ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/051/SRR33048751/SRR33048751_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/045/SRR33048745/SRR33048745_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/053/SRR33048753/SRR33048753_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/049/SRR33048749/SRR33048749_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/058/SRR33048758/SRR33048758_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/057/SRR33048757/SRR33048757_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/050/SRR33048750/SRR33048750_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/062/SRR33048762/SRR33048762_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/052/SRR33048752/SRR33048752_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/049/SRR33048749/SRR33048749_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/050/SRR33048750/SRR33048750_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/052/SRR33048752/SRR33048752_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/060/SRR33048760/SRR33048760_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/062/SRR33048762/SRR33048762_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/053/SRR33048753/SRR33048753_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/054/SRR33048754/SRR33048754_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/051/SRR33048751/SRR33048751_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/045/SRR33048745/SRR33048745_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/058/SRR33048758/SRR33048758_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/057/SRR33048757/SRR33048757_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/054/SRR33048754/SRR33048754_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR330/060/SRR33048760/SRR33048760_1.fastq.gzftp://primaryOK200GenomicsHarvard Medical Schoolhttps://www.ebi.ac.uk/ena/browser/view/PRJNA1248550Mus musculusIn vivo CRISPR screens in CD8+ T cells have previously uncovered targets for cancer immunotherapy, yet they have not been used to compare the key regulators important at different stages of CD8+ T cell activation. Here we present two 899-gene in vivo CRISPR screens using naive or activated CD8+ T cells to address this gap. These screens identified the E3 ubiquitin ligase STUB1 as a novel negative regulator of anti-tumor CD8+ T cells. Stub1 knockout (KO) CD8+ T cells control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. Among the cytokine receptors regulated by this complex, IL-27Ra is essential for Stub1/Chic2 KO-mediated tumor growth control. Together, these findings establish that the STUB1-CHIC2 complex as a novel regulator of cytokine receptor expression in CD8+ T cells and provide rationale for inhibiting this pathway to enhance CD8+ T cell-mediated anti-tumor immunity. Overall design: To investigate the differential genes between control and Stub1 KO CD8+ T cells in tumors we performed RNAseqENAfalseA STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity [RNAseq_STUB1KO]A STUB1-CHIC2 complex decreases IL-27Rα expression on CD8+ T cells to restrain tumor immunity [RNAseq_STUB1KO]2025-09-242025-06-12PRJNA1248550GSE29420210090