免疫检查点抑制剂已经彻底改变了癌症治疗，然而许多患者要么不从治疗中获益，要么对检查点抑制剂产生抵抗。内在抵抗可能是由于新抗原耗竭、缺陷的抗原呈递、PD-L1下调、免疫检查点配体上调、免疫抑制和肿瘤细胞表型变化造成的。另一方面，外在抵抗涉及抑制性免疫检查点的获得性上调，导致T细胞耗竭。目前的数据表明，PD-1、CTLA-4和LAG-3上调限制了单一免疫检查点抑制剂的疗效。正在进行的临床试验正在研究新颖的免疫检查点靶点，以避免或克服抵抗。本综述对癌症中潜在可靶向的免疫检查点进行了深入分析。我们强调它们的生物学，强调了目前对抵抗机制的理解，并着重关注正在研究的有前途的策略。我们还总结了目前的结果和该关键领域正在进行的临床试验，这可能再次改变癌症患者的预后。版权所有©2023作者。由Elsevier Ltd.出版。保留所有权利。

Immune-checkpoint inhibitors have revolutionized cancer therapy, yet many patients either do not derive any benefit from treatment or develop a resistance to checkpoint inhibitors. Intrinsic resistance can result from neoantigen depletion, defective antigen presentation, PD-L1 downregulation, immune-checkpoint ligand upregulation, immunosuppression, and tumor cell phenotypic changes. On the other hand, extrinsic resistance involves acquired upregulation of inhibitory immune-checkpoints, leading to T-cell exhaustion. Current data suggest that PD-1, CTLA-4, and LAG-3 upregulation limits the efficacy of single-agent immune-checkpoint inhibitors. Ongoing clinical trials are investigating novel immune-checkpoint targets to avoid or overcome resistance. This review provides an in-depth analysis of the evolving landscape of potentially targetable immune-checkpoints in cancer. We highlight their biology, emphasizing the current understanding of resistance mechanisms and focusing on promising strategies that are under investigation. We also summarize current results and ongoing clinical trials in this crucial field that could once again revolutionize outcomes for cancer patients.Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.