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. 2023 Jun 5;14:1186383. doi: 10.3389/fimmu.2023.1186383

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Copyright © 2023 Li, Pan, Chen, Cui, Mo, Pan, Shen, Shi, Wu, Luo, Liu and Li

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Targeting metabolic signaling that improve CAR-T cell fate and overcome exhaustion. 1.4-1BB signaling or PGC-1α activator bezafibrate upregulates PGC-1α expression through stimulation of the MAPK pathway, resulting in mitochondrial biogenesis beneficial for the differentiation of CAR-Tcm cells. PGC-1α activates NRF1, which activates Tfam involved in the transcription and replication of mtDNA. 2. Supplementation arginine enhances OXPHOS or inhibition IDO to increase tryptophan can restore the activity of CAR-T cells. 3. Promoting FAO of T cells by enhancing AMP-dependent kinases through metformin, IL-21 and PPAR agonists Fenofibrate boosts a memory-like cell differentiation trend (Tscm or Tcm). 4. Inhibition of glycolysis with 2-DG or Inhibition of PI3K/Akt/mTOR axis promotes the generation of CAR-Tcm cells. 5. Modified CAR-T cells that secrete PD-1 blockade scFv can reverse CAR-T exhaustion.