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.
Radiotherapy synergizes with an inducible AAV-based immunotherapy platform to program local and systemic antitumor immunity
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.
Amino acid supplementation enhances in vivo efficacy of lipid nanoparticle-mediated mRNA delivery in preclinical models
(1) Chen K (2) Wang W (3) Lennon A (4) McClure RA (5) Vuchkovska A (6) Kelley SO (7) Wang Z
(1) Chen K (2) Wang W (3) Lennon A (4) McClure RA (5) Vuchkovska A (6) Kelley SO (7) Wang Z
Author Info: (1) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. (2) Biohub, Chicago, IL

Author Info: (1) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. (2) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. (3) Biohub, Chicago, IL 60642, USA. (4) Biohub, Chicago, IL 60642, USA. (5) cTRL Therapeutics, Chicago, IL 60642, USA. (6) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. cTRL Therapeutics, Chicago, IL 60642, USA. Department of Chemistry, Weinberg College of Arts & Sciences, Northwestern University, Evanston, IL 60208, USA. Department of Biochemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA. Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA. (7) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA.

Citation: Sci Transl Med 2026 Mar 11 18:eadx4097 Epub03/11/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41811986
Tags:
Cancer cell-derived sialylated IgG interacting with Siglec-7/9/10 is a potential immunotherapeutic target in pancreatic cancer
(1) Zhang S (2) Cui M (3) Huang X (4) Feng X (5) Xiao R (6) Liu Q (7) Bai J (8) Han X (9) Liu X (10) Xu W (11) Huang J (12) Liao Q (13) Zhao Y (14) Qiu X
(1) Zhang S (2) Cui M (3) Huang X (4) Feng X (5) Xiao R (6) Liu Q (7) Bai J (8) Han X (9) Liu X (10) Xu W (11) Huang J (12) Liao Q (13) Zhao Y (14) Qiu X
Author Info: (1) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 10019

Author Info: (1) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (2) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: cuiming@pumch.cn. (3) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210031, China. (4) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (5) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (6) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (7) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (8) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (9) State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Research Center for Molecular Pathology, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (10) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (11) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (12) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (13) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: zhao8028@263.net. (14) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. Electronic address: qiuxy@bjmu.edu.cn.

Citation: Cell Rep Med 2026 Mar 17 7:102660 Epub
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41850238
A bispecific nanobody-drug conjugate targeting TROP2 and c-Met for low-concentration, single-dose treatment of pancreatic cancer
(1) Ning W (2) Liu H (3) Zeng H (4) Qin X (5) Xu L (6) Yang S (7) Wang Y (8) Chen F (9) Yuan N (10) Chen X (11) Xu T (12) Wu K (13) Wang P (14) Liu C (15) Chen Y (16) Xia N (17) Liu X (18) Luo W
(1) Ning W (2) Liu H (3) Zeng H (4) Qin X (5) Xu L (6) Yang S (7) Wang Y (8) Chen F (9) Yuan N (10) Chen X (11) Xu T (12) Wu K (13) Wang P (14) Liu C (15) Chen Y (16) Xia N (17) Liu X (18) Luo W
Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute

Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (2) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (3) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (4) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (5) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (6) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (7) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (8) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (9) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (10) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (11) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (13) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. (14) State Key Laboratory of Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China. (15) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: yuanzhichen@xmu.edu.cn. (16) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: nsxia@xmu.edu.cn. (17) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: liuxue1108@xmu.edu.cn. (18) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen 361102, China; National Institute of Diagnostics and Vaccine Development in Infectious Diseases, National Innovation Platform for Industry-Education Integration in Vaccine Research, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen 361102, China. Electronic address: wxluo@xmu.edu.cn.

Citation: Cell Rep Med 2026 Mar 18 102688 Epub03/18/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41856115
Engineering lipid nanoparticle-stabilized emulsions for spatiotemporal mRNA delivery and enhanced T cell immunity
(1) Zhou Y (2) Gao W (3) Huang X (4) Yan Y (5) Wu S (6) Shan X (7) Chen S (8) Qiu M (9) Ma G (10) Xia Y
(1) Zhou Y (2) Gao W (3) Huang X (4) Yan Y (5) Wu S (6) Shan X (7) Chen S (8) Qiu M (9) Ma G (10) Xia Y
Author Info: (1) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical E

Author Info: (1) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (2) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (3) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (4) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (5) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China. (6) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (7) Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Department of Thoracic Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China. (8) Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Department of Thoracic Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China. (9) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (10) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: yfxia@ipe.ac.cn.

