ATM-AMPKα mediated LAG-3 expression suppresses T cell function in prostate cancer

•LAG3 upregulation inhibits effector function of CD4 T-cells from PCa.•Insufficiency expression of ATM upregulates LAG3 expression in PCa.•ATM dysfunction impairs AMPKα which enhances the binding of EGR2 and XBP1 to LAG3 promoters.•Blocking EGR2/XBP1 or restoring ATM-AMPKα aid in the cancer immunotherapy for PCa. Immunotherapy for prostate cancer (PCa) faces serious challenges. Therefore, the co-inhibitory receptors that regulate T cell function of PCa must be elucidated. Here we identified that the inhibitory receptor LAG3 was significantly induced in T cells from PCa patients. Gene array analysis revealed that insufficient ataxia telangiectasia mutated (ATM) gene expression in PCa T cells was responsible for the elevated LAG3 expression. Mechanistically, insufficient ATM expression impaired its ability to activate AMPKα signaling and CD4+ T cell functions, which further enhances the binding of the transcription factors XBP1 and EGR2 to LAG3 promoter. Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4+ T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4+ T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment.