Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.

免疫检查点抑制剂 (ICIs) 已表现出无与伦比的临床反应，并彻底改变了肿瘤治疗的范式，而大量患者仍然对 ICI 作为单一药物无反应或产生耐药性，这可追溯到细胞代谢功能障碍。尽管代谢失调长期以来被认为是肿瘤的一个标志，但现在人们越来越多地认识到代谢重编程不仅是肿瘤细胞所独有的，而且也是免疫细胞的特征。相应地，过去人们更关注肿瘤细胞代谢对免疫细胞的影响，但实际上免疫细胞在激活和分化过程中与自身代谢功能以一种以前从未实现过的方式密切相互作用，这开辟了一个全新的领域。前沿称为免疫代谢。对肿瘤浸润免疫细胞的代谢干预可以为打破耐药性和改善现有 ICI 免疫疗法提供新的机会，其关键可能是确定代谢干预与 ICI 的协同组合，以获得协同效益并促进调整的抗肿瘤免疫反应。在此，我们从不同肿瘤浸润免疫细胞代谢重编程的新维度以及相关代谢干预的角度阐述了免疫治疗耐药的潜在机制，希望为针对代谢脆弱性规避免疫治疗耐药提供参考。