CRY1 fuels resistance to T cell-based immunotherapy in NANOGhigh cancers

Cancer immunotherapies, including immune checkpoint blockade (ICB), have marked a significant breakthrough in cancer treatment but their clinical efficacy is limited in immune-resistant tumors. Previously, we found that immunotherapy-mediated immune selection enriches immune-resistant tumors with both tumor-intrinsic and -extrinsic refractory phenotypes via the transcriptional induction of HDAC1 by NANOG. Here, we identify CRY1 as a critical transcriptional target of NANOG that stabilizes Cyclin A and MCL1 to promote cancer stem cell-like property and resistance to cytotoxic T cell-mediated killing in NANOG ^high tumor cells through HDAC1-mediated epigenetic silencing of APC3 and TRIM17. Additionally, CRY1 downregulates CXCL10 via HDAC1-mediated repression, thereby suppressing T cell infiltration. Importantly, CRY1 inhibition synergizes with PD-1 blockade and adoptive T cell transfer in reducing tumor growth by converting immune-resistant tumors into immune-sensitive tumors. Collectively, these findings highlight CRY1 as a critical mediator of the NANOG/HDAC1 axis in the multiple refractory properties of immune-resistant tumors and suggest CRY1 as a potential therapeutic target.