Journal Articles

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

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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    A structure-informed deep learning framework for modeling TCR-peptide-HLA interactions

    (1) Cao K (2) Li R (3) Stra_ar M (4) Brown EM (5) Nguyen PNU (6) Pust MM (7) Park J (8) Graham DB (9) Ashenberg O (10) Uhler C (11) Xavier RJ

    Nature communications | Free PMC Article

    Cao et al. developed StriMap – a prediction framework for modeling peptide–HLA presentation and TCR recognition as a coupled process based on physicochemical, sequence-context, and structure-informed representations that capture relevant constraints. StriMap was successfully used to screen bacterial peptides and identity candidates to activate TCRs associated with ankylosing spondylitis (AS), and a top candidate in AS was also confirmed in IBD, linking the two autoimmune diseases. In cancer, StriMap demonstrated efficacy for both TCR selection in adoptive cell therapy, and prioritizing potential neoepitopes for personalized cancer vaccines.

    Contributed by Lauren Hitchings

    (1) Cao K (2) Li R (3) Stra_ar M (4) Brown EM (5) Nguyen PNU (6) Pust MM (7) Park J (8) Graham DB (9) Ashenberg O (10) Uhler C (11) Xavier RJ

    Nature communications | Free PMC Article

    Cao et al. developed StriMap – a prediction framework for modeling peptide–HLA presentation and TCR recognition as a coupled process based on physicochemical, sequence-context, and structure-informed representations that capture relevant constraints. StriMap was successfully used to screen bacterial peptides and identity candidates to activate TCRs associated with ankylosing spondylitis (AS), and a top candidate in AS was also confirmed in IBD, linking the two autoimmune diseases. In cancer, StriMap demonstrated efficacy for both TCR selection in adoptive cell therapy, and prioritizing potential neoepitopes for personalized cancer vaccines.

    Contributed by Lauren Hitchings

    ABSTRACT: The interaction between T cell receptors (TCRs), peptides, and human leukocyte antigens (HLAs) underlies antigen-specific T cell immunity. Despite substantial advances in peptide-HLA presentation prediction, accurate modeling of coupled TCR-peptide-HLA recognition remains underdeveloped, limiting applications such as TCR and neoepitope prioritization in cancer and antigen identification in autoimmunity. Here we present StriMap, a unified framework for predicting TCR-peptide-HLA interactions by integrating physicochemical, sequence-context, and structural features at recognition interfaces. StriMap achieves state-of-the-art performance with improved generalizability and enables applications in both cancer and autoimmunity. As a case study in ankylosing spondylitis (AS), we screened 13 million peptides derived from 43,241 bacterial proteins and identified candidate molecular mimics that were experimentally validated to activate T cells expressing an AS-associated TCR. Notably, a top validated peptide was enriched in patients with inflammatory bowel disease (IBD), suggesting potential shared microbial triggers between AS and IBD. Overall, StriMap provides a generalizable framework for rational immunotherapy design and for dissecting antigenic drivers of autoimmunity.

    Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (2) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massach

    Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (2) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (3) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (4) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (5) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (6) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (7) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (8) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (9) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States. (10) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Massachusetts Institute of Technology, Cambridge, MA, United States. (11) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States. Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, United States.

    Citation: Nat com 09/25/26

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41959488

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    Peripheral Blood as the Sole Source for Cancer Neoantigen and Reactive T-Cell Discovery

    (1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

    Cancer discovery

    To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

    Contributed by Ute Burkhardt

    (1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

    Cancer discovery

    To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

    Contributed by Ute Burkhardt

    ABSTRACT: Neoantigen-targeted T-cell therapies require invasive tumor biopsies to identify neoantigens and reactive T cells, limiting their applicability and potentially underestimating tumor heterogeneity. We propose a novel strategy relying solely on peripheral blood to identify non-synonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 co-expression. Our method identified most neoantigens and increased the number of T-cell reactivities detected by standard biopsy-based techniques in an initial cohort of eight metastatic cancer patients. Critically, our approach uncovered additional neoantigens missed by tumor biopsy analysis, highlighting the potential for broader neoantigen targeting using liquid biopsies. Analysis of a cohort of 69 metastatic cancer patients revealed that approximately half could be eligible for our blood-only approach. This proof-of-concept study demonstrates the potential of using blood as a surrogate or complement for tumor biopsies to develop neoantigen-reactive T-cell therapies against a broader spectrum of neoantigens.

    Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://

    Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (3) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (4) Vall d'Hebron Institute of Oncology Spain. ROR: https://ror.org/054xx3904 (5) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (6) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (7) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (8) Universitat Aut˜noma de Barcelona Barcelona, Barcelona Spain. ROR: https://ror.org/052g8jq94 (9) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (10) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (11) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (12) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (13) National Institutes of Health United States. ROR: https://ror.org/01cwqze88 (14) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (15) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (16) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (17) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (18) Instituto de Investigaci—n Sanitaria Arag—n Zaragoza Spain. ROR: https://ror.org/03njn4610 (19) Stanford University Stanford, CA United States. ROR: https://ror.org/00f54p054 (20) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (21) Vall d'Hebron Institute of Oncology barcelona, barcelona, spain Spain. ROR: https://ror.org/054xx3904 (22) Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain. (23) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (24) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (25) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (26) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (27) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (28) Institut d'Investigaci— BiomŽdica de Bellvitge L'Hospitalet de Llobregat Spain. ROR: https://ror.org/0008xqs48 (29) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (30) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (31) Centre Hospitalier de l'UniversitŽ de MontrŽal Montreal Canada. ROR: https://ror.org/0410a8y51 (32) The Francis Crick Institute London United Kingdom. ROR: https://ror.org/04tnbqb63 (33) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (34) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (35) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904

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

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42806482

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

    (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

    (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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    Five-year survival with neoadjuvant therapy in melanoma: updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)

    (1) Long GV (2) Pires da Silva I (3) Perry KA (4) Romano J (5) Lo SN (6) Grover P (7) Ascierto PA (8) Amaria RN (9) Hieken TJ (10) Robert C (11) Heinzerling L (12) Sandhu S (13) Barros M (14) Mitchell TC (15) Eroglu Z (16) Samoylenko IV (17) Flatz L (18) LebbŽ C (19) Johnson DB (20) Rutkowski P (21) Mu–oz-Couselo E (22) Hamid O (23) Trojaniello C (24) Mallardo D (25) Block MS (26) Hammoudi N (27) Benannoune N (28) Tomsitz D (29) Wang Y (30) Dinckal C (31) Kuzmenko A (32) Forschner A (33) Carlino MS (34) Jalving M (35) Postow MA (36) Ferrucci PF (37) Kapiteijn E (38) van der Veldt AAM (39) Suijkerbuijk KPM (40) da Meda L (41) Burnette H (42) Czarnekca A (43) Mehmi I (44) Hospers G (45) Lochrin S (46) van Akkooi ACJ (47) Tawbi HA (48) Burton EM (49) Tetzlaff MT (50) Wiel BAV (51) Rawson RV (52) Blank CU (53) Menzies AM

    Nature medicine

    Long et al. performed a pooled analysis of long-term efficacy of neoadjuvant ICB and targeted therapies in stage IIIB-D melanoma. Pathological response was higher for ICB than for BRAF/MEKis, and higher for combination ICB than anti-PD-1 alone. Pathological response was associated with event-free, recurrence-free, and overall survival. Patients who had a pathological response to neoadjuvant ICB did not benefit from adjuvant ICB.

