State Key Laboratory of Protein and Plant Gene Research, Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, 100871, China.
Front Med. 2023 Oct;17(5):805-822. doi: 10.1007/s11684-023-1025-7. Epub 2023 Oct 28.
Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
基于免疫检查点阻断（ICB）的免疫疗法在过去十年中显著改善了患者的预后，并为癌症治疗提供了新的方法。迄今为止，CTLA-4 和 PD-1/PD-L1 的免疫检查点抑制剂（ICI）代表了免疫疗法的主要类别。CTLA-4 和 PD-1/PD-L1 的阻断在几种特定类型的癌症中显示出显著的疗效，然而，很大一部分难治性患者对 ICB 治疗反应不佳；并且潜在的机制仍不清楚。最近，许多研究表明，肿瘤细胞的代谢重编程通过代谢产物重塑肿瘤微环境（TME），从而抑制免疫反应，涉及代谢抑制剂和 ICI 的联合治疗为癌症治疗提供了新的方法。然而，对于不同可靶向代谢途径调节免疫检查点以克服 ICI 耐药性的方式，缺乏系统的总结。在这里，我们展示了针对三个关键免疫检查点（CTLA-4、PD-1 和 PD-L1）的癌症代谢靶向的一般机制，以影响 ICB 治疗，并提出了潜在的联合免疫治疗策略，共同靶向肿瘤代谢途径和免疫检查点。
