{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE343nnn/GSE343811/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE343811"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Microsatellite-stable colorectal tumor-derived SEMA3A drives CD8⁺ T cell senescence and immunotherapy resistance via TCF1 repression","description":"Microsatellite-stable (MSS) colorectal cancers (CRC) display inherent insensitivity to immune checkpoint blockade, and the pivotal mechanisms responsible for this immunotherapeutic resistance have not been fully clarified. Here, we demonstrate that MSS CRC elicit CD8⁺ T cell senescence to mediate immune evasion, which distinguishes them from microsatellite-instable (MSI) CRC. We further identify SEMA3A, a secreted protein markedly upregulated in MSS CRC, as a crucial mediator that directly drives CD8⁺ T cell senescence. Mechanistically, SEMA3A engages neuropilin-1 (NRP1) to hijack JAK1 signaling, which blunts cytokine-triggered STAT3 phosphorylation and ultimately reduces TCF1 expression. At the molecular level, TCF1 directly binds to and transcriptionally represses senescence-associated genes. The loss of TCF1 in CD8⁺ T cells infiltrating MSS CRC tumors abolishes this transcriptional repression, thereby inducing CD8⁺ T cell senescence and conferring refractoriness to PD-L1 blockade. In syngeneic murine models of MSS CRC, dual neutralization of SEMA3A and PD-L1 restores TCF1 expression, rescues CD8⁺ T cells from senescence, and significantly improves immunotherapy efficacy. Clinical data corroborate that SEMA3A expression is positively correlated with CD8⁺ T cell senescence and serves as a reliable prognostic biomarker for inferior immunotherapy responses in patients with MSS CRC. Collectively, this study delineates a SEMA3A/NRP1-JAK1-STAT3-TCF1 signaling axis that governs CD8⁺ T cell senescence and tumor immune evasion in MSS CRCs, validating SEMA3A as a promising predictive biomarker and druggable therapeutic target for this immunotherapy-refractory MSS CRC.","dates":{"publication":"2026/08/17"},"accession":"GSE343811","cross_references":{"GSM":["GSM9963153","GSM9963152","GSM9963144","GSM9963155","GSM9963154","GSM9963146","GSM9963145","GSM9963148","GSM9963147","GSM9963149","GSM9963151","GSM9963150"],"GPL":["24247"],"GSE":["343811"],"taxon":["Mus musculus"]}}