Journal Articles

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

Spotlight 

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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    Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks Spotlight 

    (1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

    Cancer discovery

    Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

    Contributed by Shishir Pant

    (1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

    Cancer discovery

    Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

    Contributed by Shishir Pant

    ABSTRACT: Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

    Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86

    Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (5) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (6) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (7) Dana Farber Cancer Institute Boston United States. (8) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (9) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (10) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (11) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (12) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (13) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (14) Dana-Farber Brigham Cancer Center Boston, MA United States. ROR: https://ror.org/05rgrbr06 (15) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (16) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (17) Dana-Farber Cancer Institute United States. (18) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (19) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (20) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (21) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (22) Skyline Therapeutics Cambridge, MA United States. (23) University of Cincinnati Medical Center Cincinnati United States. ROR: https://ror.org/02p72h367 (24) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (25) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (26) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (27) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (28) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (29) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (30) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (31) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (32) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (33) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (34) Massachusetts Institute of Technology Cambridge, MA United States. ROR: https://ror.org/042nb2s44 (35) Dana-Farber Cancer Institute, Harvard University Boston, MA United States.

    Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810409

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    IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8+ T cells while restraining regulatory T-cell accumulation

    Spotlight 

    (1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

    Journal for immunotherapy of cancer | Free PMC Article

    LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

    Contributed by Shishir Pant

    (1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

    Journal for immunotherapy of cancer | Free PMC Article

    LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

    Contributed by Shishir Pant

    BACKGROUND: Targeting the high-affinity interleukin-2 receptor (IL-2R) on CD8(+) T effector cells elicits potent antitumor responses that are augmented when co-administered with programmed cell death protein 1 (PD-1) blockade. METHODS: Using the mouse IL-2/CD25 fusion protein (mIL-2/CD25) at a high dose (HD) and anti-PD-1 checkpoint blockade, with the CT26 and MC38 colon carcinomas as models, the current study investigated how antitumor responses occurred when regulatory T cells (Tregs) are also a target of HD mIL-2/CD25. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) repertoire analysis of tumor-associated immune cells were used to identify how combination therapy reshaped the tumor microenvironment (TME). These data were cross-referenced with published datasets to (1) corroborate TCR specificity and (2) identify how CD8(+) T-cell differentiation is affected by different IL-2/PD-1 strategies. RESULTS: Here, we show that effective antitumor immunity by the combination therapy is a result of HD mIL-2/CD25-dependent reprogramming of CD8(+) tumor-specific T cells that increases their function and supports their expansion within the TME, the latter also shaped by PD-1 blockade. This therapy supports antitumor responses by chemokines and inflammatory cytokines that selectively favor the migration of CD8(+) T cells but not Tregs deep within the tumor. After HD mIL-2/CD25 treatment, Tregs within the TME showed impaired downstream IL-2R signaling, reflected by failed upregulation of forkhead box P3 and CD25, impaired development into effector Tregs, and enhanced cell death, the latter which likely offsets Treg proliferation. Many similarities were noted after direct comparison of these scRNA-seq findings with another study where IL-2 activity was targeted to PD-1(+) CD8(+) T cells. Notably, HD mIL-2/CD25 and anti-PD-1 combination promotes effector and 'stem-like' CD8(+) T-cell subsets, perhaps even to a greater extent than the PD-1-targeted IL-2 strategy. CONCLUSIONS: The efficient differentiation of exhausted CD8(+) T cells into highly functional cells and the resulting potent antitumor responses by HD mIL-2/CD25 plus anti-PD-1 suggest that this approach may augment durable response rates more than currently achieved with checkpoint blockade monotherapy.

    Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and

    Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. (2) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (3) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (4) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (5) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (6) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (7) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA tmalek@med.miami.edu.

    Citation: J Immunother Cancer 2026 Sep 29 14: Epub09/29/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810810

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

    Spotlight 

    (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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    Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer Spotlight 

    (1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW

    Science

    Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.

    Contributed by Shishir Pant

    (1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW

    Science

    Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.

