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Open Access Review

Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments

by Xiaoyi Zhang 1 ,  Na Xiao 2 ,  Toru Yoshino 1 ,  Zizhuo Yang 3,4  and  Jun Chen 4,*
1
Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA
2
Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
3
Department of Urology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
4
Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China
*
Author to whom correspondence should be addressed.
AI Med  2025 1(3):8; https://doi.org/10.71423/aimed.20250806
Received: 10 May 2025 / Accepted: 2 August 2025 / Published Online: 6 August 2025
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Abstract

Renal cell carcinoma (RCC) is distinguished by a highly inflamed tumor microenvironment (TME) that offers both opportunities and challenges for immunotherapy. This review synthesizes current insights into the immunological landscape of RCC, highlighting robust cluster of differentiation 8‑positiv (CD8⁺) T-cell infiltration, unconventional antigen sources such as endogenous retroviruses and frameshift neoantigens, and the heterogeneity of immune niches revealed by single-cell and spatial profiling. We then examine the clinical impact and mechanisms of immune checkpoint inhibitors —including programmed cell death protein 1 (PD‑1), programmed death‑ligand 1 (PD‑L1), and cytotoxic T‑lymphocyte‑associated protein 4 (CTLA‑4)—tumor vaccines, cellular therapies such as chimeric antigen receptor T cell (CAR‑T) therapy and tumor‑infiltrating lymphocytes (TILs) and bispecific antibody constructs, emphasizing advances in dosing, engineering, and combination regimens. Combination strategies—including dual checkpoint blockade, integration with anti-angiogenic tyrosine kinase inhibitors, radiotherapy, metabolism-targeted agents such as adenosine and poly (ADP‑ribose) polymerase (PARP) inhibitors, and hypoxia modulators—are reviewed for their capacity to overcome resistance and remodel the microenvironment. We further explore intrinsic and acquired resistance mechanisms, the immunosuppressive roles of myeloid and stromal elements, and emerging biomarker approaches spanning genomic, transcriptomic, spatial, and circulating analytes. Finally, we discuss current limitations—such as variable clinical response, toxicities, and biomarker gaps—and outline future prospects, including personalized combination regimens, next-generation engineered cell products, and artificial intelligence (AI)-driven precision monitoring. Together, these insights chart a path toward more effective, individualized immunotherapy in RCC.

Keywords: Renal cell carcinoma; Immunotherapy; Tumor microenvironment; Immune checkpoint inhibitors; Combination therapy; Single-cell analysis; Spatial transcriptomics; AI-driven biomarker; Machine learning; Resistance mechanisms; CAR-T therapy; Biomarker-guided treatment;
Copyright: © 2025 by Zhang, Xiao, Yoshino, Yang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Cite This Paper
APA Style
Zhang, X., Xiao, N., Yoshino, T., Yang, Z., & Chen, J. (2025). Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments. AI Med, 1(3), 8. doi:10.71423/aimed.20250806
ACS Style
Zhang, X.; Xiao, N.; Yoshino, T.; Yang, Z.; Chen, J. Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments. AI Med, 2025, 1, 8. doi:10.71423/aimed.20250806
AMA Style
Zhang X., Xiao N., Yoshino T. et al.. Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments. AI Med; 2025, 1(3):8. doi:10.71423/aimed.20250806
Chicago/Turabian Style
Zhang, Xiaoyi; Xiao, Na; Yoshino, Toru; Yang, Zizhuo; Chen, Jun 2025. "Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments" AI Med 1, no.3:8. doi:10.71423/aimed.20250806
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APA Style
Zhang, X., Xiao, N., Yoshino, T., Yang, Z., & Chen, J. (2025). Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments. AI Med, 1(3), 8. doi:10.71423/aimed.20250806
ACS Style
Zhang, X.; Xiao, N.; Yoshino, T.; Yang, Z.; Chen, J. Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments. AI Med, 2025, 1, 8. doi:10.71423/aimed.20250806
AMA Style
Zhang X., Xiao N., Yoshino T. et al.. Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments. AI Med; 2025, 1(3):8. doi:10.71423/aimed.20250806
Chicago/Turabian Style
Zhang, Xiaoyi; Xiao, Na; Yoshino, Toru; Yang, Zizhuo; Chen, Jun 2025. "Immunotherapy in Renal Cell Carcinoma: Modulating the Tumor Microenvironment, Overcoming Resistance Mechanisms, and Implementing Biomarker-Guided Combination Treatments" AI Med 1, no.3:8. doi:10.71423/aimed.20250806
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