Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma

Lynda, Vuong, Andrew E., Cornish, Jennifer, Pfeil, Yash, Khandwala, Hui, Jiang, Doris X.T., Zheng, Eduardo A., Mascareno, Nicole, Rittenhouse, Phillip M., Rappold, Josef, Leibold, Erich A., Sabio, Kate, Weiss, Carlene, Gonzalez, Liangliang, Ji, Jing, Zhang, Mojca, Adlesic, Oguz, Akin, Jessica, Flynn, Chirag, Krishna, Andrea, Lopez Sanmiguel, Rebecca A., Sager, Tiak J., Tan, Alejandro, Sanchez, Renzo G., Di Natale, Kyle A., Blum, Paul, Russo, Jonathan A., Coleman, Ian J., Frew, Diego, Chowell, Ying Bei, Chen, David B., Solit, Irina, Ostrovnaya, Robert J., Motzer, Martin H., Voss, Ritesh R., Kotecha, Timothy A., Chan, Hartland W., Jackson, Fengshen, Kuo, Ming O., Li, A. Ari, Hakimi

Cancer Cell |

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.