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Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8+T and tumor cells
Gui-Qi Zhu1,2, Zheng Tang1,2, Tian-Hao Chu1,2
1Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
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.
Insights
Targeting splicing factor SRSF1 in cancer cells enhances CD8+ T cell immunity and metabolism. Inhibiting SRSF1 boosts antitumor responses and immunotherapy effectiveness, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Serine arginine-rich splicing factor 1 (SRSF1) is an oncogenic splicing factor driving cancer progression.
- The impact of inhibiting tumor-intrinsic SRSF1 on antitumor immunity is not well understood.
Purpose of the Study:
- To investigate the effects of SRSF1 inhibition on the tumor microenvironment and CD8+ T cell-mediated immunity.
- To explore SRSF1 as a therapeutic target for enhancing cancer immunotherapy.
Main Methods:
- Depletion of SRSF1 in CD8+ T cells and tumor cells.
- Analysis of gene transcription factors (c-Jun, c-myc, JunB) and glycolytic metabolism.
- Treatment with the SRSF1 small-molecule inhibitor TN2008 in mouse cancer models.
- Evaluation of CD8+ T cell function and adoptive T cell therapy efficacy.
Main Results:
- Depleting SRSF1 in CD8+ T cells improved their immune function and glycolytic metabolism.
- Inactivating SRSF1 in tumor cells reduced key transcription factors, reprogramming metabolism and restoring CD8+ T cell function.
- TN2008 treatment boosted antitumor immune responses and enhanced immunotherapy effectiveness in vivo.
Conclusions:
- Targeting SRSF1 simultaneously disrupts tumor cell metabolism and enhances CD8+ T cell antitumor immunity.
- SRSF1 inhibition represents a promising strategy to improve cancer immunotherapy outcomes.
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