Journal Articles

Immunogenic tumor cell death and T-cell-derived IFN-γ elicit tumoricidal macrophages to potentiate OX40 immunotherapy

Spotlight 

(1) Liu Y (2) Zhao J (3) Yang K (4) Ma Q (5) Zhang D (6) Xu L (7) Zhang Z (8) Yin Z (9) Chen J (10) Wang Y (11) Wang H (12) Zhou F (13) Han M (14) Wang J (15) Li F (16) Xu Y (17) Yang Y (18) Wang W (19) Huggett S (20) Chung A (21) Gan J (22) Zhang B (23) Zhou Z (24) Cao Y (25) Ding D (26) Wang M (27) Zhang H

Cell reports. Medicine

Using a bilateral, humanized OX40 MC38 tumor model, Liu and Zhao et al. demonstrated that OX40 agonist Ab (agOX40) therapy increased infiltration of NOS2+ pro-inflammatory macrophages and effector CD8+ T cells. T cell-derived IFNγ synergized with DAMP-induced TLR4 signaling to reprogram TAMs toward a pro-inflammatory and tumoricidal NOS2+ state. agOX40-mediated depletion of OX40+Foxp3+ Tregs further potentiated NOS2+ TAM polarization. A combination of MPLA, IFNγ, and agOX40 reprogrammed TAMs, promoted DC maturation, and induced durable tumor regression. ICD-inducing cyclophosphamide enhanced agOX40 therapy.

Contributed by Shishir Pant

(1) Liu Y (2) Zhao J (3) Yang K (4) Ma Q (5) Zhang D (6) Xu L (7) Zhang Z (8) Yin Z (9) Chen J (10) Wang Y (11) Wang H (12) Zhou F (13) Han M (14) Wang J (15) Li F (16) Xu Y (17) Yang Y (18) Wang W (19) Huggett S (20) Chung A (21) Gan J (22) Zhang B (23) Zhou Z (24) Cao Y (25) Ding D (26) Wang M (27) Zhang H

Cell reports. Medicine

Using a bilateral, humanized OX40 MC38 tumor model, Liu and Zhao et al. demonstrated that OX40 agonist Ab (agOX40) therapy increased infiltration of NOS2+ pro-inflammatory macrophages and effector CD8+ T cells. T cell-derived IFNγ synergized with DAMP-induced TLR4 signaling to reprogram TAMs toward a pro-inflammatory and tumoricidal NOS2+ state. agOX40-mediated depletion of OX40+Foxp3+ Tregs further potentiated NOS2+ TAM polarization. A combination of MPLA, IFNγ, and agOX40 reprogrammed TAMs, promoted DC maturation, and induced durable tumor regression. ICD-inducing cyclophosphamide enhanced agOX40 therapy.

Contributed by Shishir Pant

ABSTRACT: Understanding the mechanisms limiting OX40 agonist antibody efficacy is critical for developing more effective combination immunotherapies. Tumor microenvironment (TME) analysis revealed that OX40-antibody-responsive mice harbored tumor-associated macrophages (TAMs) with elevated NOS2 expression and heightened pattern recognition receptor (PRR) activation and interferon gamma (IFN-γ) signaling. In addition, patients with more favorable treatment responses to OX40 antibody therapy exhibited increased NOS2 expression. Mechanistically, tumor-infiltrating T-cell-derived IFN-γ synergizes with endogenous ligands of PRR released during immunogenic cell death to drive NOS2+ TAMs reprogramming. Translating these insights into therapeutic strategy, a Combo approach composing of MPLA, IFN-γ, and OX40 agonist antibody is designed to actively polarize TAMs to express NOS2, which mediate tumor clearance through an NOS2-dependent cytotoxicity. Moreover, OX40-antibody-mediated regulatory T cell (Treg) depletion potentiated NOS2+ macrophage induction. This multimodal strategy offers a promising solution to overcome the limitations of OX40 antibody monotherapy and enhance outcomes of the OX40-targeted immunotherapies.

Author Info: (1) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Na

Author Info: (1) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou 450003, China; Henan Academy of Sciences, Zhengzhou 450046, China. (2) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; College of Materials Science and Engineering, Shenzhen University, Shenzhen 518071, China. (3) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (4) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (5) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (6) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (7) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (8) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (9) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (10) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (11) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (12) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (13) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (14) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (15) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (16) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (17) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (18) Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. (19) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (20) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (21) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (22) NovelBio Bio-Pharm Technology Co., Ltd., Shanghai 201114, China. (23) Faculty of Life Science, University College London, London WC1E 6BT, UK. (24) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (25) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (26) Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou 450003, China. (27) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: hongkai@nankai.edu.cn.

Citation: Cell Rep Med 2026 Mar 26 102699 Epub03/26/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41895288

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Tim-3-targeted vaccines overcome tumor immunosuppression and reduce cDC1 dependence to elicit potent anti-tumor immunity Spotlight 

(1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

Contributed by Shishir Pant

(1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

Contributed by Shishir Pant

ABSTRACT: Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti-DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti-Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-_-catenin(active) mice, which model _-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3(-/-) mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control-albeit both were reduced compared to wild-type mice- demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine-induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3-neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell-dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.

Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health

Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824. (2) Department of Computer Science and Engineering, School of Engineering and Computer Science, Oakland University, Rochester, MI 48309. (3) Institute for Molecular Medicine and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany. (4) Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA 94143. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129. (5) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824.

Citation: Proc Natl Acad Sci U S A 2026 Mar 24 123:e2518080123 Epub03/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41855265

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Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice Spotlight 

(1) Zhang X (2) Gao Y (3) Hu W (4) Liang Y (5) Yin X (6) Shi X (7) Li H (8) Liao H (9) Guo J (10) Yu X (11) Zhu M (12) Peng H (13) Wang W (14) Fu YX

Nature communications

Zhang, Gao, and Hu et al. addressed ways to enhance DC–T cell crosstalk in the TIME. BiDT, a bispecific DC–T cell engager (anti-Tim3–IFNα fusion), simultaneously bound Tim3 on exhausted TILs and activated DCs via the IFNAR receptor. In mouse models, BiDT resulted in potent antitumor activity, robust tumor specific memory, and synergized with anti-PD-L1 in an immune-cold tumor model. Mechanistically, BiDT depended on DCs and intratumoral, not LN, T cells, reactivated exhausted TIM3+ CD8+ TILs via anti-apoptotic Bcl-2 upregulation, and enhanced DC function via increased IL-2 production and B7/CD28 interactions. To address IFNα toxicity, an MMP-cleavable prodrug variant was generated.

Contributed by Katherine Turner

(1) Zhang X (2) Gao Y (3) Hu W (4) Liang Y (5) Yin X (6) Shi X (7) Li H (8) Liao H (9) Guo J (10) Yu X (11) Zhu M (12) Peng H (13) Wang W (14) Fu YX

Nature communications

Zhang, Gao, and Hu et al. addressed ways to enhance DC–T cell crosstalk in the TIME. BiDT, a bispecific DC–T cell engager (anti-Tim3–IFNα fusion), simultaneously bound Tim3 on exhausted TILs and activated DCs via the IFNAR receptor. In mouse models, BiDT resulted in potent antitumor activity, robust tumor specific memory, and synergized with anti-PD-L1 in an immune-cold tumor model. Mechanistically, BiDT depended on DCs and intratumoral, not LN, T cells, reactivated exhausted TIM3+ CD8+ TILs via anti-apoptotic Bcl-2 upregulation, and enhanced DC function via increased IL-2 production and B7/CD28 interactions. To address IFNα toxicity, an MMP-cleavable prodrug variant was generated.

