Journal Articles

Radiotherapy synergizes with an inducible AAV-based immunotherapy platform to program local and systemic antitumor immunity

Spotlight 

Sonia Marco 1; Myriam Fernández 1; Beatriz Honorato 1; Nerea Juanarena 1; Cristina Sainz 1; Ainhoa Andueza 1; David J. Gould 2; Seth Anderson 3; Carlos de Andrea 4,5 Paulo Pérez Domínguez 4,5 Paolo Wong 1; Carlos Vásquez 1; Irene Narinda 1; Carmen Unzu 6; Sergio Isola 6; Beatriz Tavira 1; Mikel Ariz 7; Gracián Camps 4,8; Miguel F. Sanmamed 4,8,9; Julián Pardo 10; Sara Labiano 1,4,11; Marta M. Alonso 1,4,11; Javier Marco-Sanz 1,4,11; Elizabeth Guruceaga 4,12; María Collantes 3,13; Jon Ander Simón 4,13; Iván Peñuelas 4,13; Joaquín Fernández-Irigoyen 14; Enrique Santamaría 14; Jesús Prieto 1,15; Juan Dubrot 1,15,16.

Cancer Cell

Marco et al. sought to expand the utility of immunizing radiation (IR) therapy by intratumorally delivering agents to remodel the tumor immune microenvironment (TIME). After observing that IR enhanced transduction of tumor cells by adeno-associated viruses (AAVs), a known durable and safe gene delivery system, AAVs were engineered to express IL-12 under the control of a type I interferon promoter (as IFN-I is highly induced in tumors by IR). Tumor irradiation followed rapidly by AAV injection led to enhanced local IL-12 expression, remodeled the TIME, and induced robust synergistic tumor elimination in multiple models, primarily through FAS-FASL cytotoxicity.

Contributed by Ed Fritsch

Sonia Marco 1; Myriam Fernández 1; Beatriz Honorato 1; Nerea Juanarena 1; Cristina Sainz 1; Ainhoa Andueza 1; David J. Gould 2; Seth Anderson 3; Carlos de Andrea 4,5 Paulo Pérez Domínguez 4,5 Paolo Wong 1; Carlos Vásquez 1; Irene Narinda 1; Carmen Unzu 6; Sergio Isola 6; Beatriz Tavira 1; Mikel Ariz 7; Gracián Camps 4,8; Miguel F. Sanmamed 4,8,9; Julián Pardo 10; Sara Labiano 1,4,11; Marta M. Alonso 1,4,11; Javier Marco-Sanz 1,4,11; Elizabeth Guruceaga 4,12; María Collantes 3,13; Jon Ander Simón 4,13; Iván Peñuelas 4,13; Joaquín Fernández-Irigoyen 14; Enrique Santamaría 14; Jesús Prieto 1,15; Juan Dubrot 1,15,16.

Cancer Cell

Marco et al. sought to expand the utility of immunizing radiation (IR) therapy by intratumorally delivering agents to remodel the tumor immune microenvironment (TIME). After observing that IR enhanced transduction of tumor cells by adeno-associated viruses (AAVs), a known durable and safe gene delivery system, AAVs were engineered to express IL-12 under the control of a type I interferon promoter (as IFN-I is highly induced in tumors by IR). Tumor irradiation followed rapidly by AAV injection led to enhanced local IL-12 expression, remodeled the TIME, and induced robust synergistic tumor elimination in multiple models, primarily through FAS-FASL cytotoxicity.

Contributed by Ed Fritsch

ABSTRACT: Radiotherapy (RT) can prime the immune system against cancer but often fails to generate effective antitumor responses due to concomitant induction of immunosuppressive factors. To overcome this limitation, we built upon the observation that RT enhances adeno-associated vectors (AAVs) tumor transduction through the epigenetic modification of vector episomes. We designed an AAV-based platform to deliver immunostimulatory cytokines through an interferon (IFN)-inducible promoter that allows for spatial control of transgene expression into irradiated tumors. As opposed to a constitutive system, local delivery of a vector encoding for inducible IL-12 (AAV-iIL12) achieves an efficient production of the cytokine without significant toxicity. Combination of RT and AAV-iIL12 generates a highly immunostimulatory tumor microenvironment (TME) leading to robust local and systemic antitumor responses in an IFNγ- and FAS-dependent manner, able to overcome common immune-evasion mechanisms. Our work shows that radiation coupled with AAV-based immune-gene delivery is an efficient and safe approach to treat cancer.

