Tumor Selective Metabolic Reprogramming as a Prospective PD‐L1 Depression Strategy to Reactivate Immunotherapy

Abstract Currently, the role of the lysosome, endoplasmic reticulum, or dictyosome in the transcription and translation of programmed cell death ligand 1 (PD‐L1) is well revealed, but the role and function of mitochondria in the PD‐L1 expression in tumors is still not fully researched, making it hard to offer a novel PD‐L1 regulation strategy. In this research, it is newly revealed that mitochondria oxidative phosphorylation (OXPHOS) depression can be used as an effective PD‐L1 down‐regulation method. To offer an ideal and high‐effective tumor mitochondria‐targeted OXPHOS depression nanosystem, IR‐LND is prepared by conjugating mitochondria‐targeted heptamethine cyanine dye IR‐68 with mitochondrial complexes I and II depression agent lonidamine (LND), which then further self‐assembled with albumin (Alb) to form IR‐LND@Alb nanoparticles. By doing this, PD‐L1 expression in tumors is selectively and effectively depressed by IR‐LND@Alb nanoparticles. As expected, the anti‐tumor efficacy of such a PD‐L1 depression strategy is superior to conventional anti‐PD‐L1 monoclonal antibodies. Interestingly, IR‐LND can also be served as a novel ideal promising photodynamic therapy (PDT) drug with self‐oxygen and self‐PD‐L1 regulation capacity. All in all, this tumor‐selective metabolic reprogramming platform to reactivate immunotherapy and sensitize for PDT effect, would open a new window for mitochondrial immunotherapy for cancer patients.