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Here we present an 899-gene in vivo CRISPR screen using naive CD8+ T cells, which identified the E3 ubiquitin ligase STUB1 as a novel negative regulator of anti-tumor CD8+ T cell responses. Stub1 knockout (KO) CD8+ T cells control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate IL-27Rα expression in mouse and human CD8+ T cells. IL-27Rα expression is essential for the accumulation of Stub1 KO or Chic2 KO CD8+ T cells in tumors and tumor growth control. Together, these findings demonstrate that the STUB1-CHIC2 complex is a novel regulator of cytokine receptor expression in CD8+ T cells and provide the rationale for inhibiting this pathway to improve CD8+ T cell-mediated anti-tumor immunity. Overall design: To investigate the genes expressed in naïve CD8+ T cells and CD8+ T cells responding to the tdLN and tumor in isotype treated or PD-1 blockade-treated mice we performed RNAseq.ENAfalseA STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunityA STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity2025-09-242025-06-12PRJNA1104988GSE26592910090