Liu Dinglin, Xiao Haoyue, Xiang Ying, Zhong Dian, Liu Yuchen, Wang Yunfei, Zhang Weijia
Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, China.
Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei 434023, China.
J Cancer. 2025 Jul 24;16(11):3425-3449. doi: 10.7150/jca.108163. eCollection 2025.
In recent years, immune checkpoint blockades (ICBs) have made rapid progress in the field of cancer treatment, providing significant therapeutic effects and survival benefits, especially in patients with advanced refractory tumors. PD-1/PD-L1 blockade is one of the most widely used ICBs. However, its application is limited by low response rate and drug resistance. It is of great significance to investigate the complex mechanisms of PD-1/PD-L1 blockade resistance. In this review, we outline some crucial aspects, including lack of effector T cells, lack of target PD-1/PD-L1, poor immunogenicity of tumors, immunosuppressive TME, and other mechanisms (such as metabolism, epigenetic alterations, and gut microbiota). Combination therapy has become a promising strategy to overcome drug resistance. Based on the upregulation of other immune checkpoints after PD-1/PD-L1 blockade treatment, we focus on the combination with other ICBs, including CTLA-4, TIM-3, LAG-3, TIGIT, VISTA, and some emerging immune checkpoints, so as to provide evidence for improving the benefit of ICBs in cancers.
近年来，免疫检查点阻断（ICB）在癌症治疗领域取得了快速进展，带来了显著的治疗效果和生存益处，尤其是在晚期难治性肿瘤患者中。PD-1/PD-L1阻断是应用最广泛的ICB之一。然而，其应用受到低反应率和耐药性的限制。研究PD-1/PD-L1阻断耐药的复杂机制具有重要意义。在本综述中，我们概述了一些关键方面，包括效应T细胞缺乏、靶标PD-1/PD-L1缺乏、肿瘤免疫原性差、免疫抑制性肿瘤微环境以及其他机制（如代谢、表观遗传改变和肠道微生物群）。联合治疗已成为克服耐药性的一种有前景的策略。基于PD-1/PD-L1阻断治疗后其他免疫检查点的上调，我们重点关注与其他ICB的联合，包括CTLA-4、TIM-3、LAG-3、TIGIT、VISTA以及一些新兴的免疫检查点，以便为提高ICB在癌症治疗中的获益提供依据。