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Citation: Epub

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    Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma Spotlight 

    (1) Peng J (2) Yang J (3) Antonopoulou G (4) Fang R (5) Adhikari B (6) Vogt M (7) Wolf E (8) Sun C (9) Du S (10) Godfrey L (11) Gupta A (12) Trajkovic-Arsic M (13) Teichmann N (14) GrŸnwald BT (15) Krebs N (16) Steiger K (17) Mogler C (18) Althoff K (19) Wang X (20) Giglio G (21) Liffers ST (22) Savvatakis K (23) Braren R (24) Lawlor RT (25) Scarpa A (26) Behrens D (27) Lang KS (28) Cheung PF (29) Siveke JT

    Nature communications | Free PMC Article

    Peng, Yang, Antonopoulou, et al. found that in human PDAC, high expression of GATA6 correlated with increased MHC-I expression, immune cell infiltration, and interactions with CD8+ T cells. In murine tumor lines, MEK inhibition (MEKi) further increased MHC-I expression in GATA6high tumor cells, leading to enhanced T cell cytotoxicity against them, while GATA6 knockout or degradation abrogated this effect. In vivo, high GATA6 expression was required for MEKi-induced tumor control, but long-term treatment reduced GATA6+ cells and increased immunosuppressive EMT, which could be overcome by combining MEKi with HDAC inhibitors.

    Contributed by Lauren Hitchings

    (1) Peng J (2) Yang J (3) Antonopoulou G (4) Fang R (5) Adhikari B (6) Vogt M (7) Wolf E (8) Sun C (9) Du S (10) Godfrey L (11) Gupta A (12) Trajkovic-Arsic M (13) Teichmann N (14) GrŸnwald BT (15) Krebs N (16) Steiger K (17) Mogler C (18) Althoff K (19) Wang X (20) Giglio G (21) Liffers ST (22) Savvatakis K (23) Braren R (24) Lawlor RT (25) Scarpa A (26) Behrens D (27) Lang KS (28) Cheung PF (29) Siveke JT

    Nature communications | Free PMC Article

    Peng, Yang, Antonopoulou, et al. found that in human PDAC, high expression of GATA6 correlated with increased MHC-I expression, immune cell infiltration, and interactions with CD8+ T cells. In murine tumor lines, MEK inhibition (MEKi) further increased MHC-I expression in GATA6high tumor cells, leading to enhanced T cell cytotoxicity against them, while GATA6 knockout or degradation abrogated this effect. In vivo, high GATA6 expression was required for MEKi-induced tumor control, but long-term treatment reduced GATA6+ cells and increased immunosuppressive EMT, which could be overcome by combining MEKi with HDAC inhibitors.

    Contributed by Lauren Hitchings

    ABSTRACT: GATA6 promotes epithelial phenotypes and limits epithelial-to-mesenchymal (EMT) transition in pancreatic ductal adenocarcinoma (PDAC). Here we show that GATA6 defines a tumor cell state that induces MHCI expression and anti-tumor cytotoxicity upon therapy. In human PDAC, GATA6 expression correlates with immune cell infiltration, and spatial analysis reveals interaction between GATA6(+) tumor cells and CD8(+) T cells. In murine PDAC, MEK inhibition (MEKi) enriches antigenicity-related gene sets in GATA6(high) cells, while GATA6 knockout or degradation impairs MEKi-induced MHCI upregulation. High-GATA6 tumors respond to MEKi with increased MHCI, enhancing T-cell cytotoxicity, whereas GATA6 loss abolishes this effect. Treatment-induced EMT reduces GATA6(+) populations and MHCI expression, which is restored by combining MEKi with HDAC inhibitors, enhancing GATA6(+) tumor cells, MHCI, CD8(+) T cell infiltration, tumor suppression, and survival. These findings suggest that therapeutic strategies promoting a GATA6-driven tumor cell state improve immune recognition of PDAC cells and potentiate anti-tumor cytotoxic effects.

