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Peer-reviewedCC BY 4.0Cells

Mechanisms of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma

  • Martina Milella1
  • Francesco Lasorsa2
  • Monica Rutigliano2
  • Alessandro Caniglia3
  • Emanuele Naglieri4
  • Savio Domenico Pandolfo5,6
  • Pasquale Ditonno2
  • Giuseppe Lucarelli1,2
6 affiliations
  1. 1Urology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
  2. 2Urology and Kidney Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy
  3. 3Pathology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
  4. 4Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
  5. 5Department of Urology, University of L’Aquila, 67100 L’Aquila, Italy
  6. 6Department of Neurosciences, Science of Reproduction and Odontostomatology, Federico II University, 80138 Naples, Italy
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Abstract

Renal cell carcinoma (RCC), particularly its clear-cell subtype (ccRCC), is characterized by metabolic reprogramming and a complex tumor microenvironment that influence responses to immune checkpoint inhibitors (ICIs). Despite clinical advances, therapeutic resistance remains a major hurdle. Here we review the molecular determinants governing ccRCC sensitivity and resistance to ICIs, integrating insights from genomic alterations such as PBRM1 and BAP1 mutations, immune cell exhaustion dynamics, stromal and metabolic barriers, and the role of endogenous retroviral antigens. We discuss how these factors modulate immune evasion and impact therapeutic outcomes. Emerging strategies including biomarker-driven patient stratification, HIF-2α inhibition, and personalized immunotherapies show promise in overcoming resistance. Our synthesis highlights the necessity of multi-omics approaches to tailor immunotherapy, aiming to enhance durable responses and survival in ccRCC patients.

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Cite

BibTeXRIS
BibTeX
@article{milella2026mechanisms,
  title = {{Mechanisms of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma}},
  author = {Martina Milella and Francesco Lasorsa and Monica Rutigliano and Alessandro Caniglia and Emanuele Naglieri and Savio Domenico Pandolfo and Pasquale Ditonno and Giuseppe Lucarelli},
  journal = {Cells},
  year = {2026},
  month = oct,
  doi = {10.3390/cells15211954},
  url = {https://www.mdpi.com/2073-4409/15/21/1954},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Mechanisms of Response and Resistance to Immune Checkpoint Inhibitors in Renal Cell Carcinoma
AU  - Martina Milella
AU  - Francesco Lasorsa
AU  - Monica Rutigliano
AU  - Alessandro Caniglia
AU  - Emanuele Naglieri
AU  - Savio Domenico Pandolfo
AU  - Pasquale Ditonno
AU  - Giuseppe Lucarelli
PY  - 2026
DA  - 2026/10/27
JO  - Cells
DO  - 10.3390/cells15211954
UR  - https://www.mdpi.com/2073-4409/15/21/1954
AB  - Renal cell carcinoma (RCC), particularly its clear-cell subtype (ccRCC), is characterized by metabolic reprogramming and a complex tumor microenvironment that influence responses to immune checkpoint inhibitors (ICIs). Despite clinical advances, therapeutic resistance remains a major hurdle. Here we review the molecular determinants governing ccRCC sensitivity and resistance to ICIs, integrating insights from genomic alterations such as PBRM1 and BAP1 mutations, immune cell exhaustion dynamics, stromal and metabolic barriers, and the role of endogenous retroviral antigens. We discuss how these factors modulate immune evasion and impact therapeutic outcomes. Emerging strategies including biomarker-driven patient stratification, HIF-2α inhibition, and personalized immunotherapies show promise in overcoming resistance. Our synthesis highlights the necessity of multi-omics approaches to tailor immunotherapy, aiming to enhance durable responses and survival in ccRCC patients.
SN  - 2073-4409
ER  -