Citation: Cell Rep Med 2026 Mar 17 7:102667 Epub
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41850240
Biodegradable targeted polymeric mRNA nanoparticles enable in vivo CD19 CAR T cell generation and lead to B cell depletion
(1) Jain M (2) Est-Witte SE (3) Shannon SR (4) Neshat SY (5) Yu X (6) Dunham S (7) Tian T (8) Cheng L (9) Harris J (10) Konig MF (11) Tzeng SY (12) Schneck JP (13) Green JJ
(1) Jain M (2) Est-Witte SE (3) Shannon SR (4) Neshat SY (5) Yu X (6) Dunham S (7) Tian T (8) Cheng L (9) Harris J (10) Konig MF (11) Tzeng SY (12) Schneck JP (13) Green JJ
Author Info: (1) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineeri

Author Info: (1) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (2) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (3) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (4) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (5) Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. (6) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (7) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (8) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (9) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (10) Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. Center for Autoimmunity and Immuno-Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (11) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (12) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. (13) Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Institute for NanoBioTechnology, and Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Johns Hopkins Translational ImmunoEngineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Department of Materials Science & Engineering, Johns Hopkins University, Baltimore, MD 21218, USA. Departments of Ophthalmology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Citation: Sci Adv 2026 Mar 13 12:eadz1722 Epub03/11/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41811961
IL-7/IL-15/IL-21 cytokine-fusion scaffold generates highly functional CAR T cells enriched in long-lived T memory stem cells
(1) Cole EB (2) Lamcaj S (3) Sydenstricker AV (4) Voss AG (5) Hiner CR (6) Hur HB (7) Kandpal M (8) Valderrama Pena N (9) Zheng JH (10) Xiong Y (11) Zhu Z (12) Zhang CC (13) Shrestha N (14) Dropulic B (15) Wong HC (16) Goldstein H
(1) Cole EB (2) Lamcaj S (3) Sydenstricker AV (4) Voss AG (5) Hiner CR (6) Hur HB (7) Kandpal M (8) Valderrama Pena N (9) Zheng JH (10) Xiong Y (11) Zhu Z (12) Zhang CC (13) Shrestha N (14) Dropulic B (15) Wong HC (16) Goldstein H
Author Info: (1) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (2) Department of Microbiology and Immunology, Albert Einstein College of

Author Info: (1) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (2) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (3) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (4) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (5) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (6) RUH Bioinformatics, Center for Clinical and Translational Science, Rockefeller University Hospital, New York, NY 10065, USA. (7) RUH Bioinformatics, Center for Clinical and Translational Science, Rockefeller University Hospital, New York, NY 10065, USA. (8) HCW Biologics Inc., Miramar, FL 33025, USA. (9) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. (10) Caring Cross, Gaithersburg, MD 20878, USA. (11) Caring Cross, Gaithersburg, MD 20878, USA. (12) Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. (13) HCW Biologics Inc., Miramar, FL 33025, USA. (14) HCW Biologics Inc., Miramar, FL 33025, USA. (15) HCW Biologics Inc., Miramar, FL 33025, USA. (16) Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.

