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Immunological features of clear-cell renal-cell carcinoma and resistance to immune checkpoint inhibitors

Nature Reviews Nephrology volume 21, pages 687–701 (2025)Cite this article

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Abstract

The advent of immunotherapy has yielded great improvements in survival outcomes of people with clear-cell renal-cell carcinoma (ccRCC). Currently, immune checkpoint inhibitors (ICIs) are the cornerstone of treatment regimens for metastatic ccRCC. Yet a substantial group of patients do not respond to ICIs and few achieve long-term remission, indicating the presence of intrinsic and acquired resistance. The mechanisms underlying ICI resistance in ccRCC remain poorly understood, potentially owing to its unique immunological landscape compared with other immunotherapy-responsive cancers. Specifically, ccRCC is characterized by one of the highest levels of T cell infiltration across different tumours; however, high T cell infiltration does not correlate consistently with improved ICI outcomes. Moreover, the tumour mutational burden in ccRCC is relatively low, compared with that of other immunotherapy-responsive cancers, and fails to predict ICI efficacy. The limited predictive value of these commonly used markers for ICI response underscores the need for deeper exploration of the immunological mechanisms driving the antitumour immune response in ccRCC. Investigating commonalities and disparities with other immunotherapy-responsive cancer types might improve understanding of ICI resistance in ccRCC and inform the development of strategies to enhance the clinical benefits of immunotherapy.

Key points

  • Although clear-cell renal-cell carcinoma (ccRCC) is sensitive to immune checkpoint inhibitors (ICIs), a substantial number of patients fail to respond to these therapies and long-term remissions are rare, indicating intrinsic and acquired resistance.

  • ccRCC has unique immunological characteristics, including low tumour mutational burden and one of the most abundant immune infiltrates across common solid tumours. However, unlike in other cancers, these features lack a strong association with ICI response.

  • Immunological factors potentially contributing to ICI resistance in ccRCC include high intratumoural heterogeneity, dysfunctional T cells within the immune cell infiltrate, B cell and tertiary lymphoid structure scarcity, and abundance of immunosuppressive myeloid cells.

  • Further investigation is required to understand the mechanisms underlying the limited ICI responses in ccRCC and to identify reliable biomarkers of response to therapy given that markers used in other cancers might not be applicable to ccRCC.

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Fig. 1: Impact of tumour mutational burden and frameshift insertions and deletions burden on antitumour T cell response in clear-cell renal-cell carcinoma.
Fig. 2: Impact of intratumoural heterogeneity on the antitumour immune response.
Fig. 3: Immune cells in the ccRCC tumour microenvironment.
Fig. 4: Potential factors contributing to resistance against immune checkpoint inhibitors in clear-cell renal-cell carcinoma.

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Authors and Affiliations

  1. Division of Medical Oncology, Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands

    Femke H. Burgers, Johannes C. K. van der Mijn, Tom T. P. Seijkens & John B. A. G. Haanen

  2. Division of Molecular Oncology and Immunology, Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands

    Femke H. Burgers, Inge Jedema & John B. A. G. Haanen

  3. Department of Urology, Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands

    Axel Bex

  4. Department of Urology, The Royal Free London NHS Foundation Trust, London, UK

    Axel Bex

  5. University College London Division of Surgery and Interventional Science, London, UK

    Axel Bex

  6. Department of Medical Oncology, Leiden University Medical Centre (LUMC), Leiden, the Netherlands

    John B. A. G. Haanen

  7. Head of Melanoma Clinic, Lausanne University Hospital (CHUV), Lausanne, Switzerland

    John B. A. G. Haanen

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Contributions

F.H.B., J.C.K.M., T.T.P.S., I.J. and J.B.A.G.H. conceptualized and designed the structure of the manuscript. F.H.B. wrote the original draft of the manuscript, with guidance from J.C.K.M. F.H.B. created the draft figures and tables. J.C.K.M., T.T.P.S., I.J., A.B. and J.B.A.G.H. critically revised the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to John B. A. G. Haanen.

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Competing interests

J.C.K.M. receives research funding from Bayer B.V. and received financial compensation for consultancy services for AstraZeneca, Merck/MSD and Ipsen. A.B. received an educational restricted grant from Pfizer for a neoadjuvant trial, holds membership on the steering committee of adjuvant trials from Roche and BMS and is on the advisory board for Ipsen. J.B.A.G.H. received compensation for advisory roles for Achilles Therapeutics, AZ, BioNTech, BMS, CureVac, Eisai, Gadeta, Imcyse, Immunocore, Instil Bio, Iovance Biotherapeutics, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, Third Rock Ventures and T-knife, and has received grants (all paid to the Institute) from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, Neogene Therapeutics and Sastra Cell Therapy. The other authors declare no competing interests.

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Burgers, F.H., van der Mijn, J.C.K., Seijkens, T.T.P. et al. Immunological features of clear-cell renal-cell carcinoma and resistance to immune checkpoint inhibitors. Nat Rev Nephrol 21, 687���701 (2025). https://doi.org/10.1038/s41581-025-00983-w

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