    Contributed by Shishir Pant

    ABSTRACT: Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

    Author Info: (1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Ketter

    Author Info: (1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. (4) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (23) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (25) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (28) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

    Citation: Science 2026 Sep 24 393:eaeg4791 Epub09/24/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42784692

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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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    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

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    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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    A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion Spotlight 

    (1) Falcomatà C (2) Schaefer MM (3) Singh B (4) Chhamalwan D (5) Tepper A (6) Nielsen SR (7) Potak HT (8) Dhainaut M (9) Mollaoglu G (10) Park MD (11) Merad M (12) Baccarini A (13) Brown BD

    Nature

    Falcomatà et al. used perturb-map spatial functional genomics to identify tumor-derived extracellular factors that promote PDAC immune evasion. SERPINE1 (encoding PAI1) and SERPINB2 promoted fibrin-rich ECM niches that retained and polarized macrophages toward immunosuppressive states while excluding cytotoxic CD8+ T cells. Loss of serpins or pharmacologic inhibition of PAI1 improved tumor control and sensitized orthotopic KPC PDAC tumors to anti-PD-1. In human PDACs, SERPINB1/2-expressing tumor cells were embedded within immunosuppressive niches enriched with SPP1+MARCO+ macrophages.

    Contributed by Shishir Pant

    (1) Falcomatà C (2) Schaefer MM (3) Singh B (4) Chhamalwan D (5) Tepper A (6) Nielsen SR (7) Potak HT (8) Dhainaut M (9) Mollaoglu G (10) Park MD (11) Merad M (12) Baccarini A (13) Brown BD

    Nature

    Falcomatà et al. used perturb-map spatial functional genomics to identify tumor-derived extracellular factors that promote PDAC immune evasion. SERPINE1 (encoding PAI1) and SERPINB2 promoted fibrin-rich ECM niches that retained and polarized macrophages toward immunosuppressive states while excluding cytotoxic CD8+ T cells. Loss of serpins or pharmacologic inhibition of PAI1 improved tumor control and sensitized orthotopic KPC PDAC tumors to anti-PD-1. In human PDACs, SERPINB1/2-expressing tumor cells were embedded within immunosuppressive niches enriched with SPP1+MARCO+ macrophages.

    Contributed by Shishir Pant

    ABSTRACT: Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity(1-4). This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

    Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.

    Citation: Nature 2026 Sep 9 Epub09/09/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42717081

    Tags:

    PLA2G2D in tumour-draining lymph nodes regulates anti-tumour immunity Featured  

    (1) van Krimpen A (2) Huang J (3) Eterman M (4) Gerretsen V (5) Umetani M (6) Janssen JC (7) van Nimwegen M (8) Rozendaal N (9) van den Bosch TPP (10) Jiang X (11) Logronio K (12) Liu AZ (13) Liu YR (14) Nagasaki Y (15) Murakami M (16) Onrust-Van Schoonhoven A (17) Leliveld A (18) Vadgama D (19) Langeveld H (20) van Wijck R (21) Bindels E (22) von der ThŸsen J (23) Mooyaart A (24) van Maldegem F (25) Brenis CM (26) Verwaerde S (27) Hendriks RW (28) Lambrecht BN (29) GrŸnhagen DJ (30) Verhoef C (31) Aerts JGJV (32) Lee LF (33) Lu KV (34) Stadhouders R (35) Dammeijer F

    Nature

    Van Krimpen and Huang et al. performed spatial proteogenomics studies on tdLNs from patients with melanoma. In addition to identifying a spatial neighborhood in the tdLN paracortex linked to poor prognosis, the researchers also identified a population of lymph node macrophages secreting PLA2G2D, which acted as an immune checkpoint that limited CD8+ T cell-mediated antitumor immunity. Blocking PLA2G2D reduced immunosuppression and enhanced antitumor immunity, resulting in reduced tumor growth, which could be further reduced in combination with anti-PD-1. PLA2G2D was also associated with poor prognosis in patient data.

