Fig. 2

Cell signaling associated with mitochondrial metabolism and strategies to counteract CAR-T cell exhaustion. A variety of signaling pathways, such as the mTOR, AMPK, and MAPK signaling pathways, and inhibiting pathways, such as the PD-1 signaling pathway, are involved in T cell activation and mitochondrial metabolism. When activated, metabolic switching mediated by the PI3K–PKB (AKT)–mTOR pathway supports the differentiation of effector T cells (T_E) cells. The AMPK pathway drives long-chain fatty acid oxidation (FAO) and mitochondrial biogenesis through phosphorylation of ACC2 and PGC-1α activity. PGC-1α activates NRF1/2, which activate Tfam. Tfam drives the transcription and replication of mitochondrial DNA (mtDNA). In addition, 4-1BB signaling upregulates PGC-1α expression through stimulation of the p38-MAPK pathway, resulting in mitochondrial fusion and biogenesis. Increased PD-1 inhibitory receptor expression induces Blimp-1 expression, a critical exhaustion-related transcription factor, to exacerbate NFAT activity. NFAT activates the transcription factor TOX, which is associated with cell exhaustion and suppresses the expression of transcription factor Tcf7, which is related to oxidative phosphorylation (OXPHOS)