Programmed cell death protein 1 (PD-1) inhibitors are the most common immune-checkpoint inhibitors and considered promising drugs for hepatocellular carcinoma (HCC). However, in clinical settings, they have a low objective response rate (15%-20%) for patients with HCC; this is because of the insufficient level and activity of tumor-infiltrating T lymphocytes (TILs). The combined administration of oxymatrine (Om) and astragaloside IV (As) can increase the levels of TILs by inhibiting the activation of cancer-associated fibroblasts (CAFs) and improve the activity of TILs by enhancing their mitochondrial function. In the present study, we constructed a magnetic metal-organic framework (MOF)-based nanoplatform with platelet membrane (Pm) coating (PmMN@Om&As) to simultaneously deliver Om and As into the HCC microenvironment. We observed that PmMN@Om&As exhibited a high total drug-loading capacity (33.77 wt %) and good immune escape. Furthermore, it can target HCC tissues in a magnetic field and exert long-lasting effects. The HCC microenvironment accelerated the disintegration of PmMN@Om&As and the release of Om&As, thereby increasing the level and activity of TILs by regulating CAFs and the mitochondrial function of TILs. In addition, the carrier could synergize with Om&As by enhancing the oxygen consumption rate and proton efflux rate of TILs, thereby upregulating the mitochondrial function of TILs. Combination therapy with PmMN@Om&As and α-PD-1 resulted in a tumor suppression rate of 84.15% and prolonged the survival time of mice. Our study provides a promising approach to improving the antitumor effect of immunotherapy in HCC.
Keywords: PD-1 inhibitors; cancer-associated fibroblasts; combination therapy; mitochondria; tumor-infiltrating T lymphocytes.