    Author Info: (1) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University

    Author Info: (1) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. (2) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (3) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (4) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (5) Institute of Biochemistry, University of Kiel, Kiel, Germany. (6) Institute of Biochemistry, University of Kiel, Kiel, Germany. (7) Institute of Biochemistry, University of Kiel, Kiel, Germany. (8) Division Immune Regulation in Cancer, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany. (9) Division Immune Regulation in Cancer, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany. (10) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (11) Department of Internal Medicine II, Klinikum rechts der Isar der Technischen UniversitŠt MŸnchen, Munich, Germany. (12) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (13) Department of Internal Medicine II, Klinikum rechts der Isar der Technischen UniversitŠt MŸnchen, Munich, Germany. (14) German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. Department of Urology, West German Cancer Center, University Hospital Essen, Essen, Germany. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (15) German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. Department of Urology, West German Cancer Center, University Hospital Essen, Essen, Germany. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. (16) Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (17) Institute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany. German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. (18) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (19) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (20) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (21) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (22) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. (23) German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany. School of Medicine and Health, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany, Department of Diagnostic and Interventional Radiology and Department of Nuclear Medicine, University Medical Center Hamburg Eppendorf, Hamburg, Germany. (24) Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy. ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. (25) ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy. Department of Diagnostics and Public Health, University of Verona, Verona, Italy. (26) EPO - Experimental Pharmacology and Oncology GmbH, Berlin, Germany. (27) Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany. (28) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. f.cheung@dkfz-heidelberg.de. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. f.cheung@dkfz-heidelberg.de. Spatiotemporal tumor heterogeneity, DKTK, partner site Essen, a partnership between DKFZ and University Hospital Essen, Essen, Germany. f.cheung@dkfz-heidelberg.de. (29) Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. j.siveke@dkfz.de. German Cancer Consortium (DKTK), partner site Essen, a partnership between German Cancer Research Center (DKFZ) and University Hospital Essen, Essen, Germany. j.siveke@dkfz.de. National Center for Tumor Diseases (NCT) West, Campus Essen, Essen, Germany. j.siveke@dkfz.de.

    Citation: Nat Commun 2026 Feb 6 17:1476 Epub02/06/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41651844

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    Meningeal blood vessel blockage enhances anti-glioblastoma immunity Spotlight 

    (1) Gao Y (2) Peng Y (3) Cheng J (4) Zhang X (5) Zhong J (6) Lu C (7) Xing X (8) Lai Y (9) Sun H (10) Zeng X (11) Liu Z (12) He K (13) Liu X (14) Xiao F (15) Wang X (16) Bai F (17) Zhang N

    Cell

    Gao, Peng, Cheng, Zhang, et al. found that surgically blocking the meningeal blood vessel hindered GBM progression in mice by restricting access to the dura mater by circulation-derived border-associated macrophages (cBAM). This reduced competition for CSF-1 and increasing expansion of resident BAMs (rBAMs), which showed enhanced antigen presentation and activation of antitumor T cells, dependent on their high expression of FcRn. The addition of CSF-1 or anti-PD-1 enhanced this antitumor effect. In patient samples, rBAM abundance correlated with increased intratumoral T cell activity and better survival outcomes.

    Contributed by Lauren Hitchings

    (1) Gao Y (2) Peng Y (3) Cheng J (4) Zhang X (5) Zhong J (6) Lu C (7) Xing X (8) Lai Y (9) Sun H (10) Zeng X (11) Liu Z (12) He K (13) Liu X (14) Xiao F (15) Wang X (16) Bai F (17) Zhang N

    Cell

    Gao, Peng, Cheng, Zhang, et al. found that surgically blocking the meningeal blood vessel hindered GBM progression in mice by restricting access to the dura mater by circulation-derived border-associated macrophages (cBAM). This reduced competition for CSF-1 and increasing expansion of resident BAMs (rBAMs), which showed enhanced antigen presentation and activation of antitumor T cells, dependent on their high expression of FcRn. The addition of CSF-1 or anti-PD-1 enhanced this antitumor effect. In patient samples, rBAM abundance correlated with increased intratumoral T cell activity and better survival outcomes.

    Contributed by Lauren Hitchings

    ABSTRACT: The dura mater, the outermost meningeal layer that samples and presents central nervous system (CNS)-derived antigens, is a pivotal interface for CNS immunosurveillance. Here, we show that meningeal blood vessel blockage effectively suppresses glioblastoma (GBM) progression in murine models. Single-cell profiling of dura reveals a resident border-associated macrophage (rBAM) subset characterized by high neonatal Fc receptor expression, which endows rBAMs with superior capacity for presenting tumor antigens and activating CNS-patrolling T cells. Meningeal blood vessel blockage preserves dural cerebrospinal fluid (CSF)-1 levels by restricting circulation-derived BAM (cBAM) and expands the rBAM pool, thereby enhancing T cell activation at the dura interface and amplifying intratumoral cytotoxic T cell responses. Clinically, rBAM abundance positively correlates with GBM patient survival. Our findings show that the dura is a critical regulator of anti-tumor immunity in CNS cancers and propose that meningeal blood vessel blockage may be a surgical strategy to potentiate GBM immunotherapy.

    Author Info: (1) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function a

    Author Info: (1) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (2) Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University (PKU), Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. (3) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (4) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (5) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (6) Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu, China. (7) Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University (PKU), Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. (8) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (9) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (10) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (11) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (12) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (13) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. (14) Department of Scientific Research Section, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China. (15) National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, Jiangsu, China. (16) Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University (PKU), Beijing, China; Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China. Electronic address: fbai@pku.edu.cn. (17) Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, Guangdong, China. Electronic address: zhangnu2@mail.sysu.edu.cn.

