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Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance

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Abstract

The successful treatment of human cancers by immunotherapy has been made possible by breakthroughs in the discovery of immune checkpoint regulators, including CTLA-4 and PD-1/PD-L1. However, the immunosuppressive effect of the tumor microenvironment still represents an important bottleneck that limits the success of immunotherapeutic approaches. The tumor microenvironment influences the metabolic crosstalk between tumor cells and tumor-infiltrating immune cells, creating competition for the utilization of nutrients and promoting immunosuppression. In addition, tumor-derived metabolites regulate the activation and effector function of immune cells through a variety of mechanisms; in turn, the metabolites and other factors secreted by immune cells can also become accomplices to cancer development. Immune-metabolic checkpoint regulation is an emerging concept that is being studied with the aim of restoring the immune response in the tumor microenvironment. In this review, we summarize the metabolic reprogramming of various cell types present in the tumor microenvironment, with a focus on the interaction between the metabolic pathways of these cells and antitumor immunosuppression. We also discuss the main metabolic checkpoints that could provide new means of enhancing antitumor immunotherapy.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81903138, 81972776, 81803025, 81772928, 81702907, 81772901, 81672993, 81672683), and the Natural Science Foundation of Hunan Province (2019JJ50778, 2018SK21210, 2018SK21211, 2018JJ3704, 2018JJ3815).

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Authors and Affiliations

  1. Center for Aging Biomedicine, Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, 410081, China

    Fang Wei & Niwen Tang

  2. Department of Stomatology, NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, 410078, China

    Fang Wei, Fang Xiong, Wei Xiong, Shanshan Zhang & Zhaoyang Zeng

  3. Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Science, Central South University, Changsha, 410078, China

    Fang Wei, Dan Wang, Le Tang, Can Guo, Ming Zhou, Xiaoling Li, Guiyuan Li, Wei Xiong & Zhaoyang Zeng

  4. Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, The Third Xiangya Hospital, Central South University, Changsha, 410013, China

    Dan Wang, Le Tang, Guiyuan Li, Wei Xiong & Zhaoyang Zeng

  5. School of Ethnic Medicine, Yunnan Minzu University, Kunming, 650031, China

    Junyuan Wei

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  1. Fang Wei
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Wei, F., Wang, D., Wei, J. et al. Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance. Cell. Mol. Life Sci. 78, 173–193 (2021). https://doi.org/10.1007/s00018-020-03581-0

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