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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Macrophages restrict tumor immune infiltration by controlling collagen topography Spotlight 

(1) Fusilier Z (2) Clément A (3) Simon F (4) Calvente I (5) Jean-Marie R (6) Mathieu M (7) Calmettes V (8) Piastra-Facon F (9) Quintana-Perez Y (10) Clement JG (11) Crestey L (12) Lumineau E (13) Henninger R (14) Tonani M (15) Manriquez V (16) Lacerda Mariano L (17) Bensaid L (18) de Villemagne P (19) Piaggio E (20) Semetey V (21) Coscoy S (22) Martini E (23) Scita G (24) Gelly JC (25) Ivaska J (26) Isambert H (27) Goudot C (28) Pierobon P (29) Lennon-Duménil AM (30) Moreau HD

Science immunology

Using tissue imaging, transcriptional analysis, and machine learning, Fusilier et al. found that immune cell infiltration and localization within established fibrotic tumors could be predicted by the local topography of fibrillar collagens. This topography was controlled by cancer and stromal cell expression of Tcf4, which promoted collagen III deposition, resulted in disorganized fibrillar networks at the tumor periphery, and favored infiltration of T cells and neutrophils. Macrophages repressed this Tcf4 pathway, negatively regulating immune infiltration. Analysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures.

Contributed by Lauren Hitchings

(1) Fusilier Z (2) Clément A (3) Simon F (4) Calvente I (5) Jean-Marie R (6) Mathieu M (7) Calmettes V (8) Piastra-Facon F (9) Quintana-Perez Y (10) Clement JG (11) Crestey L (12) Lumineau E (13) Henninger R (14) Tonani M (15) Manriquez V (16) Lacerda Mariano L (17) Bensaid L (18) de Villemagne P (19) Piaggio E (20) Semetey V (21) Coscoy S (22) Martini E (23) Scita G (24) Gelly JC (25) Ivaska J (26) Isambert H (27) Goudot C (28) Pierobon P (29) Lennon-Duménil AM (30) Moreau HD

Science immunology

Using tissue imaging, transcriptional analysis, and machine learning, Fusilier et al. found that immune cell infiltration and localization within established fibrotic tumors could be predicted by the local topography of fibrillar collagens. This topography was controlled by cancer and stromal cell expression of Tcf4, which promoted collagen III deposition, resulted in disorganized fibrillar networks at the tumor periphery, and favored infiltration of T cells and neutrophils. Macrophages repressed this Tcf4 pathway, negatively regulating immune infiltration. Analysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures.

Contributed by Lauren Hitchings

ABSTRACT: During tumorigenesis, the extracellular matrix is extensively remodeled. Whereas the impact of such remodeling on tumor growth and invasion is well described, the consequences on immune infiltration are not well understood. Combining tissue imaging and machine learning, we show that immune cell localization in tumors can be predicted by the local topography of fibrillar collagens. Such topographies are dictated by a fibrotic pathway driven by transcription factor 4 (Tcf4) in both cancer and stromal cells, which promotes collagen III deposition and results in intermingled collagen networks that favor intratumor infiltration of T cells and neutrophils. Macrophages inhibit this pathway, highlighting their key structural role in shaping the tumor extracellular matrix. Reanalysis of data from human solid tumors revealed a strong correlation between TCF4, COL3A1, and T cell and neutrophil signatures. Together, our data identify collagen network topographies as a key regulator of tumor-infiltrating immune cells.

Author Info: (1) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. UniversitŽ Paris-CitŽ, Paris, France. (2) Institut Curie, PSL University, INSERM U932, Immunity

Author Info: (1) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. UniversitŽ Paris-CitŽ, Paris, France. (2) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (3) Institut Curie, UniversitŽ PSL, Sorbonne UniversitŽ, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (4) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. Institut Curie, UniversitŽ PSL, Sorbonne UniversitŽ, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (5) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. UniversitŽ Paris CitŽ, INSERM, EFS, BIGR U1134, Team DSIMB, Paris, France. (6) Turku Bioscience Centre, University of Turku and bo Akademi University, Turku, Finland. (7) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (8) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (9) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (10) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (11) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (12) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (13) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (14) IFOM ETS, AIRC Institute of Molecular Oncology, Milan, Italy. Department of Oncology and Hematology-Oncology, Universitˆ degli Studi di Milano, Milan, Italy. (15) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (16) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (17) Pathologie ExpŽrimentale PMDT, Department of Pathology (PATHEX), Institut Curie, Paris, France. (18) Kaer Labs, Nantes, France. (19) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (20) Chimie ParisTech, UniversitŽ PSL, CNRS, Institut de Recherche de Chimie Paris, Paris, France. (21) Institut Curie, UniversitŽ PSL, Sorbonne UniversitŽ, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (22) IFOM ETS, AIRC Institute of Molecular Oncology, Milan, Italy. Department of Oncology and Hematology-Oncology, Universitˆ degli Studi di Milano, Milan, Italy. (23) IFOM ETS, AIRC Institute of Molecular Oncology, Milan, Italy. Department of Oncology and Hematology-Oncology, Universitˆ degli Studi di Milano, Milan, Italy. (24) UniversitŽ Paris CitŽ, INSERM, EFS, BIGR U1134, Team DSIMB, Paris, France. (25) Turku Bioscience Centre, University of Turku and bo Akademi University, Turku, Finland. Department of Life Technologies, University of Turku, Turku, Finland. InFLAMES Research Flagship, University of Turku, Turku, Finland. Western Finnish Cancer Center (FICAN West), University of Turku, Turku, Finland. Foundation for the Finnish Cancer Institute, Tukholmankatu 8, Helsinki, Finland. (26) Institut Curie, UniversitŽ PSL, Sorbonne UniversitŽ, CNRS UMR168, Physics of Cells and Cancer, Paris, France. (27) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (28) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. UniversitŽ Paris CitŽ, CNRS, Inserm, Institut Cochin, Paris, France. (29) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France. (30) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, Paris, France.