Citation: Sci Adv 2026 Mar 13 12:eaec2632 Epub03/13/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41824575
Modulating AP-1 enables CAR T cells to establish an intratumoral stemlike reservoir and overcomes resistance to PD-1 blockade Spotlight
(1) Snyder AJ (2) Garrison SM (3) Kluesner MG (4) Nutt WS (5) Shasha C (6) Ho T (7) Marsh SA (8) Linde M (9) Wu F (10) Meyer L (11) Wilhelm AR (12) Ortiz-Espinosa S (13) Zepeda V (14) Bingham E (15) Malik H (16) Mak SR (17) Gad E (18) Bhise SS (19) Fan E (20) Sarvothama M (21) Wang X (22) Potluri S (23) Long A (24) Elz A (25) Ghajar CM (26) Furlan SN (27) Newell EW (28) Srivastava S
ROR1 CAR T cells infiltrated ROR1+ NSCLC mouse tumors, but lost TCF1 expression and failed to maintain a progenitor exhausted (Tpex) population. The addition of anti-PD-L1 did not improve CAR T cell counts or efficacy, and further drove exhaustion. Snyder et al. found that co-delivery of c-Jun by the ROR1 CAR transiently increased CAR-T tumor accumulation and Tpex phenotype, and combining with anti-PD-L1 further improved tumor T cell counts, c-Jun expression, phenotype, and efficacy. Spatial transcriptomics found that c-Jun CAR-T were distributed throughout lung tumors, proximal to PD-L1+ myeloid cells, and Tpex-enriched relative to standard CAR-T.
Contributed by Alex Najibi
(1) Snyder AJ (2) Garrison SM (3) Kluesner MG (4) Nutt WS (5) Shasha C (6) Ho T (7) Marsh SA (8) Linde M (9) Wu F (10) Meyer L (11) Wilhelm AR (12) Ortiz-Espinosa S (13) Zepeda V (14) Bingham E (15) Malik H (16) Mak SR (17) Gad E (18) Bhise SS (19) Fan E (20) Sarvothama M (21) Wang X (22) Potluri S (23) Long A (24) Elz A (25) Ghajar CM (26) Furlan SN (27) Newell EW (28) Srivastava S
ROR1 CAR T cells infiltrated ROR1+ NSCLC mouse tumors, but lost TCF1 expression and failed to maintain a progenitor exhausted (Tpex) population. The addition of anti-PD-L1 did not improve CAR T cell counts or efficacy, and further drove exhaustion. Snyder et al. found that co-delivery of c-Jun by the ROR1 CAR transiently increased CAR-T tumor accumulation and Tpex phenotype, and combining with anti-PD-L1 further improved tumor T cell counts, c-Jun expression, phenotype, and efficacy. Spatial transcriptomics found that c-Jun CAR-T were distributed throughout lung tumors, proximal to PD-L1+ myeloid cells, and Tpex-enriched relative to standard CAR-T.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor T (CAR T) cell therapy has shown limited synergy with immune checkpoint inhibitors, but the mechanisms underlying resistance remain unclear. Stemlike T cells coexpressing programmed cell death protein 1 (PD-1) and T cell factor 1 (TCF1) mediate responses to PD-1-PD-L1 (programmed death ligand 1) blockade and are maintained by major histocompatibility complex (MHC)-dependent interactions with dendritic cells in lymphoid tissues. Because CAR T cells recognize intact antigen rather than peptide-MHC, their activation is restricted to tumors, potentially limiting maintenance of this critical subset. In murine models of lung cancer, CAR T cells down-regulated TCF1, became exhausted, and were not enhanced by PD-L1 blockade. Overexpression of the transcription factor c-Jun increased intratumoral PD-1(+)TCF1(+) CAR T cells but did not prevent exhaustion, given that PD-1 induced posttranscriptional c-Jun down-regulation. PD-L1 blockade restored c-Jun levels, markedly increased CAR T cells, and enabled near-complete tumor clearance, revealing a mechanism by which MHC-independent CAR T cells can be engineered to overcome resistance to PD-1-PD-L1 blockade.
Author Info: (1) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Sc

Author Info: (1) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. (2) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (3) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. (4) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. (5) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (6) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (7) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA. (8) Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA,USA. (9) Genomics and Bioinformatics Shared Resources, Fred Hutchinson Cancer Center, Seattle, WA, USA. (10) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (11) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA, USA. Medical Scientist Training Program, University of Washington, Seattle, WA, USA. (12) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (13) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (14) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (15) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Invent Program, Seattle Children's Research Institute, Seattle, WA, USA. (16) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (17) Comparative Medicine, Translational Research Model Services, Fred Hutchinson Cancer Center, Seattle, WA, USA. (18) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (19) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (20) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (21) Lyell Immunopharma, South San Francisco, CA, USA. (22) Lyell Immunopharma, South San Francisco, CA, USA. (23) Fred Hutch Innovation Lab, Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA. (24) Fred Hutch Innovation Lab, Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA, USA. (25) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA,USA. Center for Metastasis Research eXcellence (MET-X), Fred Hutchinson Cancer Center, Seattle, WA, USA. (26) Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA. (27) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. (28) Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Department of Immunology, University of Washington, Seattle, WA, USA.

