biostudies-literatureFu CU.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research (NIDCR)8572https://www.ebi.ac.uk/biostudies/studies/S-EPMC12480505biostudies-literatureUnknown16(1)Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increases CD8⁺ T cell infiltration and improved ICB responses. Uchl5 deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL1Nature communicationsIn vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target.PMC12480505U01DE029188Kim SYPerera JJEgloff AMYates KBAnderson SAdkins DRManguso RTCheruiyot CKTang SUppaluri RChinai JMKammula AVLane-Reticker SKLuna SMChernock RDColvin KJTiwari PBernstein BEAlipour ZMuscato AJSaddawi-Konefka RDubrot JKistler ENChuong CLFu CGriffin GKJiang AGutkind JSFetterman RAfalseIn vivo CRISPR screening in head and neck cancer reveals Uchl5 as an immunotherapy target.Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increases CD8⁺ T cell infiltration and improved ICB responses. Uchl5 deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL12025-01-01T00:00:00Z2025 Sep2026-06-03T23:07:30.767Z2026-05-02T03:12:08.544ZS-EPMC124805054102273410.1038/s41467-025-63592-y