Citation: Sci Immunol 2026 Mar 20 11:eadw8291 Epub03/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41860994

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

Spotlight 

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

Cancer Cell

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

Contributed by Ed Fritsch

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

Cancer Cell

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

Contributed by Ed Fritsch

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

Author Info:

Author Info:

Citation: Epub

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    Amino acid supplementation enhances in vivo efficacy of lipid nanoparticle-mediated mRNA delivery in preclinical models Featured  

    (1) Chen K (2) Wang W (3) Lennon A (4) McClure RA (5) Vuchkovska A (6) Kelley SO (7) Wang Z

    Science translational medicine

    Chen, Wang, et al. assessed how metabolic differences may impact lipid nanoparticle (LNP) delivery. In physiologic culture medium, LNP delivery was limited, due to the downregulation of amino acids. Amino acid supplementation (AAS) improved LNP delivery of mRNA cargo in vitro and in vivo. AAS was also found to be beneficial in two preclinical models: in a liver inflammation model for growth hormone delivery via LNPs, where it improved outcomes, and for the specific delivery of gene editing components by LNPs.

    (1) Chen K (2) Wang W (3) Lennon A (4) McClure RA (5) Vuchkovska A (6) Kelley SO (7) Wang Z

    Science translational medicine

    Chen, Wang, et al. assessed how metabolic differences may impact lipid nanoparticle (LNP) delivery. In physiologic culture medium, LNP delivery was limited, due to the downregulation of amino acids. Amino acid supplementation (AAS) improved LNP delivery of mRNA cargo in vitro and in vivo. AAS was also found to be beneficial in two preclinical models: in a liver inflammation model for growth hormone delivery via LNPs, where it improved outcomes, and for the specific delivery of gene editing components by LNPs.

    ABSTRACT: Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic messenger RNA (mRNA). Despite extensive efforts to optimize lipid formulations for in vivo delivery, efficacy of mRNA by LNPs remains suboptimal in many organs. Here, we demonstrate that LNP delivery efficacy is influenced by cellular metabolism, with the physiologic metabolome imposing constraints on mRNA expression from LNPs. Using an in vitro system, we found that simulated physiologic metabolic conditions led to the down-regulation of certain amino acid metabolic programs. Supplementation with an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Coadministration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro by promoting clathrin-independent carrier-mediated endocytosis. Delivery of mRNA by LNPs coadministered with AAS by multiple routes enhanced in vivo mRNA expression in preclinical models. Delivery of mRNA encoding growth hormone by LNPs with coadministration of AAS improved the liver growth hormone expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through an intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized AAS as a codelivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.

    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 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

    Tags:

    Engineering lipid nanoparticle-stabilized emulsions for spatiotemporal mRNA delivery and enhanced T cell immunity Spotlight 

    (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

    Cell reports. Medicine

    As an alternative to conventional lipid nanoparticles (LNPs), Zhou, Gao, Huang, and Yan et al. developed a colloid-engineered, LNP-stabilized emulsion (LSE) that was preferentially taken up by APCs (rather than stromal cells or fibroblasts), enhancing chemokine-driven activation and localized antigen presentation while reducing off-target antigen expression and non-immune cell cross-presentation. LSE fostered Th1-polarizization, expanded the T cell repertoire, and increased IFNγ and IL-2, with responses lasting up to 300 days. In murine tumor models, LSE vaccines elicited protective and therapeutic antitumor immunity that enhanced survival.

    Contributed by Lauren Hitchings

    (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

    Cell reports. Medicine

    As an alternative to conventional lipid nanoparticles (LNPs), Zhou, Gao, Huang, and Yan et al. developed a colloid-engineered, LNP-stabilized emulsion (LSE) that was preferentially taken up by APCs (rather than stromal cells or fibroblasts), enhancing chemokine-driven activation and localized antigen presentation while reducing off-target antigen expression and non-immune cell cross-presentation. LSE fostered Th1-polarizization, expanded the T cell repertoire, and increased IFNγ and IL-2, with responses lasting up to 300 days. In murine tumor models, LSE vaccines elicited protective and therapeutic antitumor immunity that enhanced survival.

    Contributed by Lauren Hitchings

    ABSTRACT: Achieving strong T cell responses remains a key challenge in mRNA vaccines and therapeutics. Here, we develop a colloid-engineered, lipid nanoparticle-stabilized emulsion (LSE) to study how spatiotemporal mRNA delivery influences immune dynamics. Multi-omic analyses (single-cell RNA sequencing [scRNA-seq], flow cytometry, and enzyme-linked immunosorbent assay [ELISA]) illustrate that LSE facilitates localizing mRNA to immunocytes, increasing antigen presentation while reducing off-target antigen secretion, and non-immune cell cross-presentation, which are key factors linked to T cell exhaustion in conventional LNP-based systems. This targeted delivery induces durable interferon (IFN)-γ+ and interleukin (IL)-2+ T cell responses lasting up to 300 days and expands the T cell repertoire in mice compared to the AS01-adjuvanted Shingrix vaccine. Furthermore, LSE elicits potent protective and therapeutic effects against B16-OVA and LLC-NY-ESO1 inoculation in mice. These results indicate the potential of spatially controlled mRNA delivery for enhanced mRNA vaccinations.

    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

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