    Citation: Cell 2026 Feb 4 Epub02/04/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41643677

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    DCC-2036 induces repolarization of TAMs to M1 type and enhances CD8+ T cell immunity in TNBC

    Spotlight 

    (1) Liang Y (2) Zeng Q (3) Xiao M (4) Li P (5) He R (6) Chen Z (7) Liu J (8) Cao J (9) Li J (10) Yin L (11) Zhong J (12) Chen X (13) Feng J (14) He J (15) Chen X (16) Zu X (17) Shen Y

    Molecular therapy | Free PMC Article

    Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.

    Contributed by Shishir Pant

    (1) Liang Y (2) Zeng Q (3) Xiao M (4) Li P (5) He R (6) Chen Z (7) Liu J (8) Cao J (9) Li J (10) Yin L (11) Zhong J (12) Chen X (13) Feng J (14) He J (15) Chen X (16) Zu X (17) Shen Y

    Molecular therapy | Free PMC Article

    Liang and Zeng et al. showed that small-molecule tyrosine kinase inhibitor DCC-2036 repolarized TAMs from an “M2” to an “M1” phenotype and enhanced antitumor CD8+ T cell immunity in a 4T1 TNBC tumor model. DCC-2036 selectively targeted hematopoietic cell kinase (HCK) and reprogrammed TAM metabolism from oxidative phosphorylation to glycolysis via the HCK-AKT/mTOR-GS-HIF1α axis. DCC-2036-mediated TAM repolarization to an M1 phenotype, decreased IL-10 production and secretion, enhanced antitumor CD8+ T cell immunity, and sensitized 4T1 tumors to immune checkpoint therapy.

    Contributed by Shishir Pant

    ABSTRACT: Therapies for triple-negative breast cancer (TNBC) still need innovative approaches, while repolarizing tumor-associated macrophages (TAMs) may offer a breakthrough in the targeted therapy and immunotherapy of TNBC. In this study, our group found that the small-molecule tyrosine kinase inhibitor DCC-2036 could induce repolarization of TAMs from M2 to M1 type and enhance anti-tumor CD8+ T cell immunity in TNBC. Mechanistically, targeting inhibition of the non-receptor tyrosine kinase hematopoietic cell kinase (HCK) in TAMs regulated the downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-glutamine synthetase (GS)-HIF1α signaling pathway, leading to a reprogramming of TAM metabolism from oxidative phosphorylation to glycolysis. This metabolic shift repolarized TAMs to the M1 phenotype, resulting in a decrease in interleukin (IL)-10 secretion, which enhanced the immune response of anti-tumor CD8+ T cells and increased the sensitivity of TNBC to immune checkpoint blockade therapy. This project uncovers a previously unrecognized anti-tumor mechanism of DCC-2036 and proposes a combination strategy that utilizes DCC-2036 alongside immune checkpoint inhibitors to improve TNBC immunotherapy.

    Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of

    Author Info: (1) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (2) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (3) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (4) Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (5) Department of Pathology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (6) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (7) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (8) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (9) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (10) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (11) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (12) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (13) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (14) Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421002, China. (15) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. (16) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: zuxuyu@usc.edu.cn. (17) Cancer Research Institute, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. Electronic address: shenyingying1113@usc.edu.cn.

    Citation: Mol Ther 2026 Feb 4 34:985-1008 Epub10/24/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41137391

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    Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling

    Spotlight 

    (1) van Haften FJ (2) van der Sluis TC (3) Hepp HS (4) MŸlling N (5) Nadafi R (6) Sampadi B (7) van Duikeren S (8) Mostert JS (9) van der Sterre R (10) van Veelen PA (11) Heieis GA (12) Veerkamp DMB (13) Wesselink TH (14) Vleeshouwers W (15) Beijnes M (16) Pardieck IN (17) van Horssen ELF (18) de Groot AF (19) van der Ploeg M (20) Kroep JR (21) de Miranda NFCC (22) van der Zanden SY (23) Neefjes J (24) Mei H (25) Vertegaal ACO (26) Everts B (27) van der Burg SH (28) Arens R

    Nature immunology

    Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.

    Contributed by Shishir Pant

    (1) van Haften FJ (2) van der Sluis TC (3) Hepp HS (4) MŸlling N (5) Nadafi R (6) Sampadi B (7) van Duikeren S (8) Mostert JS (9) van der Sterre R (10) van Veelen PA (11) Heieis GA (12) Veerkamp DMB (13) Wesselink TH (14) Vleeshouwers W (15) Beijnes M (16) Pardieck IN (17) van Horssen ELF (18) de Groot AF (19) van der Ploeg M (20) Kroep JR (21) de Miranda NFCC (22) van der Zanden SY (23) Neefjes J (24) Mei H (25) Vertegaal ACO (26) Everts B (27) van der Burg SH (28) Arens R

    Nature immunology

    Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.