    (1) Long GV (2) Pires da Silva I (3) Perry KA (4) Romano J (5) Lo SN (6) Grover P (7) Ascierto PA (8) Amaria RN (9) Hieken TJ (10) Robert C (11) Heinzerling L (12) Sandhu S (13) Barros M (14) Mitchell TC (15) Eroglu Z (16) Samoylenko IV (17) Flatz L (18) LebbŽ C (19) Johnson DB (20) Rutkowski P (21) Mu–oz-Couselo E (22) Hamid O (23) Trojaniello C (24) Mallardo D (25) Block MS (26) Hammoudi N (27) Benannoune N (28) Tomsitz D (29) Wang Y (30) Dinckal C (31) Kuzmenko A (32) Forschner A (33) Carlino MS (34) Jalving M (35) Postow MA (36) Ferrucci PF (37) Kapiteijn E (38) van der Veldt AAM (39) Suijkerbuijk KPM (40) da Meda L (41) Burnette H (42) Czarnekca A (43) Mehmi I (44) Hospers G (45) Lochrin S (46) van Akkooi ACJ (47) Tawbi HA (48) Burton EM (49) Tetzlaff MT (50) Wiel BAV (51) Rawson RV (52) Blank CU (53) Menzies AM

    Nature medicine

    Long et al. performed a pooled analysis of long-term efficacy of neoadjuvant ICB and targeted therapies in stage IIIB-D melanoma. Pathological response was higher for ICB than for BRAF/MEKis, and higher for combination ICB than anti-PD-1 alone. Pathological response was associated with event-free, recurrence-free, and overall survival. Patients who had a pathological response to neoadjuvant ICB did not benefit from adjuvant ICB.

    ABSTRACT: Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB-D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs (n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF-mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.

    Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Faculty of Health and Medicine, The University of Sydne

    Author Info: (1) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Faculty of Health and Medicine, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia. georgina.long@sydney.edu.au. (2) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. Champalimaud Foundation, Lisbon, Portugal. (3) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (4) Tygat Institute for Intestinal and Liver Research, Amsterdam UMC, Amsterdam, The Netherlands. (5) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. (6) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Fiona Stanley Hospital, University of Western Australia, Perth, Western Australia, Australia. (7) Universitˆ degli Studi di Napoli 'Federico II', Naples, Italy. Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (8) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. (10) Gustave Roussy, DŽpartement de MŽdecine Oncologique, UniversitŽ Paris-Saclay, Villejuif, France. (11) LMU University Hospital, Munich, Germany. (12) Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (13) Centro de Referncia em Tumores Cut‰neos, AC Camargo Cancer Center, S‹o Paulo, Brazil. (14) Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (16) FSBI 'N. N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. (17) University of TŸbingen, TŸbingen, Germany. (18) UniversitŽ Paris Cite, AP-HP Dermato-oncology and CIC, Cancer Institute APHP.nord Paris citŽ, INSERM U1342-Equipe-CNRS EMR8000, Saint Louis Hospital, Paris, France. (19) Vanderbilt University Medical Center, Nashville, TN, USA. (20) Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. (21) Vall d'Hebr—n Hospital and Vall d'Hebr—n Institute of Oncology (VHIO), Barcelona, Spain. (22) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (23) Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (24) Istituto Nazionale Tumori IRCCS Fondazione 'G. Pascale', Naples, Italy. (25) Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA. (26) Gustave Roussy, DŽpartement de MŽdecine Oncologique, UniversitŽ Paris-Saclay, Villejuif, France. (27) Gustave Roussy, DŽpartement de MŽdecine Oncologique, UniversitŽ Paris-Saclay, Villejuif, France. (28) LMU University Hospital, Munich, Germany. (29) Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. (30) H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. (31) FSBI 'N. N. Blokhin National Medical Research Center of Oncology' of the Ministry of Health of the Russian Federation, Moscow, Russian Federation. (32) University of TŸbingen, TŸbingen, Germany. (33) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia. (34) University Medical Center Groningen, Groningen, The Netherlands. (35) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (36) European Institute of Oncology, IRCCS Milan, Milan, Italy. (37) Leiden University Medical Center, Leiden, The Netherlands. (38) Erasmus Medical Center, Rotterdam, The Netherlands. (39) University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. (40) UniversitŽ Paris Cite, AP-HP Dermato-oncology and CIC, Cancer Institute APHP.nord Paris citŽ, INSERM U1342-Equipe-CNRS EMR8000, Saint Louis Hospital, Paris, France. (41) Vanderbilt University Medical Center, Nashville, TN, USA. (42) Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. (43) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (44) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (45) Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. (46) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. (47) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (48) University of Texas MD Anderson Cancer Center, Houston, TX, USA. (49) University of California San Francisco, San Francisco, CA, USA. (50) Netherlands Cancer Institute, Amsterdam, The Netherlands. (51) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. NSW Health Pathology, Sydney, New South Wales, Australia. (52) Leiden University Medical Center, Leiden, The Netherlands. University Clinic Regensburg, Regensburg, Germany. European Institute of Oncology, Milan, Italy. (53) Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia. Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia. Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.

