{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE294nnn/GSE294006/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Homo sapiens"],"gds_type":["Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294006"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma [Spatial Transcriptomics]","description":"Vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and aPD1 combinations are effective in multiple solid tumors, particularly in clear cell renal cell carcinoma (ccRCC), due it’s characteristic pseudo-hypoxic, hyper-angiogenic state driven by biallelic VHL-loss. However, long-term durability is inferior to dual aPD1/aCTLA4 regimens, yet the mechanisms underlying these differences remain unclear. Since tumor-associated macrophages (TAMs) are implicated in therapeutic resistance, we used scRNAseq to investigate TAM evolution following VEGFR-TKI, aPD1 and combined VEGFR-TKI/aPD1 treatment in a transgenic ccRCC mouse model. We identify hypoxia-responsive SPP1+ TAMs that are absent in baseline pseudo-hypoxic tumors. This proxy of true hypoxia tracks with successful response to VEGFR-TKI/aPD1 in mouse and human on-treatment samples, reflecting treatment-induced hypoxic necrosis. Paradoxically, pretreatment hypoxia predicted worse outcomes across multiple VEGFR-TKI/aPD1 trial and real-world cohorts and extended exposure to hypoxia-inducing VEGFR-TKIs and aPD1 exacerbated metastasis in mice, highlighting the dual implications of hypoxia in ccRCC disease trajectory.","dates":{"publication":"2026/04/23"},"accession":"GSE294006","cross_references":{"GSM":["GSM8896252","GSM8896254","GSM8896253"],"GPL":["24676"],"GSE":["294006"],"taxon":["Homo sapiens"]}}