ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR329/004/SRR32938604/SRR32938604.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR288/092/SRR28803792/SRR28803792_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR288/092/SRR28803792/SRR28803792_1.fastq.gzprimaryOK200GenomicsHarvard Medical Schoolhttps://www.ebi.ac.uk/ena/browser/view/PRJNA1104636In vivo CRISPR screens using activated CD8+ T cells have uncovered novel immunotherapy targets for cancer, yet similar high-throughput screens have not been performed using naive CD8+ T cells. 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-27Ra expression in mouse and human CD8+ T cells. IL-27Ra 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.ENAfalseA STUB1-CHIC2 complex decreases IL-27Ra expression on CD8+ T cells to restrain tumor immunity2025-05-032025-05-03PRJNA1104636