biostudies-literatureZhang YScience and Technology Commission of Shanghai MunicipalityNational Natural Science Foundation of China107982https://www.ebi.ac.uk/biostudies/studies/S-EPMC11665689biostudies-literatureUnknown300(12)Effective cancer immunotherapy relies on enhancing the host's immune response, particularly by boosting T cell-mediated cytotoxicity against tumor cells. In this study, we identify CWF19-like cell cycle control factor 1 (CWF19L1) as a novel splicing regulator that enhances T cell-mediated cytotoxicity. CWF19L1 interacts prominently with key splicing factors within the nucleus, including components of the U5 small nuclear ribonucleoprotein and the pre-mRNA processing factor 19 (PRPF19) complex. Deficiency of CWF19L1 disrupts alternative splicing of immune-related genes, resulting in diminished expression of cytotoxic molecules. Furthermore, CWF19L1 plays a critical role in promoting T cell-mediated antitumor responses by upregulating the expression of effector cytokines. Our findings unveilThe Journal of biological chemistryCWF19L1 promotes T-cell cytotoxicity through the regulation of alternative splicing.PMC1166568921JC14009003237092620ZR140760082071780Yi JYang HZhang DZhang YZhang HWei GRen TZhao HfalseCWF19L1 promotes T-cell cytotoxicity through the regulation of alternative splicing.Effective cancer immunotherapy relies on enhancing the host's immune response, particularly by boosting T cell-mediated cytotoxicity against tumor cells. In this study, we identify CWF19-like cell cycle control factor 1 (CWF19L1) as a novel splicing regulator that enhances T cell-mediated cytotoxicity. CWF19L1 interacts prominently with key splicing factors within the nucleus, including components of the U5 small nuclear ribonucleoprotein and the pre-mRNA processing factor 19 (PRPF19) complex. Deficiency of CWF19L1 disrupts alternative splicing of immune-related genes, resulting in diminished expression of cytotoxic molecules. Furthermore, CWF19L1 plays a critical role in promoting T cell-mediated antitumor responses by upregulating the expression of effector cytokines. Our findings unveil2024-01-01T00:00:00Z2024 Dec2026-04-08T19:47:18.343Z2025-04-06T22:12:45.306ZS-EPMC116656893954224810.1016/j.jbc.2024.107982