Ribonuclease 1 Induces T-Cell Dysfunction and Impairs CD8⁺ T-Cell Cytotoxicity to Benefit Tumor Growth through...

T-cell-based immunotherapy holds promise for eliminating cancer through T-cell activation. However, prolonged interaction between T cells and tumors and the presence of immunosuppressive factors can diminish T-cell cytotoxicity, leading to treatment failure. Here, ribonuclease 1 (RNase1), which degrades RNA, reduced the expression of effector cytokines and increases immune checkpoint protein levels, inducing T-cell dysfunction. RNase1 expression is positively associated with exhausted T-cell gene signatures and immune checkpoint proteins across several cancer types. Cancer cells expressing RNase1 are resistant to CD8⁺ T-cell-mediated killing. RNase1 promotes tumor growth in immunocompetent, but not in immunodeficient, mouse models and inhibits CD8⁺ T-cell activity in vivo. Mechanistically, RNase1 enters T cells and deactivates signal transducer and activator of transcription 1 (STAT1), causing T-cell dysfunction. Loss of RNase1-STAT1 interaction restores CD8⁺ T-cell cytotoxicity. Notably, a study has found RNase1 might activate CD4⁺ T cells to inhibit breast cancer growth, while another has indicated it causes immunosuppression in liver cancer. The current research shows that RNase1 does not impact CD4⁺ T cells in vivo. Overall, the study supports the immunosuppressive role of RNase1 in cancer of negatively regulating STAT1 to impair CD8⁺ T-cell cytotoxicity. Targeting the RNase1-STAT1 interaction could prevent CD8⁺ T-cell dysfunction in RNase1-highly expressing cancer patients.