Quercetin‐zinc coordination polymer coated CaCO ₃ nanoparticles potentiate radiotherapy through reprogramming tumor immunosuppression

Radiotherapy has demonstrated broad applications in treating solid tumors, but the hostile tumor microenvironment features significantly limit its clinical outcomes by impairing the priming of systemic antitumor immune responses. In this study, we developed a pH‐responsive nanomedicine by coating calcium carbonate nanoparticles with a quercetin‐zinc coordination polymer to potentiate radiotherapy through synergistic reprogramming of the immunosuppressive tumor microenvironment. Our results demonstrated that Zn 2+ induced pyroptosis in cancer cells further improves their immunogenicity, while quercetin upon being delivered to tumor sites significantly alleviates tumor hypoxia by sequentially decreasing extracellular collagen deposition and promoting tumor perfusion. The QZCaCO 3 ‐PEG, when administered intravenously, exhibited synergistic activity with localized X‐ray irradiation, triggering robust antitumor immunity and substantially inhibiting growth in both irradiated primary tumors and non‐targeted distant lesions. Additionally, QZCaCO 3 ‐PEG combined with radiotherapy elicited a durable immune memory response, effectively suppressing tumor recurrence in multiple murine rechallenge models. This study establishes a versatile strategy for designing multifunctional pH‐responsive nanomedicine as an immunogenic nano‐radiosensitizer to amplify radiotherapy via concurrent pyroptosis induction and tumor hypoxia alleviation.