Calcium peroxide-embedded alginate hydrogels potentiate microwave ablation by synergizing with subtherapeutic heating to induce immunogenic necroptosis.

Subtherapeutic microwave heating at tumor margins, arising from the need to balance therapeutic efficacy with clinical safety during microwave ablation, represents a major cause of postoperative tumor recurrence. Therefore, developing biomaterials that combine strong microwave susceptibility with immunostimulatory activity is of practical significance for enhancing the therapeutic impact of current microwave ablation techniques on tumor rim cells. In this study, we prepared an injectable calcium peroxide nanoparticle-embedded alginate hydrogel (CaO2-ALGel) to synergistically sensitize cancer cells to microwave hyperthermia. Upon decomposition in response to tumor acidity, CaO2 enhances microwave heating through ion confinement effects and synergizes with subtherapeutic microwave heating to broadly induce necroptosis in cancer cells via activation of the phosphorylated receptor-interacting protein kinase 3 and phosphorylated mixed lineage kinase domain-like signaling pathways. Following locoregional administration, CaO2-ALGel with its superior tumor acidity-neutralizing ability synergized with subtherapeutic microwave hyperthermia to elicit potent therapeutic and protective antitumor immunity, effectively suppressing both primary and rechallenged tumors. Moreover, CaO2-ALGel-assisted microwave hyperthermia inhibited systemic tumor metastasis, particularly when combined with immune checkpoint blockade therapy in an orthotopic murine model of triple-negative breast cancer. This study underscores the dual capacity of CaO2-ALGel to enhance microwave ablation by simultaneously improving microwave heating efficacy and promoting immunogenicity.