Immunometabolism: a new dimension in immunotherapy resistance

Abstract

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.

Keywords

immune cell / immunometabolism / metabolic reprogramming / immunotherapy / resistance / tumor microenvironment / immune checkpoint inhibitor

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Acknowledgements

We appreciate the multi-disciplinary team (MDT) for thoracic tumors of the Second Xiangya Hospital of Central South University for the inspiration and guidance of this manuscript. This work was partially supported by research grants from the National Natural Science Foundation of China (No. 82272806), the Natural Science Foundation of Hunan Province for Excellent Young Scholars (No. 2021JJ20088), and Frontier Cross Research Project of Central South University (2023QYJC039) to Fang Wu.

Compliance with ethics guidelines

Conflicts of interest Chaoyue Xiao, Wei Xiong, Yiting Xu, Ji’an Zou, Yue Zeng, Junqi Liu, Yurong Peng, Chunhong Hu, and Fang Wu declare that they have no conflict of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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