Biomimetic Hf-MOF/Mn3O4 STING nanoagonist potentiates radio-immunotherapy by remodeling tumor microenvironment and activating cGAS-STING pathway.

Abstract

Tumor hypoxia and immunosuppression not only drive radioresistance in cancer radiotherapy but also compromise the efficacy of immunotherapy. Here, a biomimetic core-shell nanoagonist (CM/HPM) integrating a radiosensitizing hafnium-based metal-organic framework (Hf-MOF) core with a tumor microenvironment (TME)-responsive Mn3O4 shell is reported to orchestrate robust radio-immunotherapy. The Hf-MOF core serves as a powerful radiosensitizer, enhancing localized radiation energy deposition and amplifying radiation-induced DNA damage. The Mn3O4 shell exhibits multienzyme-mimicking activities, catalyzing oxygen generation to relieve hypoxia, depleting glutathione to amplify oxidative stress, and releasing Mn2+ ions upon TME-triggered degradation. The liberated Mn2+ acts as a critical immune co-agonist, sensitizing cyclic GMP-AMP synthase (cGAS) to cytosolic DNA fragments from Hf-MOF-enhanced radiotherapy, thereby synergistically activating the cGAS-STING pathway. Moreover, the cancer-cell-membrane coating enables homologous targeting and facilitates uptake by both tumor cells and immune cells. In bilateral 4T1 tumor-bearing mice, CM/HPM combined with X-ray irradiation ablates primary tumors and evokes a potent abscopal effect, suppressing distant tumors via enhanced intratumoral T-cell infiltration and dendritic cell (DC) maturation. This synergistic nanoplatform overcomes radioresistance and elicits systemic antitumor immunity, offering a promising paradigm for metastatic cancer therapy.

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