Citation: Sci Immunol 2026 Mar 6 11:eadw7685 Epub03/06/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41790934
Dynamic reprogramming of the tumor immune network via multicycle checkpoint degradation for cancer immunotherapy Spotlight
(1) Shi T (2) Wu Y (3) Cai Y (4) Luo Y (5) Ren S (6) Cao Y (7) Tang Y (8) Jiang Z (9) Hu S (10) Xie W (11) Chen Y (12) Shen L (13) Xing H (14) Wei J
Chi et al. engineered a recyclable PD-L1 degrader (RECYC) by fusing a moderate-affinity peptide binder of PD-L1 to an aptamer against the ubiquitous endolysosomal trafficking receptor CI-M6PR. RECYC robustly degraded PD-L1 in tumor and myeloid cells, and exhibited pH-sensitive dissociation from PD-L1, enabling repeated knockdown following membrane recycling. I.v. RECYC outperformed anti-PD-L1 in multiple tumor models. and drove greater PD-L1 knockdown in tumor and myeloid cells, which correlated with efficacy. RECYC enhanced T cell infiltration and early activation, and uniquely promoted M1/N1-like skewing in tumor-associated macrophages and neutrophils.
Contributed by Morgan Janes
(1) Shi T (2) Wu Y (3) Cai Y (4) Luo Y (5) Ren S (6) Cao Y (7) Tang Y (8) Jiang Z (9) Hu S (10) Xie W (11) Chen Y (12) Shen L (13) Xing H (14) Wei J
Chi et al. engineered a recyclable PD-L1 degrader (RECYC) by fusing a moderate-affinity peptide binder of PD-L1 to an aptamer against the ubiquitous endolysosomal trafficking receptor CI-M6PR. RECYC robustly degraded PD-L1 in tumor and myeloid cells, and exhibited pH-sensitive dissociation from PD-L1, enabling repeated knockdown following membrane recycling. I.v. RECYC outperformed anti-PD-L1 in multiple tumor models. and drove greater PD-L1 knockdown in tumor and myeloid cells, which correlated with efficacy. RECYC enhanced T cell infiltration and early activation, and uniquely promoted M1/N1-like skewing in tumor-associated macrophages and neutrophils.
Contributed by Morgan Janes
ABSTRACT: The efficacy of immune checkpoint blockade is often limited by intrinsic immunosuppressive networks within the tumor immune microenvironment (TIME). Despite progress in cancer treatment, current extracellular targeted protein degradation approaches often overlook the multicellular distribution and crosstalk of immune checkpoints. Here we reported a Receptor-mediated Endolysosomal recYcling Chimera (RECYC) platform. RECYC employs a CI-M6PR-targeting aptamer that remains stable across late endosomal pH and a protein-binding peptide with moderate affinity and pH responsiveness, which together drive recycling and sustained checkpoint clearance. In ex vivo co-culture and in vivo murine models, RECYC efficiently eliminated programmed death-ligand 1 (PD-L1) expression from both tumor cells and tumor-associated myeloid cells (macrophages, neutrophils and dendritic cells). By converting an immunosuppressive TIME to an immunostimulatory state, RECYC remodeled the tumor-immune network in an anti-tumor direction, thereby enhancing CD8(+) T cell response and repolarizing immunosuppressive myeloid cells. Moreover, in both immune-cold and immune-hot murine cancer models, RECYC demonstrated superior anti-tumor effect compared to PD-L1 blockade treatment. Collectively, we propose an effective strategy to induce recycling and broad checkpoint clearance in the TIME, which in turn reprograms the multicellular tumor-immune network to achieve durable immunotherapy responses.
Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) Institute of Chemical Biology and Nan

Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (3) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (4) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (5) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (6) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (7) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (8) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (9) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (10) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (11) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (12) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (13) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (14) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing 210061, China. Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.

