GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE293nnn/GSE293450/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293450GEOGSEfalseHypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinomaVascular 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.2026/04/23GSE293450GSM8882518GSM8882517GSM8882519GSM8882488GSM8882521GSM8882520GSM8882523GSM8882501GSM8882522GSM8882500GSM8882489GSM8882525GSM8882503GSM8882502GSM8882524GSM8882505GSM8882504GSM8882507GSM8882506GSM8882509GSM8882508GSM8882491GSM8882490GSM8882493GSM8882492GSM8882495GSM8882494GSM8882497GSM8882496GSM8882499GSM8882510GSM8882498GSM8882512GSM8882511GSM8882514GSM8882513GSM8882516GSM888251524247293450Mus musculus