Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma
Menée à l'aide de lignées cellulaires, d'un modèle murin transgénique, d'échantillons sanguins d'origine humaine et d'échantillons tumoraux provenant de patients atteints d'un carcinome rénal à cellules claires, cette étude examine le mécanisme par lequel l'hypoxie affecte la durabilité de la réponse des traitements par anti-PD-1 et inhibiteur de tyrosine kinase du récepteur VEGFR
Vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and anti-PD-1 (aPD-1) combinations are effective in multiple solid tumors, particularly in clear cell renal cell carcinoma (ccRCC), due to its characteristic pseudohypoxic, hyper-angiogenic state driven by biallelic VHL loss. However, long-term durability is inferior to dual aPD-1/anti-CTLA-4 regimens, yet the underlying mechanisms remain unclear. We investigated tumor microenvironment evolution following VEGFR-TKI, aPD-1, and combined VEGFR-TKI/aPD-1 treatment in a transgenic ccRCC mouse model. We identify hypoxia-responsive SPP1+ tumor-associated macrophages (TAMs) that infrequently infiltrate baseline pseudohypoxic tumors. This proxy of true hypoxia tracks with successful response to VEGFR-TKI/aPD-1 in mouse and human on-treatment single-cell RNA sequencing and imaging mass cytometry cohorts, reflecting treatment-induced hypoxic necrosis. Paradoxically, pretreatment hypoxia predicted worse outcomes across VEGFR-TKI/aPD-1 trials and real-world cohorts while extended exposure to hypoxia-inducing VEGFR-TKIs exacerbated metastasis in mice, highlighting the dual implications of hypoxia in ccRCC disease trajectory.
Cancer Cell , article en libre accès, 2026