Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8+T and tumor cells
Gui‐Qi Zhu, Zheng Tang, Tian-Hao Chu, Biao Wang, Shiping Chen, Chenyang Tao, Jialiang Cai, Rui Yang, Wei‐Feng Qu, Yi Wang, Qianfu Zhao, Run Huang, Meng‐Xin Tian, Yuan Fang, Jun Gao, Xiaoling Wu, Jian Zhou, Wei‐Ren Liu, Zhi Dai, Ying–Hong Shi, Jia Fan
Abstract
Abstract Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8 + T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8 + T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8 + T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8 + T cells.