Transarterial Chemoembolization Modulates the Exosomal miR-32-5p/cGAS-STING Axis Mediated Macrophage Ferroptosis, Triggers Immune Remodeling, and Enhances Anti-PD-1/L1 Efficacy in HCC.

Hepatocellular carcinoma (HCC) is a cancer type that causes a high rate of cancer death in the world. The standard therapy plan of intermediate and advanced stages of the HCC is transarterial chemoembolization (TACE). The treatment effectiveness is, however, limited because of the heterogeneity of tumors and the resistance to drugs. This paper shows that the HCC patients with TACE resistance alter their tumor immune homeostasis by reducing the secretion of exosomal miR-32-5p, which has a negative relationship with the population of CD68 macrophages. Both in-cellular and animal studies show that exosomal miR-32-5p leads to ferroptotic cell death in tumor-associated macrophages (TAMs) characterized by augmented lipid oxidation, iron buildup, depletion of glutathione, and mitochondrial malfunction. At the same time, miR-32-5p increases production of M1-type proinflammatory factors such as CD86, CCL2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), thereby enabling macrophage polarization toward tumor-suppressive phenotype. Mechanistically, miR-32-5p activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway through ARID1B down-regulation, ultimately remodeling the tumor immune microenvironment. Experimental murine models indicated that the delivery of exosomal miR-32-5p was a strong tumor suppressor and disseminator, increased the recruitments of CD86 + antigen-presenting cells and CD8 + T lymphocytes, and boosted anti-neoplastic immunity. It should be highlighted that exosomal miR-32-5p also increased the levels of PD-L1, which reflected its complementary value to anti-PD-L1 immunotherapy. Such a combined treatment led to excellent tumor control and enhanced survival without loss of acceptable toxicity profiles. The essential role of ferroptosis was confirmed by the use of Fer-1 to inhibit the chemical reactions, which revealed a new approach by which TACE-resistant exosomal miR-32-5p could inhibit the progression of HCC and complement the anti-PD-L1 therapeutic effects through ferroptosis using TAM, providing insights as well as potential therapeutic objectives in the treatment of HCC.