GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE293nnn/GSE293952/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE293952GEOGSEfalseHypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma [bulk RNA-seq]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.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 sapiens