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Comment
. 2021 Jul;18(7):1634-1637.
doi: 10.1038/s41423-021-00709-5. Epub 2021 Jun 7.

Reversing the mitochondrial stress-induced exhaustion of CD8+ T cells for improving cancer immunotherapy

Cheng Qian  1 , Xuetao Cao  2   3
Affiliations
Comment

Reversing the mitochondrial stress-induced exhaustion of CD8+ T cells for improving cancer immunotherapy

Cheng Qian et al. Cell Mol Immunol. 2021 Jul.
No abstract available

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Various mitochondria-related metabolic regulators fine-tune T-cell exhaustion in a stress-inducing tumor microenvironment. An important consequence of the specialized metabolism of cancer cells is a poorly vascularized, nutrient-deprived tumor microenvironment (TME), which presents considerable hurdles to the effector function of tumor-infiltrating T cells (TILs). Various extrinsic and intrinsic cell signals are probably integrated to influence mitochondrial stress during T-cell exhaustion. Continuous activation under hypoxia rapidly promotes an exhaustion-like dysfunctional state of CD8+ T cells, partially because of heightened Blimp-1-mediated repression of PGC1α-dependent mitochondrial fitness, which is essential for T-cell immunity. Subsequently, the presence of dysfunctional mitochondrial ROS increases the elevation of phosphotyrosine signaling and NFAT localization, which ultimately reinforces the transcriptional machinery driving exhaustion. Moreover, hostile microenvironmental conditions within tumor masses, such as nutrient stress, have been found to dampen the tumoricidal activity of CD8+ TILs. Impaired glycolysis in tumor-infiltrating T cells, mainly resulting from elevated glucose consumption in cancer cells, has been shown to promote IRE1–XBP1 signaling to drive mitochondrial dysfunction and inhibit antitumor capacity. Interestingly, the TME is lipid enriched, and excessive cholesterol uptake by TILs may facilitate T-cell exhaustion and has been shown to elicit XBP1 expression and ER stress. Furthermore, immune checkpoint engagement can trigger changes in mitochondrial dynamics. For instance, 4-1BB costimulation of exhausted CD8+ T cells can induce enhanced mitochondrial capacity and engage PGC1α-mediated pathways via activation of p38. PD-1 engagement in CD8+ T cells promotes fatty acid oxidation (FAO) and suppresses mitochondrial fitness. Collectively, the precise balance of mitochondria-related signals may be involved in epigenetic reprogramming and determine the fate of intratumor CD8+ T-cell exhaustion, which represent potential targets for rescuing the immune effector functions of exhausted CD8+ T cells
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