Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8+ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.
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P.-C.H. was supported in part by a European Research Council Staring Grant (802773-MitoGuide), the Swiss National Science Foundation (31003A_182470), the Swiss Institute for Experimental Cancer Research (ISREC 26075483), the Swiss Cancer League (KFS-3949-08-2016), a Swiss Bridge Award, a Cancer Research Institute–CLIP Investigator award and an EMBO Young Investigator award.
P.-C.H. is serving as a scientific advisory board member for Elixiron Immunotherapeutics and Acepodia. P.-C.H. receives research grants from Roche and has received honoraria from Pfizer and Chugai. P.R. also receives research grants from Roche. The other authors have no conflict of interest.
Peer review information Primary Handling Editor: Pooja Jha.
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Franco, F., Jaccard, A., Romero, P. et al. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2, 1001–1012 (2020). https://doi.org/10.1038/s42255-020-00280-9