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 ...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.展开更多
γδT cells are a conserved population of innate lymphocytes with diverse structural and functional heterogeneity that participate in various immune responses during tumor progression. γδT cells perform potent immun...γδT cells are a conserved population of innate lymphocytes with diverse structural and functional heterogeneity that participate in various immune responses during tumor progression. γδT cells perform potent immunosurveillance by exerting direct cytotoxicity, strong cytokine production and indirect antitumor immune responses. However, certain γδT-cell subsets also contribute to tumor progression by facilitating cancer-related inflammation and immunosuppression. Here, we review recent observations regarding the antitumor and protumor roles of major structural and functional subsets of human γδT cells, describing how these subsets are activated and polarized, and how these events relate to subsequent function in tumor immunity. These studies provide insights into the manipulation of γδT-cell function to facilitate more targeted approaches for tumor therapy.展开更多
基金funded by the National Natural Science Foundation of China(Grant No.).This research was supported by grants from the National Natural Science Foundation of China(Grant Nos.82073217,82403555,82073218,82003084)the National Key Research and Development Program of China(Grant No.2018YFC1312100)+3 种基金the Shanghai Municipal Key Clinical Specialty,and the CAMS Innovation Fund for Medical Sciences(CIFMS 2019-I2M-5-058)the Leading Project of the Science and Technology Commission of Shanghai Municipality(No.21Y21900100)the Project of the Shanghai Municipal Health Commission This research was also supported by the Outstanding Resident Clinical Postdoctoral Program at Zhongshan Hospital,Fudan University,and the China Postdoctoral Science Foundation(KLF152165,202140269)The authors appreciated for the technical assistance in the virtual screening job described in this study by Prof.Renxiao Wang,School of Pharmacy,Fudan University.
文摘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.
文摘γδT cells are a conserved population of innate lymphocytes with diverse structural and functional heterogeneity that participate in various immune responses during tumor progression. γδT cells perform potent immunosurveillance by exerting direct cytotoxicity, strong cytokine production and indirect antitumor immune responses. However, certain γδT-cell subsets also contribute to tumor progression by facilitating cancer-related inflammation and immunosuppression. Here, we review recent observations regarding the antitumor and protumor roles of major structural and functional subsets of human γδT cells, describing how these subsets are activated and polarized, and how these events relate to subsequent function in tumor immunity. These studies provide insights into the manipulation of γδT-cell function to facilitate more targeted approaches for tumor therapy.