Contributed by Katherine Turner

ABSTRACT: Tumor infiltrating T cells (TIL) are key players in the anti-tumor immune response. However, chronic exposure to tumor-derived antigens drives the differentiation into 'exhausted' TILs. Whether intratumoral dendritic cells (DC) can mitigate TILs exhaustion and maintain function is unclear. Here, we develop a bispecific DC-T cell engager (BiDT), consisting of an anti-TIM3-IFN fusion protein, and demonstrate that, in preclinical mouse tumor models, this engager simultaneously targets TIM3 on exhausted TILs and activates DCs via the IFNAR receptor. Mechanistically, BiDT reactivates exhausted TIM3(+)TILs by preventing apoptosis through increased Bcl-2 expression and enhances DC function to reactivate T cells via IL-2 signalling and co-stimulatory CD80/86-CD28 interactions within the tumor microenvironment. Finally, to mitigate IFN_-induced toxicity, we engineer a Pro-BiDT engager featuring a pro-IFN_ and report potent antitumor activity with reduced systemic toxicity. Thus, by bridging DC-T cells together, BiDT treatment enhances the critical communication pathways and cellular circuits necessary for effective anti-tumor immunity.

Author Info: (1) Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. xuhaozhang@cqmu.edu.cn. School of Basic Medical Sciences, Tsinghua University, Beiji

Author Info: (1) Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing, China. xuhaozhang@cqmu.edu.cn. School of Basic Medical Sciences, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. xuhaozhang@cqmu.edu.cn. (2) School of Basic Medical Sciences, Tsinghua University, Beijing, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (3) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (4) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (5) School of Basic Medical Sciences, Tsinghua University, Beijing, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. (6) School of Basic Medical Sciences, Tsinghua University, Beijing, China. China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (7) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (8) Changping Laboratory, Beijing, China. (9) National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. University of Chinese Academy of Sciences, Beijing, China. (10) Changping Laboratory, Beijing, China. (11) CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. (12) Guangzhou National Laboratory, Bio-Island, Guangzhou, China. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. (13) School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. (14) School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. State Key Laboratory of Molecular oncology, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. Changping Laboratory, Beijing, China. yangxinfu@tsinghua.edu.cn.

Citation: Nat Commun 2026 Mar 17 Epub03/17/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41844634

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Targeting NK cell CLEC12B enhances cancer immunotherapy Spotlight 

(1) Sun P (2) Xu X (3) Hu B (4) Zhang K (5) Khan A (6) Chen H (7) Liu H (8) Khan S (9) Tao Q (10) Nashan B (11) Sun C

Nature immunology

Sun and Xu et al. showed that high expression of the C-type lectin receptor CLEC12B by tumor-infiltrating cells correlated with poor clinical prognosis in patients with HCC. NK cell- specific-Clec12b-/- mice exhibited reduced cancer cell growth and extended survival in HCC, CRC, and metastatic melanoma models. CLEC12B was upregulated on NK cells in the TIME and interacted with lipoprotein lipase to induce CLEC12B–ITIM-mediated inhibitory signaling in NK cells. A nanobody specific for CLEC12B safely revived NK cell activity, suppressed tumor progression, and synergized with anti-PD-1 and chemotherapy in mouse and humanized mouse tumor models.

Contributed by Paula Hochman

(1) Sun P (2) Xu X (3) Hu B (4) Zhang K (5) Khan A (6) Chen H (7) Liu H (8) Khan S (9) Tao Q (10) Nashan B (11) Sun C

Nature immunology

Sun and Xu et al. showed that high expression of the C-type lectin receptor CLEC12B by tumor-infiltrating cells correlated with poor clinical prognosis in patients with HCC. NK cell- specific-Clec12b-/- mice exhibited reduced cancer cell growth and extended survival in HCC, CRC, and metastatic melanoma models. CLEC12B was upregulated on NK cells in the TIME and interacted with lipoprotein lipase to induce CLEC12B–ITIM-mediated inhibitory signaling in NK cells. A nanobody specific for CLEC12B safely revived NK cell activity, suppressed tumor progression, and synergized with anti-PD-1 and chemotherapy in mouse and humanized mouse tumor models.

