Wei Jing, Li Wenke, Zhang Pengfei, Guo Fukun, Liu Ming
Department of Medical Oncology, Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA.
Mol Cancer. 2024 Dec 26;23(1):279. doi: 10.1186/s12943-024-02179-5.
Immune checkpoint inhibitors (ICIs) have dramatically transformed the treatment landscape for various malignancies, achieving notable clinical outcomes across a wide range of indications. Despite these advances, resistance to immune checkpoint blockade (ICB) remains a critical clinical challenge, characterized by variable response rates and non-durable benefits. However, growing research into the complex intrinsic and extrinsic characteristics of tumors has advanced our understanding of the mechanisms behind ICI resistance, potentially improving treatment outcomes. Additionally, robust predictive biomarkers are crucial for optimizing patient selection and maximizing the efficacy of ICBs. Recent studies have emphasized that multiple rational combination strategies can overcome immune checkpoint resistance and enhance susceptibility to ICIs. These findings not only deepen our understanding of tumor biology but also reveal the unique mechanisms of action of sensitizing agents, extending clinical benefits in cancer immunotherapy. In this review, we will explore the underlying biology of ICIs, discuss the significance of the tumor immune microenvironment (TIME) and clinical predictive biomarkers, analyze the current mechanisms of resistance, and outline alternative combination strategies to enhance the effectiveness of ICIs, including personalized strategies for sensitizing tumors to ICIs.
免疫检查点抑制剂（ICIs）极大地改变了各种恶性肿瘤的治疗格局，在广泛的适应症中取得了显著的临床疗效。尽管取得了这些进展，但对免疫检查点阻断（ICB）的耐药性仍然是一个关键的临床挑战，其特点是反应率多变且获益不持久。然而，对肿瘤复杂的内在和外在特征的研究不断深入，增进了我们对ICI耐药背后机制的理解，有望改善治疗结果。此外，强大的预测生物标志物对于优化患者选择和最大化ICB的疗效至关重要。最近的研究强调，多种合理的联合策略可以克服免疫检查点耐药并增强对ICIs的敏感性。这些发现不仅加深了我们对肿瘤生物学的理解，还揭示了致敏剂独特的作用机制，扩展了癌症免疫治疗的临床获益。在这篇综述中，我们将探讨ICIs的潜在生物学机制，讨论肿瘤免疫微环境（TIME）和临床预测生物标志物的意义，分析当前的耐药机制，并概述增强ICIs有效性的替代联合策略，包括使肿瘤对ICIs致敏的个性化策略。