    (1) van Krimpen A (2) Huang J (3) Eterman M (4) Gerretsen V (5) Umetani M (6) Janssen JC (7) van Nimwegen M (8) Rozendaal N (9) van den Bosch TPP (10) Jiang X (11) Logronio K (12) Liu AZ (13) Liu YR (14) Nagasaki Y (15) Murakami M (16) Onrust-Van Schoonhoven A (17) Leliveld A (18) Vadgama D (19) Langeveld H (20) van Wijck R (21) Bindels E (22) von der ThŸsen J (23) Mooyaart A (24) van Maldegem F (25) Brenis CM (26) Verwaerde S (27) Hendriks RW (28) Lambrecht BN (29) GrŸnhagen DJ (30) Verhoef C (31) Aerts JGJV (32) Lee LF (33) Lu KV (34) Stadhouders R (35) Dammeijer F

    Nature

    Van Krimpen and Huang et al. performed spatial proteogenomics studies on tdLNs from patients with melanoma. In addition to identifying a spatial neighborhood in the tdLN paracortex linked to poor prognosis, the researchers also identified a population of lymph node macrophages secreting PLA2G2D, which acted as an immune checkpoint that limited CD8+ T cell-mediated antitumor immunity. Blocking PLA2G2D reduced immunosuppression and enhanced antitumor immunity, resulting in reduced tumor growth, which could be further reduced in combination with anti-PD-1. PLA2G2D was also associated with poor prognosis in patient data.

    ABSTRACT: Systemic anti-tumour immunity results from T cell priming in tumour-draining lymph nodes (TDLNs)(1-4). Although the suppression of T cells in tumours is well characterized(5-8), whether this occurs in TDLNs-and if so, through which mechanisms-remains poorly understood. Here, using imaging mass cytometry of TDLNs from patients with melanoma, we identify a spatial neighbourhood in the TDLN paracortex that is linked to the development of distant metastases. Targeted spatial transcriptomics of cells inside this neighbourhood revealed activated CD8(+) T cells engaging with myeloid cells that expressed high levels of the immunosuppressive secretory phospholipase PLA2G2D. PLA2G2D(+) myeloid cells were substantially more abundant in TDLNs than they were in primary tumours or metastases. Genetic loss-of-function or antibody-mediated inhibition of PLA2G2D reduced tumour growth markedly, and single-cell transcriptomics in melanoma-bearing mice revealed that expression of Pla2g2d is confined to lymph-node macrophages. Mechanistically, PLA2G2D directly suppressed the early proliferation of T cells in vitro, and inhibiting PLA2G2D resulted in an expansion of tumour-specific T cells in TDLNs, leading to an increase in these T cells in the circulation and subsequently in tumours. Notably, PLA2G2D and PD-1 act as non-redundant immune checkpoints, with combination treatment showing additive or synergistic efficacy in humanized mice treated with human-specific antibodies. Collectively, our in-depth spatial profiling identifies PLA2G2D as a TDLN-centred targetable immune checkpoint for cancer immunotherapy.

    Author Info: (1) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam

    Author Info: (1) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (2) Apeximmune Therapeutics, Burlingame, CA, USA. (3) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (4) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. (5) Apeximmune Therapeutics, Burlingame, CA, USA. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA. (6) Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (7) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (8) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (9) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (10) Apeximmune Therapeutics, Burlingame, CA, USA. (11) Apeximmune Therapeutics, Burlingame, CA, USA. (12) Apeximmune Therapeutics, Burlingame, CA, USA. (13) Taipei Medical University, Taipei City, Taiwan. (14) Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. (15) Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. (16) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (17) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (18) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (19) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (20) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (21) Department of Haematology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (22) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (23) Department of Pathology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (24) Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, The Netherlands. (25) Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (26) Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (27) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (28) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Centre for Inflammation Research, Ghent, Belgium. Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. (29) Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (30) Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Department of Surgical Oncology, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (31) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. (32) Apeximmune Therapeutics, Burlingame, CA, USA. llee@apeximmune.com. (33) Apeximmune Therapeutics, Burlingame, CA, USA. klu@apeximmune.com. (34) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. r.stadhouders@erasmusmc.nl. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. r.stadhouders@erasmusmc.nl. (35) Department of Pulmonary Medicine, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. f.dammeijer@erasmusmc.nl. Erasmus MC Cancer Institute, Erasmus MC University Medical Centre, Rotterdam, The Netherlands. f.dammeijer@erasmusmc.nl.

    Citation: Nature 2026 Sep 9 Epub09/09/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42717091

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