    Contributed by Shishir Pant

    ABSTRACT: Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8(+) T cells that undergo synchronized proliferation and differentiation. How CD8(+) T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8(+) T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8(+) T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8(+) T cells following arrest. Transient arrest in vivo enables superior CD8(+) T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8(+) T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

    Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. De

    Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (4) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (5) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (6) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (7) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (8) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (9) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (10) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (11) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (12) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (13) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (14) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (15) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (16) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (17) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (18) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (19) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (20) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (21) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (22) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (23) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (24) Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands. (25) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (26) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (27) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (28) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. r.arens@lumc.nl.

    Citation: Nat Immunol 2026 Jan 19 Epub01/19/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41555086

    Tags:

    Pseudomonas aeruginosa induces tumor pyroptosis and immune activation to enhance checkpoint blockade in colorectal cancer Spotlight 

    (1) Hu Y (2) Li R (3) Feng J (4) Sun N (5) Zheng W (6) Jin X (7) Wang G (8) He Y (9) Hao Y (10) Zhang J (11) Ren K (12) Wu X

    Cancer immunology, immunotherapy | Free PMC Article

    Hu et al. demonstrated that Pseudomonas aeruginosa (P.a) initiates caspase-3-dependent apoptosis in MC38 CRC cell lines. Pyroptosis – characterized by GSDME cleavage, intracellular ROS accumulation, and release of damage-associated molecular patterns, such as HMGB1 – is a form of immunogenic cell death that induces inflammatory cytokine secretion, PD-L1 upregulation on tumor cells, and functional maturation of dendritic cells in vitro. Intratumoral injection of P.a reprogrammed TMEs, increased CD8+ T cell infiltration, and led to synergistic tumor regression, without systemic toxicity when combined with anti-PD-L1 in an MC38 tumor model.

    Contributed by Shishir Pant

    (1) Hu Y (2) Li R (3) Feng J (4) Sun N (5) Zheng W (6) Jin X (7) Wang G (8) He Y (9) Hao Y (10) Zhang J (11) Ren K (12) Wu X

    Cancer immunology, immunotherapy | Free PMC Article

    Hu et al. demonstrated that Pseudomonas aeruginosa (P.a) initiates caspase-3-dependent apoptosis in MC38 CRC cell lines. Pyroptosis – characterized by GSDME cleavage, intracellular ROS accumulation, and release of damage-associated molecular patterns, such as HMGB1 – is a form of immunogenic cell death that induces inflammatory cytokine secretion, PD-L1 upregulation on tumor cells, and functional maturation of dendritic cells in vitro. Intratumoral injection of P.a reprogrammed TMEs, increased CD8+ T cell infiltration, and led to synergistic tumor regression, without systemic toxicity when combined with anti-PD-L1 in an MC38 tumor model.

    Contributed by Shishir Pant

    ABSTRACT: Colorectal cancer (CRC) exhibits limited responsiveness to immune checkpoint inhibitors (ICIs), largely due to its immunosuppressive tumor microenvironment (TME) and poor baseline immunogenicity. Here, we report that Pseudomonas aeruginosa (P. aeruginosa) triggers caspase-3-dependent pyroptosis in murine CRC MC38 cells, characterized by GSDME cleavage, intracellular reactive oxygen species (ROS) accumulation, and the release of damage-associated molecular patterns (DAMPs). This form of immunogenic cell death promotes robust inflammatory cytokine secretion, upregulation of PD-L1 on tumor cells, and functional maturation of bone marrow-derived dendritic cells (BMDCs) in vitro. In vivo, intratumoral injection of P. aeruginosa leads to significant reprogramming of the TME, including increased expression of proinflammatory genes, DC maturation, and enhanced infiltration of CD8(+) T lymphocytes. Notably, combination therapy with P. aeruginosa and an anti-PD-L1 antibody results in synergistic tumor regression, markedly outperforming either monotherapy, without inducing detectable systemic toxicity. Together, our findings reveal that P. aeruginosa-induced pyroptosis serves as a potent immunogenic stimulus that reshapes the CRC tumor microenvironment and overcomes resistance to immune checkpoint blockade. This strategy represents a promising approach to enhance immunotherapy efficacy in poorly immunogenic solid tumors.

