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. 2022 Mar 28;15:38. doi: 10.1186/s13045-022-01255-x

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 1 — Features of T cell exhaustion and mitochondrial alterations. During persistent antigen stimulation and under hypoxia during chronic virus infection or cancer, CD8⁺ T cells enter a state of exhaustion. Tonic signaling in CAR-T cells is induced by autologous physical interactions between CAR receptors. Exhausted T cells and CAR-T cells exhibit decreased cytokine production and reduced proliferation capability; persistently high expression of multiple inhibitory receptors, such as PD-1, TIM-3, LAG-3 and CTLA4; and altered transcriptional landscapes, such as changes in changes in NR4A, TOX, TCF1 and NFAT transcription. Mitochondrial reprogramming characteristics in T cells include both functional and structural alterations. Mitochondria in exhausted cells are swollen and undergo increased fission. The mitochondrial cristae are slightly wider and more loosely organized in intermembrane regions. Functional alterations are characterized by an increased ADP/ATP ratio, decreased ATP generation and mitochondrial biogenesis, and decelerated fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS)