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

  • Cancer Cell. 2026 Jun 4:S1535-6108(26)00252-7. doi: 10.1016/j.ccell.2026.05.007.
Lynda Vuong  1 ,  Andrew E Cornish  2 ,  Jennifer Pfeil  3 ,  Yash Khandwala  4 ,  Hui Jiang  5 ,  Doris X T Zheng  5 ,  Eduardo A Mascareno  5 ,  Nicole Rittenhouse  5 ,  Phillip M Rappold  4 ,  Josef Leibold  6 ,  Erich A Sabio  7 ,  Kate Weiss  4 ,  Carlene Gonzalez  8 ,  Liangliang Ji  9 ,  Jing Zhang  9 ,  Mojca Adlesic  10 ,  Oguz Akin  11 ,  Jessica Flynn  12 ,  Chirag Krishna  13 ,  Andrea Lopez Sanmiguel  4 ,  Rebecca A Sager  4 ,  Tiak J Tan  3 ,  Alejandro Sanchez  4 ,  Renzo G Di Natale  4 ,  Kyle A Blum  4 ,  Paul Russo  4 ,  Jonathan A Coleman  4 ,  Ian J Frew  10 ,  Diego Chowell  14 ,  Ying-Bei Chen  15 ,  David B Solit  16 ,  Irina Ostrovnaya  12 ,  Robert J Motzer  8 ,  Martin H Voss  8 ,  Ritesh R Kotecha  8 ,  Timothy A Chan  17 ,  Hartland W Jackson  3 ,  Fengshen Kuo  5 ,  Ming O Li  9 ,  A Ari Hakimi  18
Affiliations
  • 1. 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: [email protected].
  • 2. 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.
  • 3. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 4. Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 5. 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.
  • 6. 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.
  • 7. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8. Department of Medicine, Genitourinary Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10. Centre for Translational Cell Research, University Hospital Freiburg, Freiburg, Germany.
  • 11. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 12. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 13. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Inflammation and Immunology Research Unit, Pfizer, Cambridge, MA, USA.
  • 14. Department of Oncological Sciences, The Precision Immunology Institute, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 15. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 16. 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.
  • 17. Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
  • 18. 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: [email protected].
PMID: 42242232 DOI: 10.1016/j.ccell.2026.05.007
Abstract

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.

Keywords
GPNMB; SPP1; angiogenesis inhibitors; clear cell renal cell carcinoma; hypoxia; immune checkpoint blockade; pseudohypoxia; tumor microenvironment; tumor-associated macrophages; vascular normalization.
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