Lynda Vuong, Andrew Cornish, Jennifer Pfeil, Yash Khandwala, Hui Jiang, Doris X. T. Zheng, Eduardo A. Mascareno, Nicole Rittenhouse, Phillip M. Rappold, Josef Leibold, Erich A. Sabio, Käte Weiss, Carlene Gonzalez, Liangliang Ji, Jing Zhang, Mojca Adlesic, Oguz Akin, Jessica Flynn, Chirag Krishna, Andrea López Sanmiguel, Rebecca Sager, Tiak J. Tan, Alejandro Sánchez, 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
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.