    Author Info: (1) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (2) Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, 610500,

    Author Info: (1) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (2) Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, 610500, China. (3) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (4) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. (5) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (6) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. (7) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. (8) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. (9) Taishan Community Health Service Center, Jiangbei New District, Nanjing, 210032, China. (10) Department of Neurology, Xindu District People's Hospital of Chengdu, Chengdu, 610500, China. 501838695@qq.com. (11) Department of Clinical Microbiology, School of Laboratory Medicine, Chengdu Medical College, Clinical IVD Joint Research Center of Chengdu Medical College-Maccura Biotechnology, Chengdu, 610500, China. renke@cmc.edu.cn. Sichuan Provincial Engineering Laboratory for Prevention and Control Technology of Veterinary Drug Residue in Animal-Origin Food, Chengdu Medical College, Chengdu, 610500, China. renke@cmc.edu.cn. (12) The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, 210032, China. 2608236988@qq.com.

    Citation: Cancer Immunol Immunother 2026 Jan 3 75:32 Epub01/03/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41484455

    Tags:

    Physical activity decreases cancer burden by alleviating immunosenescence-related inflammation and improving overall immunity Spotlight 

    (1) Jin Y (2) Yang Z (3) Li Z (4) Ding Z (5) Zhang X (6) Zeng H (7) Fang L (8) Shi Y (9) Xing P (10) Liu W (11) Chen H (12) Jing C (13) Cao G

    Cell reports. Medicine

    In participants in the UK Biobank and a US National Survey, inflammation scores increased with age and in cases of chronic health conditions, and correlated positively with cancer incidence and mortality. 8 cancers were identified as inflammation-related, and aerobic physical activity correlated negatively with inflammation and cancer mortality. In C57 mice and Syrian hamsters, exercise impacted expression of genes associated with senescence, innate/adaptive immunity, and apoptosis, and boosted anti-inflammatory serum cytokines, compared to non-exercised controls. Mki67+ B and T cells had particularly high senescence-related gene scores.

    Contributed by Alex Najibi

    (1) Jin Y (2) Yang Z (3) Li Z (4) Ding Z (5) Zhang X (6) Zeng H (7) Fang L (8) Shi Y (9) Xing P (10) Liu W (11) Chen H (12) Jing C (13) Cao G

    Cell reports. Medicine

    In participants in the UK Biobank and a US National Survey, inflammation scores increased with age and in cases of chronic health conditions, and correlated positively with cancer incidence and mortality. 8 cancers were identified as inflammation-related, and aerobic physical activity correlated negatively with inflammation and cancer mortality. In C57 mice and Syrian hamsters, exercise impacted expression of genes associated with senescence, innate/adaptive immunity, and apoptosis, and boosted anti-inflammatory serum cytokines, compared to non-exercised controls. Mki67+ B and T cells had particularly high senescence-related gene scores.

    Contributed by Alex Najibi

    ABSTRACT: The associations between physical activity (PA) and the incidence and mortality of cancers and their underlying mechanisms remain largely unknown. Using mutually verifiable cohort studies with 443,768 adults in the United Kingdom and United States, we find that systemic inflammation, whose level increases with age, is dose-dependently associated with higher risks of eight inflammation-related cancers and all-cancer mortality. PA is dose-dependently associated with lower levels of systemic inflammation. Aerobic PA (117-500 min/week) is significantly associated with lower risks of inflammation-related cancers and all-cancer mortality. Single-cell sequencing, RNA sequencing, cytometry, and inflammation array show that aerobic exercise training downregulates immunosenescence-related gene expression, Mki67(+) immune cells, and pro-inflammatory molecules and upregulates anti-inflammatory factors, Flt3(+) immune cells, natural killers, and T lymphocytes in mice and hamsters, especially in older animals. These findings link exercise training to cancer risk reduction by alleviating inflammation, decreasing immunosenescence, and improving the reservoirs of overall immunity for cancer prevention.

    Author Info: (1) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical Uni

    Author Info: (1) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (2) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (3) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (4) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (5) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (6) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (7) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (8) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (9) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China; Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (10) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (11) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. (12) Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China. (13) Department of Epidemiology, Second Military Medical University, Shanghai 200433, China; Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China. Electronic address: gcao@smmu.edu.cn.

