Vulnerability and Immunogenic Cell Death under Microwave Ablation for Synergistic Treatment of Hepatocellular Carcinoma

Abstract

Microwave ablation (MWA) holds great promise for hepatocellular carcinoma but is often limited by incomplete tumor eradication and recurrence. Here, we report a tumor-killing nanoimmunoreactor driven by endogenous immune cues that synergizes with MWA to eliminate residual tumors and activate systemic antitumor immunity. The 17-AAG–MnO2PEG nanoimmunoreactor consists of a self-responsive PEGylated MnO2 platform loaded with the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), which is designed to respond to the oxidative tumor microenvironment. 17-AAG disrupts tumor cell thermotolerance, enhancing sensitivity to microwave-induced thermal stress, thereby improving ablation efficacy and inducing immunogenic cell death. PEGylation facilitates tumor-targeted accumulation, while the degradable MnO2 responds to hydrogen peroxide (H2O2) and tumor debris generated after MWA, enabling sustained local drug release. The combination treatment promotes dendritic cell maturation and T cell infiltration, effectively suppresses residual tumor regrowth, reduces the risk of metastasis, and establishes durable immune memory. By leveraging post-ablation tumor debris and microenvironmental cues, this strategy couples local tumor ablation with systemic antitumor immunity, providing a mechanistically distinct paradigm for durable cancer therapy.