To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8+ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8+ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8+ T cells.
Contributed by Paula Hochman
(1) Tang M (2) Huang Y (3) Bi J (4) Meng D (5) Zheng X (6) Peng H (7) Sun R (8) Ma H (9) Tian Z (10) Sun H (11) Zheng X
To mitigate systemic IL-12 activation, Tang et al. generated T-12, a fusion protein linking IL-12 to an anti-TIGIT scFv that blocks TIGIT binding to its inhibitory receptor. Compared to wild-type IL-12, T-12 selectively localized to tumor sites and activated intratumoral NK and CD8+ T cells (both highly expressing TIGIT) to promote NK cell proliferation and reprogram CD8+ T cells toward a proliferative, memory-like effector phenotype. T-12 exhibited an MTD ~100X higher than wild-type IL-12, suppressed tumor growth in multiple mouse models (including immunologically “cold”/anti-PD-1 resistant), and reduced metastatic lesions to promote survival by mechanisms requiring both NK and CD8+ T cells.
Contributed by Paula Hochman
ABSTRACT: The limitation of wild-type interleukin-12 (IL-12) in its clinical application lies in its systemic activation, which results in severe toxicities. Here, we develop a fusion protein named _TIGIT-IL12 (T-12), which fuses the 13G6 (_TIGIT) antibody scFv fragment in tandem with IL-12. T-12 can selectively localize to the tumor site and concurrently target intratumoral natural killer (NK) and CD8(+) T cells in vivo. T-12 demonstrated exceptional efficacy in reducing tumor burden across multiple tumor models in mice, dependent on NK and CD8(+) T cells. T-12 preferentially activates tumor-infiltrating NK and CD8(+) T cells over their peripheral counterparts, in contrast to wild-type IL-12. Compared with wild-type IL-12, T-12 exhibits greater safety upon systemic administration while treating tumor-bearing models, and the maximal tolerance dosage was elevated by up to about 100-fold. T-12 exhibits potent therapeutic efficacy in checkpoint-insensitive tumor models and metastatic tumor models. These findings underscore the potential of the T-12 fusion protein as a strategy in immunotherapy.
Author Info:
(1) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedic
ine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (2) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Center for Genomic and Personalized Medicine, Guangxi key Laboratory for Genomic and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, The First Affiliated Hospital of Guangxi Medical University, Guangxi Medical University, Nanning 530021, Guangxi, China. (3) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (4) CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. (5) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (6) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (7) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. (8) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. Electronic address: mahongdi@ustc.edu.cn. (9) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: tzg@ustc.edu.cn. (10) Department of Immunology, School of Basic Medical Sciences, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: haoyusun@ustc.edu.cn. (11) State Key Laboratory of Immune Response and Immunotherapy, Institute of Immunology, School of Basic Medical Sciences, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Hefei TG ImmunoPharma Corporation Limited, Hefei, China. Electronic address: ustczxh@ustc.edu.cn.
Citation: Cell Rep Med 2026 Jun 16 102876 Epub06/16/2026