Contributed by Paula Hochman

ABSTRACT: Natural killer (NK) cells are innate immune effectors, but their cytotoxic potential can be compromised within the immunosuppressive tumor microenvironment. Identifying molecular mechanisms that underly this dysfunction is essential for advances in cancer immunotherapy. Here we show that CLEC12B, a C-type lectin receptor, functions as an inhibitory checkpoint that restricts NK cell-mediated antitumor immunity. High expression of CLEC12B by tumor-infiltrating NK cells correlates with poor clinical prognosis in patients with hepatocellular carcinoma. We identify lipoprotein lipase as a functional ligand for CLEC12B, triggering inhibitory signaling that suppresses NK cell activation. We developed a high-affinity nanobody as a potential therapeutic that disrupts the CLEC12B-lipoprotein lipase axis, thereby revitalizing NK cell activity and suppressing tumor progression in preclinical models. Furthermore, this nanobody has potent synergistic efficacy when combined with PD-1 blockade. These findings establish CLEC12B as a promising therapeutic target for rearming the immune system against solid malignancies.

Author Info: (1) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Prov

Author Info: (1) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (2) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (3) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (4) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (5) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (6) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (7) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (8) Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (9) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (10) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Transplant & Immunology Laboratory, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. The Transplantation Center, First Affiliated Hospital, School of Life Sciences and Medical Center, University of Sciences & Technology of China, Hefei, China. Research Centre of Big Data and Artificial Intelligence of Medicine, Hospital of Sun Yat-Sen University, Guangzhou, China. (11) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn.

Citation: Nat Immunol 2026 Mar 17 Epub03/17/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41844941

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Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering Spotlight 

(1) Chen X (2) Mao Z (3) Kolawole EM (4) Persechino M (5) Jude KM (6) Ogishi M (7) Mo KC (8) McLaughlin J (9) Cheng D (10) Xiang X (11) Yang X (12) Gee C (13) Liu S (14) Yang A (15) Obenaus M (16) Wang N (17) Noguchi M (18) Stoyanova T (19) Lee JK (20) Good Z (21) Latorraca NR (22) Evavold BD (23) Witte ON (24) Garcia KC

Science | Free PMC Article

To improve the potency of a prostate TAA-specific TCR, Chen and Mao et al. screened for CDR hotspot mutations that could increase catch-bond formation and thus TCR sensitivity, without modifying TCR affinity (and the potential for off-target toxicity). Several variants increased TCR–pHLA bond lifetime, which correlated with TCR response to cognate peptide. These variants increased T cell proliferation, cytotoxicity, in vivo tumor efficacy, and effector/proliferative gene expression among TILs. Crystal structures and in silico modeling revealed alterations to water inclusion and hydrogen-bonding, supporting HLA, TCR, or peptide interactions.

Contributed by Alex Najibi

(1) Chen X (2) Mao Z (3) Kolawole EM (4) Persechino M (5) Jude KM (6) Ogishi M (7) Mo KC (8) McLaughlin J (9) Cheng D (10) Xiang X (11) Yang X (12) Gee C (13) Liu S (14) Yang A (15) Obenaus M (16) Wang N (17) Noguchi M (18) Stoyanova T (19) Lee JK (20) Good Z (21) Latorraca NR (22) Evavold BD (23) Witte ON (24) Garcia KC

Science | Free PMC Article

To improve the potency of a prostate TAA-specific TCR, Chen and Mao et al. screened for CDR hotspot mutations that could increase catch-bond formation and thus TCR sensitivity, without modifying TCR affinity (and the potential for off-target toxicity). Several variants increased TCR–pHLA bond lifetime, which correlated with TCR response to cognate peptide. These variants increased T cell proliferation, cytotoxicity, in vivo tumor efficacy, and effector/proliferative gene expression among TILs. Crystal structures and in silico modeling revealed alterations to water inclusion and hydrogen-bonding, supporting HLA, TCR, or peptide interactions.

Contributed by Alex Najibi

ABSTRACT: T cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding "hotspot" whose mutation enhanced T cell activity by increasing TCR-pMHC (peptide-major histocompatibility complex) bond lifetime while preserving physiological affinities and antigen fine specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes, and tumor elimination. Crystal structures and molecular dynamics simulations revealed a single amino acid mutation at the catch-bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch-bond engineering is a viable biophysically based strategy for transforming tolerized antitumor T cells into potent TCR-T cell therapy killers.