    Citation: Nat Med 2026 Oct 1 Epub10/01/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42823486

    Tags:

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

    (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

    Tags:

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

    Spotlight 

    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

    Tags:

      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

      Tags:

      Computational design of optimized and preferentially paired human TCR constant regions for improved T cell function Spotlight 

      (1) Radman M (2) Shamul-Raybi A (3) Parker J (4) Fleishman SJ (5) Cohen CJ

      Science advances | Free PMC Article

      Using a computational strategy, Radman et al. mutated the constant and transmembrane regions of the MART-1 DMF4 TCR α/β chains to reduce mispairing and improve expression. TCR variants were found that increased expression and TNFα production against MART-1+ cells compared to the WT TCR, and the modified α/β chains expressed better together than with their WT counterparts. Modified TCR-T cells generated by retroviral vector had superior cytokine production to WT TCR-T (in bulk T cells and CD4+ or CD8+ T cells), as well as cytotoxicity and in vivo efficacy. This same strategy was successfully applied to other antitumor and antiviral TCRs.

      Contributed by Alex Najibi

      (1) Radman M (2) Shamul-Raybi A (3) Parker J (4) Fleishman SJ (5) Cohen CJ

      Science advances | Free PMC Article

      Using a computational strategy, Radman et al. mutated the constant and transmembrane regions of the MART-1 DMF4 TCR α/β chains to reduce mispairing and improve expression. TCR variants were found that increased expression and TNFα production against MART-1+ cells compared to the WT TCR, and the modified α/β chains expressed better together than with their WT counterparts. Modified TCR-T cells generated by retroviral vector had superior cytokine production to WT TCR-T (in bulk T cells and CD4+ or CD8+ T cells), as well as cytotoxicity and in vivo efficacy. This same strategy was successfully applied to other antitumor and antiviral TCRs.

      Contributed by Alex Najibi

      ABSTRACT: T cell receptor (TCR) gene transfer is a promising approach for cancer immunotherapy, but its efficacy is limited by mispairing of TCR chains, which reduces surface expression and may generate off-target specificities. We applied the PROSS and FuncLib algorithms to engineer human TCR constant regions for improved stability and preferential pairing. After several screening rounds, we identified a variant, termed structurally enhanced TCR (SET), that exhibited markedly enhanced surface expression, functional avidity, and reduced mispairing. SET-expressing T cells secreted higher cytokine levels, displayed increased activation, and mediated superior cytotoxicity. Notably, SET demonstrated function in CD4(+) T cells and mediated potent tumor control in xenograft models, significantly delaying tumor growth and improving survival. SET's benefits were reproducible across six different TCRs, supporting its broad applicability. These findings highlight the potential of rational design to improve the potency of TCR-based therapies.

      Author Info: (1) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (2) The Laboratory of Tumor

      Author Info: (1) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (2) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (3) Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. (5) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.

      Citation: Sci Adv 2026 Sep 25 12:eaeb9189 Epub09/23/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42777048

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