{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE319nnn/GSE319746/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"," Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE319746"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"In vivo CRISPR-based screen identifies ZC3H12C as a mediator of CAR-T cell dysfunction in solid tumors","description":"CAR-T cell therapy has shown limited efficacy in solid tumors, largely due to T cell dysfunction driven by chronic antigen exposure. To uncover mediators of this dysfunction, we developed an in vivo screening platform using an ovarian xenograft tumor model in which CD28-based CAR-T cells undergo exhaustion leading to tumor escape. Transcriptomic profiling of tumor-infiltrating CAR-T cells at different stages revealed dynamic upregulation of exhaustion-associated genes. We used this data to design a focused CRISPR/Cas9 library and performed an in vivo screen. We identified 14 significantly enriched candidate genes, among which ZC3H12C emerged as the top hit. Single-cell RNA and ATAC-seq confirmed ZC3H12C expression in CAR-T cells undergoing early exhaustion in vivo. ZC3H12C disruption enhanced CAR-T cell persistence and antitumor efficacy while reducing exhaustion, across both CD28- and 4-1BB-based CARs targeting distinct antigens. These results highlight ZC3H12C as a promising target to improve CAR-T therapy in solid tumors.","dates":{"publication":"2026/09/22"},"accession":"GSE319746","cross_references":{"GSM":["GSM9525684","GSM9525685","GSM9525682","GSM9525683","GSM9525680","GSM9525681"],"GPL":["24676"],"GSE":["319746"],"taxon":["Homo sapiens"]}}