AbstractT cell exhaustion is one of the main reasons of tumor immune escape. Using single cell transcriptome data of CD8+ T cells in multiple cancers, we identified different cell types, in which Pre_exhaust and exhausted T cells participated in negative regulation of immune system process. By analyzing the co-expression network patterns and differentially expressed genes of Pre_exhaust, exhausted and effector T cells, we identified 35 genes related to T cell exhaustion, which high GSVA scores were associated with significantly poor prognosis in various cancers. In the differentially expressed genes,RGS1showed the greatest fold change in Pre_exhaust and exhausted cells of three cancers compared with effector T cells, and high expression ofRGS1was also associated with poor prognosis in various cancers. Additionally, RGS1 protein was upregulated significantly in tumor tissues in the immunohistochemistry verification. Furthermore,RGS1displayed positive correlation with the 35 genes, especially highly correlated withPDCD1, CTLA4, HAVCR2andTNFRSF9in CD8+ T cells and cancer tissues, indicating important roles ofRGS1in CD8+ T cell exhaustion. Considering the GTP-hydrolysis activity ofRGS1and significantly high mRNA and protein expression in cancer tissues, we speculated thatRGS1potentially mediate the T cell retention to lead to the persistent antigen stimulation, resulting in T cell exhaustion. In conclusion, our findings suggest that RGS1 is a new marker and promoting factor for CD8+ T cell exhaustion, and provide theoretical basis for research and immunotherapy of exhausted cells.