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. 2026 Jun 04 [Epub ahead of print]
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
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: ., Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen, Germany; DFG Cluster of Excellence 2180 Image-Guided and Functional Instructed Tumor Therapy (iFIT), University of Tuebingen, Tuebingen, Germany., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medicine, Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Centre for Translational Cell Research, University Hospital Freiburg, Freiburg, Germany., Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA, USA., Department of Oncological Sciences, The Precision Immunology Institute, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: .