A dual-ion/immune checkpoint nanoplatform-activated pyroptosis/cGAS-STING signaling transform iMWA into systemic immunotherapy against HCC recurrence

Abstract

Incomplete microwave ablation (iMWA) remains a major challenge in the clinical management of hepatocellular carcinoma (HCC), as residual tumors often foster an immunosuppressive microenvironment and upregulate PD-L1 expression, thereby promoting immune evasion and recurrence. This study systematically elucidates the mechanisms underlying HCC progression and metastasis following iMWA and describes the design of a dual-ion/immune checkpoint nanoplatform (aP@Mn/Ca) based on a metal-organic framework (MOF). Leveraging the excellent biocompatibility and tumor microenvironment-responsive degradability of MOFs, this platform enables efficient co-delivery of Ca2+, Mn2+, and an anti-PD-L1 (aPD-L1) antibody specifically to residual tumor tissues to overcome post-ablation immune barriers. Specifically, upon tumor accumulation, controlled Ca2+ release induces mitochondrial stress and inflammasome activation, triggering gasdermin-mediated pyroptosis and immunogenic cell death (ICD). Concurrently, Mn2+ activates innate immunity by potentiating the cGAS-STING signaling pathway. This synergistic induction of pyroptosis and STING activation promotes inflammatory cytokine production, antigen presentation, and cytotoxic T cell priming. Meanwhile, the local delivery of aPD-L1 mitigates adaptive immunosuppression and reduces systemic toxicity. Consequently, aP@Mn/Ca transforms iMWA into a systemic immunotherapeutic strategy, effectively suppressing HCC recurrence and metastasis both in vitro and in vivo. In summary, this work establishes an ion-based immunomodulatory paradigm integrating ICD, innate immune activation, and immune checkpoint blockade, offering a promising nanotherapeutic framework for preventing post-ablation HCC recurrence and enhancing immunotherapy in solid tumors.