicity of p53 neoantigens emerging from these truncal mutations. Comprehensive immunopeptidomics revealed that hotspot mutations in human tumors preferentially localize to p53 regions resistant to antigen processing, thereby avoiding display altogether. Moreover, for neoantigens presentable by HLA-A∗02:01 or HLA-B∗07:02 and structurally divergent from corresponding wild-type p53 peptide-HLA complexes, clinical tumors commonly lacked the relevant presenting HLA allele. Tumor cells further resisted T cell killing through increased activity of the aminopeptidase ERAP1, preventing display of high-affinity HLA-A∗02:01 complexes containing an immunogenic p53I195F-derived 11-mer, or by expressing low-affinity HLA-A∗02:01 complexes containing a p53R175H-derived 9-mer with poor antigenicity despite high-quality human TCRs. These findings define mechanisms by which tumors restrict targetable truncal neoantigen display and suggest immunopeptidome shift strategies to circumvent immune escape.

      Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncolo

      Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (5) Structural Biology Center, X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, 9700 S. Cass Avenue, Lemont, IL 60439, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Laboratory of Immunobiology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Dermatology, Harvard Medical School, Boston, MA, USA. (7) Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (10) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (11) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (12) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (13) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (15) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Department of Pathology, Boston Children's Hospital, Boston, MA, USA; Department of Molecular Biotechnology and Health Sciences, University of Torino, 10125 Torino, Italy; Division of Hematopathology, IEO European Institute of Oncology IRCCS, Milan, Italy. (24) Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: david_barbie@dfci.harvard.edu. (26) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: ellis_reinherz@dfci.harvard.edu.

      Citation: Immunity 2026 Sep 17 Epub09/17/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42753739

      Tags:

      FasL-mediated death of activated intratumoral T cells drives secondary resistance to cancer immunotherapy Spotlight 

      (1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

      Cancer immunology research

      Qing and Ghorani et al. explored mechanisms of secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at initial response, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells became lost over time.

      Contributed by Alex Najibi

      (1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

      Cancer immunology research

      Qing and Ghorani et al. explored mechanisms of secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at initial response, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells became lost over time.

      Contributed by Alex Najibi

      ABSTRACT: Cancer progression following an initial response to immunotherapy (secondary resistance; 2°R) is a major and poorly understood problem. We treated mice bearing B16 melanoma with a combination of a regulatory T cell (Treg) depleting, non-IL-2 blocking antibody (anti-CD25NIB) and an autologous cancer cell vaccine (GVAX). The regimen yielded initial tumor shrinkage followed by 2°R; lethal progression occurred in ~90% of partially responsive (PR) tumors by days 35-50. Cell lines derived from 2°R tumors retained treatment sensitivity upon re-implantation into naïve mice, suggesting resistance was related to a loss of immune control over time. Profiling PR and 2°R tumors by flow cytometry and single-cell RNA/TCR sequencing, we found that activated CD8⁺ T cells with tumor-reactive features declined in abundance, whereas non-activated T cells and Tregs increased. Activated CD8⁺ cells showed heightened TCR stimulation, clonal expansion, and expression of apoptotic signatures and death receptors, including Fas. Their loss was not explained by lymph node accumulation or differentiation to non-activated states. These findings were validated in a clinically relevant MC38 colon carcinoma model treated with anti-PD-L1 checkpoint blockade, confirming that depletion of activated, tumor-reactive clones is a shared mechanism of 2°R across therapeutic modalities. Fas ligand (FasL) blockade reversed this loss and prolonged survival. Longitudinal transcriptional and tissue staining data from human checkpoint blockade studies similarly indicated that activated T cells decline in abundance over time and at 2°R. These findings implicate death of activated T cells as a mechanism of 2°R and suggest Fas-FasL blockade may extend response durability.

      Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer In

      Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (4) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (5) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (6) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (7) University of Oxford Oxford United Kingdom. ROR: https://ror.org/052gg0110 (8) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (9) Roche (Switzerland) Schlieren Switzerland. ROR: https://ror.org/00by1q217 (10) University College London Cancer Institute, London United Kingdom. (11) University College London London United Kingdom. ROR: https://ror.org/02jx3x895

      Citation: Cancer Immunol Res 2026 Sep 15 Epub09/15/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42743199

      Tags:

      Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma Spotlight 

      (1) Asano Y (2) Veatch JR (3) Sung CJ (4) Tang TH (5) Mazziotta F (6) Natsuki S (7) McAfee M (8) Bakhtiari J (9) Lee B (10) Martin L (11) Rizzi A (12) Zhang T (13) Smith CW (14) Paulson KG (15) Schmitt TM (16) Newell EW (17) Elz AE (18) Chen DG (19) Su Y (20) Gustafson HH (21) Yeung CCS (22) Seaton B (23) Hunter D (24) Koelle DM (25) Bhatia S (26) Hall ET (27) Voillet V (28) Cao J (29) Gooley T (30) Greenberg PD (31) Gottardo R (32) Oda SK (33) Nghiem P (34) Chapuis AG

      Science translational medicine

      Asano, Veatch, and Sung et al. identified TCRMCC1, a high-avidity HLA-A*02:01-restricted TCR targeting Merkel cell polyomavirus large-T antigen and treated seven patients who had ICI-refractory metastatic MCC using autologous TCRMCC1-transduced T cells plus ICB. TTCR-MCC1 cells trafficked to tumors and induced regression in two patients, but HLA class I silencing limited activity. In one patient, delayed regression coincided with endogenous effector T cell activation and restored tumor HLA expression. TTCR-MCC1 cells armored with CD8αβ and a CD200R-CD28 switch receptor showed enhanced tumor infiltration, HLA expression, and control of HLA-low MCC in vivo.

      Contributed by Shishir Pant

      (1) Asano Y (2) Veatch JR (3) Sung CJ (4) Tang TH (5) Mazziotta F (6) Natsuki S (7) McAfee M (8) Bakhtiari J (9) Lee B (10) Martin L (11) Rizzi A (12) Zhang T (13) Smith CW (14) Paulson KG (15) Schmitt TM (16) Newell EW (17) Elz AE (18) Chen DG (19) Su Y (20) Gustafson HH (21) Yeung CCS (22) Seaton B (23) Hunter D (24) Koelle DM (25) Bhatia S (26) Hall ET (27) Voillet V (28) Cao J (29) Gooley T (30) Greenberg PD (31) Gottardo R (32) Oda SK (33) Nghiem P (34) Chapuis AG

      Science translational medicine

      Asano, Veatch, and Sung et al. identified TCRMCC1, a high-avidity HLA-A*02:01-restricted TCR targeting Merkel cell polyomavirus large-T antigen and treated seven patients who had ICI-refractory metastatic MCC using autologous TCRMCC1-transduced T cells plus ICB. TTCR-MCC1 cells trafficked to tumors and induced regression in two patients, but HLA class I silencing limited activity. In one patient, delayed regression coincided with endogenous effector T cell activation and restored tumor HLA expression. TTCR-MCC1 cells armored with CD8αβ and a CD200R-CD28 switch receptor showed enhanced tumor infiltration, HLA expression, and control of HLA-low MCC in vivo.

      Contributed by Shishir Pant

      ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)MCC1, a highly avid, HLA-A*02:01-restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen15-23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). TTCR-MCC1 cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.

      Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Translational Science and Therapeutics Division, Fred Hutchinson Can

      Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (3) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (4) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (5) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (6) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (7) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (8) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. (9) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (11) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (12) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (13) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (14) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (15) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (16) Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (17) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (18) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (19) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (20) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. (21) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. (22) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (23) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (24) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Global Health, University of Washington School of Medicine, Seattle, WA 98195, USA. Benaroya Research Institute, Seattle, WA 98101, USA. (25) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (26) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (27) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (28) Shared Resources, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (29) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (30) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (31) Biomedical Data Science Center, Centre Hospitalier Universitaire Vaudois, 1010 Lausanne, Switzerland. University of Lausanne, 1015 Lausanne, Switzerland. School of Life Sciences, EPFL, 1015 Lausanne, Switzerland. (32) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. (33) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Dermatology, University of Washington School of Medicine, Seattle, WA 98195, USA. (34) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.

      Citation: Sci Transl Med 2026 Sep 9 18:eaea8773 Epub09/09/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42715345

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