Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance.

CD276, is a fatal recently discovered immune checkpoint proteins of B7 family. Due to the not clearly uncovered signal pathways that involved in the expression of CD276 in tumors, few strategies were discovered to regulate CD276. Here, we newly discovered that abnormal tumor mitochondrial activation played a vital important role in raising CD276 expression through targeting AMPK/mTOR signal pathway. Then, it was also revealed that clinical usable lipid-lowering drugs with mitochondria oxidative phosphorylation (OXPHOS) and glycolysis inhibiting capacity, like fenofibric acid (FFA), exhibited desired programmed death ligand-1 (PD-L1) and CD276 co-suppression capacity. To better deliver FFA to tumor mitochondria, IR-FFA was synthesized by linking the mitochondria-targeting heptamethylene cyanine IR-68 with FFA, followed by self-assembly with albumin (Alb) to create IR-FFA@Alb nanoparticles. By doing so, the dosage needed for IR-FFA@Alb to depress CD276 and PD-L1 expression was 100 times lower than free FFA. Then, IR-FFA@Alb monotherapy effectively inhibited tumor growth both in vitro and in vivo. Moreover, the combination therapy of IR-FFA@Alb nanoparticles and radiotherapy (RT) effectively avoid the frequently occurred immune tolerance phenomenon of RT by co-depression CD276 and PD-L1. These results altogether showed the possibility of using lipid-lowering drugs as multi-functional immune checkpoint inhibitors to sensitize tumor therapy.