Fig. 1

Mechanism of mitochondrial dysfunction in the disturbing anti-tumor activity of CD8+ T cells. (The red arrows indicate promotion, and the green arrows indicate inhibition) ①The decrease of mitochondrial membrane potential and the high expression of PD-1 restrict OXPHOS, reducing ATP synthesis. ②mROS accumulation in turn inhibits OXPHOS or limits respiratory metabolism by decreasing the MMP of CD8+ T cells. ③High level of mROS suppresses CD8+ T cell activation and proliferation by inhibiting NF-κB, mTOR, and NFAT5 signaling pathways. ④mROS accumulation plays a role in attritting telomeres and promoting senescence of CD8+ T cells. ⑤An excessively high mROS concentration activates the caspase signaling cascade and induces CD8+ T cell apoptosis. ⑥PD-1 hinders mitochondrial biogenesis through increasing repression of PGC1-α mediated by Akt. ⑦Imbalance in Bax and Bal-2 accelerates the release of cytochrome c from mitochondria and initiates CD8+ T cell apoptosis. ⑧Low MMP causes a high mitochondrial membrane permeability, triggering the subsequent release of cytochrome c and CD8+ T cell apoptosis. ⑨High MMP leads to a high level of mROS production. ⑩Increased cytoplasmic Ca2+ caused by failed mitochondrial Ca2+ buffering initiates the intrinsic apoptosis process. ⑪Accumulated Ca2+ in matrix inhibits mitochondrial biogenesis