Autophagic stress-induced nanomedicine potentiates radioimmunotherapy against liver cancer through cGAS-STING signaling and immune remodeling.

Abstract

Radioimmunotherapy is increasingly recognized as an immune-activating modality. However, its therapeutic efficacy in hepatocellular carcinoma (HCC) remains unsatisfactory. Herein, a hyaluronic acid (HA)-modified, HCQ-loaded ZIF-8@MnOx nanoplatform (HCQ@ZIF-8@MnOx@HA, CZMH) is engineered to induce autophagic stress for enhanced radioimmunotherapy. CZMH was synthesized via a ZIF-8 based coordination-driven self-assembly strategy, followed by MnOx deposition, hydroxychloroquine loading, and hyaluronic acid surface modification. CZMH induces pronounced autophagic stress through concurrent autophagy initiation and autophagic flux blockade. CZMH activates cGAS-STING signaling by preventing STING degradation and mitochondrial DNA clearance. By amplifying reactive oxygen species generation and mitochondrial dysfunction, CZMH robustly induces immunogenic cell death. Cytokine release from CZMH-treated cells contributes to reprogramming of the tumor immune microenvironment. When combined with radiotherapy, CZMH markedly enhances tumor control by amplifying tumor-intrinsic damage and radiotherapy-driven immune activation. CZMH potentiates the abscopal effect of radiotherapy by increasing infiltration and activation of CD8+ T cells in distant tumors and sustaining systemic antitumor immunity. The triple therapy of immune checkpoint inhibitor, CZMH and radiotherapy achieves a pronounced synergistic therapeutic benefit. Collectively, this work establishes CZMH as a potent radio-sensitizing and immunomodulatory nanoplatform to improve therapeutic outcomes in liver cancer treatment.