    Citation: Cell Rep Med 2025 Dec 16 6:102484 Epub

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41406938

    Tags:

    Harnessing cuproptosis for pancreatic cancer therapy: From molecular insights to clinical prospects

    (1) Darzi A (2) Boroumandi S (3) Khajegi P (4) Dehdashti MR (5) Abdali P (6) Amerinia MM (7) Kheirkhah F (8) Ajalli MM (9) Shokouhfar M

    Biomedicine & pharmacotherapy

    (1) Darzi A (2) Boroumandi S (3) Khajegi P (4) Dehdashti MR (5) Abdali P (6) Amerinia MM (7) Kheirkhah F (8) Ajalli MM (9) Shokouhfar M

    Biomedicine & pharmacotherapy

    Pancreatic cancer (PC) remains a high-fatality malignancy with limited clinical progress, characterized by aggressive biology, marked resistance to standard therapies, and dismal outcomes. Even with state-of-the-art resection, radiotherapy, and multidrug chemotherapy, median survival benefits are modest, highlighting an urgent need for mechanism-based interventions. Cuproptosis, a newly delineated modality of regulated cell death initiated by intracellular copper accumulation and mitochondrial stress, presents a biologically coherent therapeutic avenue. Distinct from apoptosis, necroptosis, and ferroptosis, cuproptosis is driven by the direct binding of copper to lipoylated enzymes of the tricarboxylic acid (TCA) cycle, resulting in bioenergetic failure, misfolded protein aggregation, and collapse of cytotoxic proteostasis. Converging studies suggest that copper disequilibrium and metabolic reprogramming are recurrent features of PC, potentially contributing to malignant progression, immune evasion, and chemoresistance. These insights motivate two complementary strategies: first, therapeutic manipulation of copper flux, via chelators, ionophores, or transport modulators, to selectively trigger cuproptosis in tumor cells; and second, sensitization of mitochondrial metabolism, through targeting lipoic-acid pathway components, pyruvate utilization, or TCA load, to lower the threshold for cuproptotic killing. In parallel, multi-omic interrogation of cuproptosis-associated genes, proteins, and metabolites may yield prognostic and predictive biomarkers, enabling risk-adapted treatment selection and rational combinations with cytotoxic, targeted, or immunotherapeutic modalities. This review synthesizes recent advances on cuproptosis in PC and outlines its translational potential as both a therapeutic target and a biomarker framework.

    Author Info: (1) School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2) School of Medicine, Ardabil university of medical Sciences, Ardabil, Iran. (3) Student Res

    Author Info: (1) School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (2) School of Medicine, Ardabil university of medical Sciences, Ardabil, Iran. (3) Student Research Committee, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran. (4) School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran. (5) Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. (6) School of Dentistry, Islamic Azad University of Isfahan, Isfahan, Iran. (7) School of Medicine, Islamic Azad University, Najafabad Branch, Isfahan, Iran. (8) School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. (9) School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: Mahlashokouhfarr@gmail.com.

    Citation: Biomed Pharmacother 2025 Dec 2 193:118852 Epub12/02/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41337879

    Tags:

    Gut microbial metabolites in cancer immunomodulation

    (1) Liu H (2) Xiong X (3) Zhu W (4) Wang S (5) Huang W (6) Zhu G (7) Xu H (8) Yang L

    Molecular cancer

    (1) Liu H (2) Xiong X (3) Zhu W (4) Wang S (5) Huang W (6) Zhu G (7) Xu H (8) Yang L

    Molecular cancer

    Gut microbiota-derived metabolites are emerging as systemic "remote immunoregulators" that shape tumor immunity across tissues. Integrating evidence across short-chain fatty acids, tryptophan derivatives, secondary bile acids, polyamines and other metabolites, we advance a metabolite-immune pathway-cancer framework that links receptor-mediated signaling, epigenetic remodeling and metabolic reprogramming to context-dependent, bidirectional immune effects. Importantly, in addition to the g protein-coupled receptor / aryl hydrocarbon receptor pathway, the selected microbial small molecule metabolites are the true T-cell receptor ligands of unconventional T cells, directly shaping the tissue resident immune and tumor microenvironment, supplementing the receptor signaling and epigenetic programs in our framework. We synthesize how these metabolites recalibrate the tumor immune microenvironment-modulating antigen presentation, T-cell effector fitness and exhaustion, regulatory T-cell activity, and myeloid polarization-and why the same metabolite can either potentiate immune surveillance or entrench immunosuppression depending on ligand-receptor pairing, dose and tissue niche. We compare tumor-type specific patterns (e.g., colorectal, liver, lung, breast and prostate cancers) to highlight common circuits and organ-restricted idiosyncrasies. Methodologically, we outline how single-cell and spatial multi-omics, imaging mass spectrometry and functional biosensors now enable co-registration of metabolite exposure with immune-cell states in human tumors, providing an actionable basis for biomarker discovery. Given ongoing debate about signals attributed to intratumoral microbiota in low-biomass tumor tissues, we foreground quantifiable, spatially mappable and pharmacologically tractable metabolite-receptor pathways, using microbe-associated molecular patterns / translocation as comparators to judge when chemical signals should be prioritized as intervention targets. Finally, we evaluate precision intervention avenues-including fecal microbiota transplantation, rational bacterial consortia, engineered microbes and nanoparticle-enabled metabolite delivery-and propose stratification rules that pair metabolite/receptor signatures with fit-for-purpose delivery. Together, mapping tissue-specific metabolite-immune circuits and embedding them in robust biomarker frameworks may convert microbial metabolites from correlative markers into therapeutic targets and tools, improving the efficacy and durability of cancer immunotherapy.

