{"database":"GEO","file_versions":[],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294109"],"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 [scRNAseq]","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":"GSE294109","cross_references":{"GSM":["GSM8898820","GSM8898821","GSM8898824","GSM8898802","GSM8898825","GSM8898803","GSM8898822","GSM8898823","GSM8898806","GSM8898807","GSM8898826","GSM8898804","GSM8898805","GSM8898819","GSM8898810","GSM8898813","GSM8898814","GSM8898811","GSM8898812","GSM8898817","GSM8898818","GSM8898815","GSM8898816","GSM8898808","GSM8898809"],"GPL":["24676","34281"],"GSE":["294109"],"taxon":["Homo sapiens"]}}