Zinc-Iron Bimetallic MOF-Integrated Thermosensitive Hydrogel for Breast Cancer Immunotherapy via Ferroptosis-Induced cGAS–STING Activation

Qingdao Key Laboratory of Biomacromolecular Drug Discovery and Development, State Key Laboratory Base of Eco-Chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China

^* Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it. (Xiangyan Chen), This email address is being protected from spambots. You need JavaScript enabled to view it. (Yantao Li).

Abstract

Breast cancer is characterized by a profoundly immunosuppressive tumor microenvironment (TME), which severely limits therapeutic efficacy and immune activation. Here, we develop a zinc-iron bimetallic MOF-integrated thermosensitive hydrogel (ZF-Gel) for in situ breast cancer immunotherapy via ferroptosis-induced cGAS-STING activation. Upon intratumoral injection, ZF-Gel undergoes rapid temperature-triggered sol-gel transition, forming a stable intratumoral depot that enables sustained local retention. Mechanistically, the Zn/Fe bimetallic MOF induces oxidative stress and lipid peroxidation, triggering ferroptosis. Ferroptosis-associated damage signals, together with Zn2+-mediated regulation, activate the cGAS–STING pathway, leading to IRF3 phosphorylation and downstream immune gene expression, thereby coupling tumor cell death with innate immune sensing and adaptive immune activation. In vitro, ZF-Gel exhibits pronounced antiproliferative effects against breast cancer cells. This work establishes a mechanism-driven hydrogel-MOF platform that integrates local retention, regulated cell death, and innate–adaptive immune crosstalk, offering a promising strategy for immunologically cold breast tumors.