Citation: Proc Natl Acad Sci U S A 2026 Mar 10 123:e2525047123 Epub03/02/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41770936
VISTA drives pancreatic tumor progression through modulation of the tumor-associated macrophage polarity Spotlight
(1) Shin SK (2) Kim G (3) Park SM (4) Seo EB (5) Ye SK (6) Kang GH (7) Jung K (8) Shin HM (9) Kim HR (10) Lee DS
Shin and Kim et al. demonstrated that VISTA deletion enhanced macrophage and CD8+ T cell infiltration and reduced tumor growth in orthotopic Pan02 and KPC pancreatic mouse tumor models. VISTA deficiency reprogrammed TAMs from a suppressive SPP1+ to a stimulatory CXCL9+ phenotype. CXCL9+ TAMs exhibited enhanced antigen processing and cross-presentation, and increased recruitment of CXCR3+ CD8+ T cells with sustained cytotoxicity and reduced exhaustion. Anti-VISTA plus gemcitabine produced a synergistic antitumor response. In human PDAC datasets, expression of VSIR (encoding VISTA) correlated with immunosuppressive macrophage states.
Contributed by Shishir Pant
(1) Shin SK (2) Kim G (3) Park SM (4) Seo EB (5) Ye SK (6) Kang GH (7) Jung K (8) Shin HM (9) Kim HR (10) Lee DS
Shin and Kim et al. demonstrated that VISTA deletion enhanced macrophage and CD8+ T cell infiltration and reduced tumor growth in orthotopic Pan02 and KPC pancreatic mouse tumor models. VISTA deficiency reprogrammed TAMs from a suppressive SPP1+ to a stimulatory CXCL9+ phenotype. CXCL9+ TAMs exhibited enhanced antigen processing and cross-presentation, and increased recruitment of CXCR3+ CD8+ T cells with sustained cytotoxicity and reduced exhaustion. Anti-VISTA plus gemcitabine produced a synergistic antitumor response. In human PDAC datasets, expression of VSIR (encoding VISTA) correlated with immunosuppressive macrophage states.
Contributed by Shishir Pant
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies due to its highly immunosuppressive tumor microenvironment (TME), which limits effective therapeutic interventions. Here, we demonstrate that V-domain immunoglobulin suppressor of T cell activation (VISTA) plays a crucial role in orchestrating macrophage polarity within the PDAC TME. Using murine PDAC models, we show that VISTA deficiency markedly impairs tumor growth, leading to prolonged survival. Functionally, VISTA deficiency is linked to a shift in tumor-associated macrophages (TAMs) from an immunosuppressive phenotype marked by secreted phosphoprotein 1 (SPP1), to one enriched for C-X-C motif chemokine ligand 9 (CXCL9), indicative of a pro-inflammatory state. This shift is accompanied by enhanced recruitment of CXCR3⁺ CD8⁺ T cells with sustained cytotoxic potential, among which terminal exhaustion-like CD8+ T cell states are less prevalent. Additionally, VISTA-deficient TAMs exhibit increased antigen cross-presentation, further amplifying CD8+ T cell response against tumors. These findings are corroborated by human PDAC data, which reflect similar immune reprogramming trends. By defining the role of VISTA in controlling Cxcl9:Spp1 ratio and modulating CD8⁺ T cell dynamics, this study positions VISTA inhibition as a promising strategy to reshape the TME and potentiate anti-tumor immunity in PDAC.
Author Info: (1) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul

Author Info: (1) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. (2) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea. (3) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. (4) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. (5) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. (6) Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea. (7) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. (8) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. hyunmu.shin@snu.ac.kr. Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. hyunmu.shin@snu.ac.kr. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. hyunmu.shin@snu.ac.kr. Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea. hyunmu.shin@snu.ac.kr. (9) Samsung Precision Genome Medicine Institute, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea. hangrae.kim@skku.edu. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea. hangrae.kim@skku.edu. (10) Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. dlee5522@snu.ac.kr. Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, Republic of Korea. dlee5522@snu.ac.kr. BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea. dlee5522@snu.ac.kr.

Citation: Nat Commun 2026 Mar 3 Epub03/03/2026
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41776161