    Author Info: (1) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (2) Department of Urology

    Author Info: (1) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (2) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (3) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (4) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (5) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (6) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. (7) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. hangxu@wchscu.cn. (8) Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, People's Republic of China. wycleflue@scu.edu.cn.

    Citation: Mol Cancer 2025 Dec 3 Epub12/03/2025

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41339918

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    ‘‘Cancer-treating-cancer’’ strategy- Entrapping chemically engineered dying cancer cells in immunotherapeutic hydrogel against tumor recurrence

    Spotlight 

    Yiming Zhang1,2,3,4 ∙ Zhuoming Zhou3 ∙ Tian Hao3 ∙ Shuying Chen3 ∙ Wei Luo4 ∙ Muhammad Muzamil Khan3 ∙ Yesi Shi3 ∙ Xinru You3 ∙ Qimanguli Saiding3 ∙ Xueyan Zhen3 ∙ Wei Tao3 ∙ Tian Xie4 ∙ Wei Chen3 ∙ Na Kong1,2,4,5

    Cell Biomaterials

    Zhang et al employed cytotoxic B-elemene (ELE)-treated dying cancer cells (DCCs) as an immunogenic cell source within a sprayable fibrin hydrogel (with additional ELE). In a 4T1 orthotopic partial resection model, the gel controlled primary and untreated distal tumor growth, increasing the M1:M2 macrophage ratio, and activated CD103+ DCs. The gel increased T cell frequency in the tumor, lymph nodes, and spleen, Tcm polarization, and stimulatory cytokines. Proteomics profiling of tumor fluid and plasma revealed differential expression of clinically prognostic proteins and pathways related to apoptosis, immune function, and metastasis.

    Contributed by Morgan Janes

    Yiming Zhang1,2,3,4 ∙ Zhuoming Zhou3 ∙ Tian Hao3 ∙ Shuying Chen3 ∙ Wei Luo4 ∙ Muhammad Muzamil Khan3 ∙ Yesi Shi3 ∙ Xinru You3 ∙ Qimanguli Saiding3 ∙ Xueyan Zhen3 ∙ Wei Tao3 ∙ Tian Xie4 ∙ Wei Chen3 ∙ Na Kong1,2,4,5

    Cell Biomaterials

    Zhang et al employed cytotoxic B-elemene (ELE)-treated dying cancer cells (DCCs) as an immunogenic cell source within a sprayable fibrin hydrogel (with additional ELE). In a 4T1 orthotopic partial resection model, the gel controlled primary and untreated distal tumor growth, increasing the M1:M2 macrophage ratio, and activated CD103+ DCs. The gel increased T cell frequency in the tumor, lymph nodes, and spleen, Tcm polarization, and stimulatory cytokines. Proteomics profiling of tumor fluid and plasma revealed differential expression of clinically prognostic proteins and pathways related to apoptosis, immune function, and metastasis.

    Contributed by Morgan Janes

    ABSTRACT: Postsurgical tumor recurrence remains a major challenge, primarily driven by the resurgence of residual microtumors at surgical margins. The tumor microenvironment (TME) in these regions plays a decisive role in treatment outcomes. Here, we present an in situ sprayed fibrin hydrogel system that integrates chemically engineered homologous dying cancer cells (DCCs) as a sustained antigen reservoir with the anticancer agent β-elemene (ELE) to enhance anti-tumor immune responses and suppress local tumor recurrence. This immunotherapeutic hydrogel (DCCs@ELE@Gel) modulates the TME by promoting a favorable M1/M2 tumor-associated macrophage balance, facilitating dendritic cell maturation, and enhancing the cross-priming of cytotoxic T cells, collectively preventing tumor regrowth. Additionally, comprehensive proteomic analysis reveals key mechanisms linking the chemo-immunotherapeutic hydrogel to tumor recurrence suppression. Our findings introduce an approach that leverages engineered tumor cells within a hydrogel matrix for improved cancer immunotherapy, offering a versatile strategy for postsurgical tumor management.

    Author Info: 1- Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Ey

    Author Info: 1- Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, Zhejiang Provincial Engineering Institute on Eye Diseases, Eye Center of Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China 2- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China 3- Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA 4- School of Pharmacy, Hangzhou Normal University, Hangzhou 311121, China 5- Lead contact

    Citation: Cell biomaterials Nov 4, 2025

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