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics,

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. (3) Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. (4) Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (9) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (10) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (13) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. (14) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (15) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (16) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (17) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (18) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Department of Urology, UCLA, Los Angeles, CA, USA. (19) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (20) Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. (21) Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. (22) Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. (23) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Molecular Biology Institute, UCLA, Los Angeles, CA, USA. (24) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.

Citation: Science 2026 Mar 19 391:eadx3162 Epub03/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41855322

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Cancer cell-derived sialylated IgG interacting with Siglec-7/9/10 is a potential immunotherapeutic target in pancreatic cancer Spotlight 

(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

Cell reports. Medicine

Zhang et al. identified sialic acid-bearing IgG (SIA-IgG) in PDAC cells, which correlated positively with immunosuppressive (IS) TAM infiltration, and negatively with survival. SIA-IgG potently induced IS TAMs via sialic acid binding to Siglecs 7/9/10, which upregulated CD206, ARG1, and M2-like cytokines in TAMs. In a positive feedback loop, TAM-derived TGFβ promoted SIA-IgG secretion in cancer cells by enhancing the IgG heavy chain and sialyltransferase ST6GAL1. An anti-SIA-IgG mAb was effective in s.c. and orthotopic PDAC models, including PDX and T cell-deficient tumors, inhibited IS-TAM infiltration, and increased CD8+ T cell infiltration.

Contributed by Morgan Janes

(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

Cell reports. Medicine

Zhang et al. identified sialic acid-bearing IgG (SIA-IgG) in PDAC cells, which correlated positively with immunosuppressive (IS) TAM infiltration, and negatively with survival. SIA-IgG potently induced IS TAMs via sialic acid binding to Siglecs 7/9/10, which upregulated CD206, ARG1, and M2-like cytokines in TAMs. In a positive feedback loop, TAM-derived TGFβ promoted SIA-IgG secretion in cancer cells by enhancing the IgG heavy chain and sialyltransferase ST6GAL1. An anti-SIA-IgG mAb was effective in s.c. and orthotopic PDAC models, including PDX and T cell-deficient tumors, inhibited IS-TAM infiltration, and increased CD8+ T cell infiltration.

Contributed by Morgan Janes

ABSTRACT: The limited effectiveness of T cell-based immune checkpoint blockade (ICB) therapy in most patients with pancreatic ductal adenocarcinoma (PDAC) is largely due to poor CD8(+) T cell infiltration and a highly immunosuppressive microenvironment driven by excessive myeloid cell accumulation. This highlights the urgent need for new immunotherapy targets and strategies. In this study, an identified pro-cancer factor, cancer cell-derived sialylated IgG (SIA-IgG), is found to be significantly overexpressed in pancreatic cancer cells. SIA-IgG inhibits macrophage phagocytosis and induces an M2-like immunosuppressive phenotype through interactions with Siglec-7/9/10. SIA-IgG and TGF-_1, a key immunosuppressive factor, reinforce each other in a positive feedback loop, promoting immune evasion in PDAC. Blocking SIA-IgG with specific monoclonal antibodies shows significant therapeutic potential through reversal of PDAC's immunosuppressive microenvironment. Our findings identify the SIA-IgG/Siglec axis as an immunotherapeutic target for PDAC, offering a feasible approach for the development of immunotherapeutic strategies.

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

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A bispecific nanobody-drug conjugate targeting TROP2 and c-Met for low-concentration, single-dose treatment of pancreatic cancer Spotlight 

(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

Cell reports. Medicine

To address limitations of pancreatic cancer treatment, Ning, Liu, Liu, Zeng, and Qin et al. developed an internalizing, nanobody-based, bispecific ADC (B6ADC) that simultaneously bound TROP2 and c-MET, and was conjugated to the microtubule cytotoxic inhibitor MMAE. B6ADC demonstrated broad spectrum activity in multiple pancreatic models, and outperformed clinically approved ADCs for TROP2 and c-MET, both alone and in combination. B6ADC showed improved tumor selectivity with dual-positive or weakly positive Ag expression, had a favorable safety profile, and eradicated large tumors at a single low dose of 2.2 mg/kg in several models.

