International Journal of Clinical Case Reports 2024, Vol.14, No.4, 189-201 http://medscipublisher.com/index.php/ijccr 189 Research Report Open Access Immune Checkpoint Blockade in Renal Cell Carcinoma: Therapeutic Efficacy and Mechanisms of Resistance ManmanLi Hainan Institute of Biotechnology, Haikou, 570206, Hainan, China Corresponding email: manman.li@hibio.org International Journal of Clinical Case Reports 2024, Vol.14, No.4 doi: 10.5376/ijccr.2024.14.0020 Received: 29 May, 2024 Accepted: 30 Jun., 2024 Published: 20 Jul., 2024 Copyright © 2024 Li, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Li M.M., 2024, Immune checkpoint blockade in renal cell carcinoma: therapeutic efficacy and mechanisms of resistance, International Journal of Clinical Case Reports, 14(4): 189-201 (doi: 10.5376/ijccr.2024.14.0020) Abstract Renal cell carcinoma (RCC) remains a significant therapeutic challenge, especially in advanced and metastatic cases. In recent years, PD-1/PD-L1 and CTLA-4 inhibitors have demonstrated significant efficacy in the treatment of metastatic RCC, particularly in combination therapies that have improved patient survival rates and objective response rates. However, the issue of immune resistance remains prominent, hindering the widespread application of these therapies. This study explores the mechanisms behind both primary and acquired resistance to immune checkpoint inhibitors in RCC, including the immunosuppressive factors within the tumor microenvironment. To address this challenge, the study discusses emerging immunotherapies, such as bispecific antibodies and CAR-T cell therapy, as well as the prospects for personalized immunotherapy. The study summarizes the current clinical challenges and highlights the future potential of optimizing RCC immunotherapy through combination therapies and personalized medicine. Keywords Renal cell carcinoma; Immune checkpoint blockade; Immune resistance; Bispecific antibodies; CAR-T cell therapy 1 Introduction Renal cell carcinoma (RCC) is the most prevalent type of kidney cancer, accounting for around 90% of kidney malignancies. The most common subtype, clear-cell renal cell carcinoma (ccRCC), comprises 70-80% of all RCC cases. Historically, RCC has been regarded as resistant to conventional therapies such as chemotherapy and radiotherapy, which led to the exploration of alternative treatments like targeted therapy and immunotherapy. The introduction of immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 has revolutionized the treatment landscape for metastatic RCC, offering patients new hope with durable responses and improved survival rates (Xu et al., 2020). However, the efficacy of these treatments is limited by intrinsic and acquired resistance mechanisms, necessitating further research to improve patient outcomes. This study will provide a detailed exploration of the mechanisms underlying resistance to immune checkpoint blockade, the therapeutic efficacy of ICIs in RCC, and emerging strategies to overcome these barriers (Chatwal et al., 2023). The development of ICI therapies has provided a foundation for understanding how the immune system can be harnessed to target cancer cells. Yet, the dynamic interplay between tumor cells and the immune system can limit the long-term effectiveness of these therapies. Understanding the immune microenvironment of RCC, identifying biomarkers predictive of response to ICIs, and overcoming resistance are essential components of advancing treatment for patients with advanced disease (Diaz-Montero et al., 2020). Renal cell carcinoma (RCC) develops from the renal epithelium, with clear-cell RCC (ccRCC) being the most common histological subtype. This form of cancer is often associated with mutations in the von Hippel-Lindau (VHL) gene, which leads to an upregulation of hypoxia-inducible factors (HIFs) and promotes angiogenesis through increased production of vascular endothelial growth factor (VEGF) (Diaz-Montero et al., 2020). The VHL-HIF-VEGF axis is central to the biology of RCC, resulting in a highly vascularized tumor microenvironment (TME) that facilitates tumor growth and metastasis. This explains why anti-angiogenic therapies, such as tyrosine kinase inhibitors (TKIs), have historically been effective in treating advanced RCC (Xu et al., 2020). Additionally, RCC is characterized by an immunosuppressive TME, which is rich in regulatory T cells (Tregs), myeloid-derived
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