pH-responsive R848-loaded Cu MOF NPs potentiate anti-tumor immunity via synergistic photothermal therapy and immunotherapy in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC), the most common type of liver cancer, remains a major cause of cancer-related mortality worldwide, with limited treatment options and poor prognosis in advanced stages. Immunotherapy has shown promise in treating advanced HCC, with the TLR7/8 agonist resiquimod (R848) effectively activating both innate and adaptive immunity. However, its clinical application is limited by poor solubility, rapid clearance, toxicity, and the inherently low immunogenicity of HCC. To enhance therapeutic efficacy, combination strategies are increasingly explored. Here, we developed a multifunctional copper-based metal–organic framework (Cu MOF) nanoparticles encapsulating R848 (Cu MOF/R848) for synergistic photoimmunotherapy against HCC. Cu MOF/R848 achieves efficient pH-responsive release in the tumor microenvironment. Photothermal therapy (PTT) utilizes the light-absorbing properties of Cu MOF to convert near-infrared (NIR) light into heat, thereby disrupting mitochondria, inducing tumor cell apoptosis, and promoting immunogenic cell death (ICD). This photothermal effect facilitates the release of tumor-associated antigens, while R848 acts as an immune stimulant, together eliciting a robust systemic antitumor response. In vitro, Cu MOF/R848 combined with NIR irradiation induced apoptosis in hepatoma cells by modulating pro- and anti-apoptotic proteins, including upregulating Bax and downregulating Bcl-2, thereby effectively inhibiting cell proliferation and promoting dendritic cell maturation. In vivo, the treatment achieved effective tumor ablation, suppressed neovascularization, and enhanced systemic immune responses by activating CD8+ and CD4+ T cells, promoting their infiltration into tumor tissues, and elevating serum levels of TNF-α and IFN-γ. Collectively, these findings demonstrate that Cu MOF/R848 integrates photothermal ablation with immune activation, providing a promising nanoplatform for HCC therapy.