Contributed by Katherine Turner

(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

Cell reports. Medicine

To address limitations of pancreatic cancer treatment, Ning, Liu, Liu, Zeng, and Qin et al. developed an internalizing, nanobody-based, bispecific ADC (B6ADC) that simultaneously bound TROP2 and c-MET, and was conjugated to the microtubule cytotoxic inhibitor MMAE. B6ADC demonstrated broad spectrum activity in multiple pancreatic models, and outperformed clinically approved ADCs for TROP2 and c-MET, both alone and in combination. B6ADC showed improved tumor selectivity with dual-positive or weakly positive Ag expression, had a favorable safety profile, and eradicated large tumors at a single low dose of 2.2 mg/kg in several models.

Contributed by Katherine Turner

ABSTRACT: Pancreatic cancer remains highly lethal with limited treatment options. Although antibody-drug conjugates (ADCs) have emerged as promising therapeutic agents, their efficacy is often limited by heterogeneous antigen expression and poor tumor penetration. To address these limitations, we develop B6ADC, a nanobody-based bispecific ADC that simultaneously targets TROP2 and c-Met. In preclinical studies, B6ADC exhibits potent cytotoxicity in vitro across various TROP2/c-Met-expressing cancer cell lines and superior tumor inhibition in vivo compared with single-target ADC combination, including the clinically approved TROP2 ADC sacituzumab govitecan and c-Met ADC Teliso-V, as well as their combination. Notably, B6ADC eradicates giant tumors with a single dose at a low concentration of 2.2 mg/kg. We present a nanobody-based BsADC that simultaneously targets TROP2 and c-Met, with broad-spectrum antitumor activity, and improves selectivity for tumors with dual-positive or weakly positive antigen expression, offering a promising strategy for treating pancreatic cancer and other TROP2/c-Met-expressing malignancies.

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

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Biodegradable targeted polymeric mRNA nanoparticles enable in vivo CD19 CAR T cell generation and lead to B cell depletion Spotlight 

(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

Science advances | Free PMC Article

To enhance nanoparticle (NP) uptake by, target gene delivery to, and activation of T cells, Jain et al. generated stable (to lyophilization and freeze/thaw), biodegradable, beta-­amino ester polymer-based NPs with PEG-lipid-­anchored ligands/Abs (tPNPs). Anti-CD3/anti-CD28-expressing tPNPs with CAR-encoding mRNA cargo achieved high CAR expression by and stimulation of primary murine T cells in vitro, and enhanced lymphoid selectivity and T cell activation, proliferation, and effector and memory T cell generation upon i.v. delivery to mice. Anti-CD19 CAR-encoding tPNP safely and robustly depleted B cells in the peripheral blood and spleens of healthy mice.

Contributed by Paula Hochman

(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

Science advances | Free PMC Article

To enhance nanoparticle (NP) uptake by, target gene delivery to, and activation of T cells, Jain et al. generated stable (to lyophilization and freeze/thaw), biodegradable, beta-­amino ester polymer-based NPs with PEG-lipid-­anchored ligands/Abs (tPNPs). Anti-CD3/anti-CD28-expressing tPNPs with CAR-encoding mRNA cargo achieved high CAR expression by and stimulation of primary murine T cells in vitro, and enhanced lymphoid selectivity and T cell activation, proliferation, and effector and memory T cell generation upon i.v. delivery to mice. Anti-CD19 CAR-encoding tPNP safely and robustly depleted B cells in the peripheral blood and spleens of healthy mice.

Contributed by Paula Hochman

ABSTRACT: While chimeric antigen receptor (CAR) T cell therapies have demonstrated therapeutic efficacy against B cell malignancies, widespread implementation of these therapies is hindered by a cumbersome, ex vivo manufacturing process. Delivery of CAR-encoding messenger RNA (mRNA) to endogenous T cells can generate these therapeutic cells in vivo and streamline this manufacturing workflow. To accomplish this, T cell-activating ligands were conjugated to a biodegradable polymeric mRNA nanoparticle to form T cell-targeted particles. By conjugating multiple activating ligands, T cell transfection and stimulation in vitro was increased, and greater T cell transfection and selectivity in vivo was achieved compared to an untargeted particle. These nanoparticles can flexibly encapsulate mRNA cargos and were used to deliver anti-CD19 CAR mRNA in vivo, enabling depletion of 95% of B cells in the peripheral blood and 50% depletion of splenic B cells in healthy mice. These findings regarding nanoparticle tropism and their potential therapeutic efficacy highlight the importance of this nonviral, polymeric platform to address key limitations associated with current CAR T practices.

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

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IL-7/IL-15/IL-21 cytokine-fusion scaffold generates highly functional CAR T cells enriched in long-lived T memory stem cells Spotlight 

(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

Science advances | Free PMC Article

Cole et al. used HCW9206 – a soluble tissue factor fusion protein that links IL-7, IL-15/IL-15Rα superagonist, and IL-21 – for the generation of T stem cell memory (TSCM)-enriched polyfunctional CAR T cells, without requiring anti-CD3/CD28 activation. In a humanized mouse model of HIV infection, HCW9206-stimulated duoCAR T cells (simultaneously targeting two HIV epitopes) showed superior viremia suppression compared to duoCAR TαCD3/CD28 cells. CD19 CAR THCW9206 cells exhibited increased functional persistence and elimination of an initial and subsequent rechallenge with NALM-6 leukemia cells in vivo compared to CD19 CAR TαCD3/CD28 cells.

Contributed by Ute Burkhardt

(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

Science advances | Free PMC Article

Cole et al. used HCW9206 – a soluble tissue factor fusion protein that links IL-7, IL-15/IL-15Rα superagonist, and IL-21 – for the generation of T stem cell memory (TSCM)-enriched polyfunctional CAR T cells, without requiring anti-CD3/CD28 activation. In a humanized mouse model of HIV infection, HCW9206-stimulated duoCAR T cells (simultaneously targeting two HIV epitopes) showed superior viremia suppression compared to duoCAR TαCD3/CD28 cells. CD19 CAR THCW9206 cells exhibited increased functional persistence and elimination of an initial and subsequent rechallenge with NALM-6 leukemia cells in vivo compared to CD19 CAR TαCD3/CD28 cells.

Contributed by Ute Burkhardt

ABSTRACT: Functional persistence of chimeric antigen receptor T cells (CAR T cells) is limited by conventional CAR T cell manufacturing using anti-CD3/CD28 (αCD3/28) stimulation, which generates terminally differentiated and shorter-lived CAR T cells. We demonstrated that HCW9206, a unique protein scaffold linking interleukin-7 (IL-7), an IL-15/IL-15 receptor α (IL-15Rα) complex, and IL-21, generates CAR T cells without requiring αCD3/28 activation, which are highly enriched in long-lived T memory stem cells (TSCM cells) (>50%) and display potent activity across distinct disease models, HIV-1 or B cell leukemia. In a humanized mouse HIV infection model, HCW9206-generated anti-HIV duoCAR T cells suppressed viremia more effectively than αCD3/28-generated anti-HIV duoCAR T cells. In a xenograft leukemia mouse model, a recall proliferative response and complete clearance of leukemia rechallenge were displayed by HCW9206-generated but not by αCD3/28-generated anti-CD19 CAR T cells. HCW9206, a first-in-class cytokine scaffold-based platform, enables production of more potent CAR T cell-based immunotherapies by generating a CAR T cell population, which is highly functional and also markedly enriched for long-lived TSCM cells. This strategy is broadly applicable to increase persistence and functionality of CAR T cells, enhancing their efficacy for treating infectious disease and cancer.

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

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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

Science immunology

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

Science immunology

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

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