Microenvironment-responsive injectable marine polysaccharide hydrogel empowered by bimetallic MOF nanozymes for in situ pancreatic cancer immunotherapy via ferroptosis-mediated cGAS-STING activation.

Pancreatic cancer is characterized by a dense desmoplastic stroma and a profoundly immunosuppressive tumor microenvironment (TME), which jointly impede drug penetration and immune activation. Here, we report a microenvironment-responsive injectable marine polysaccharide hydrogel (G@ZnFe-Gel) empowered by a Zn/Fe bimetallic MOF nanozyme to achieve in situ pancreatic cancer immunotherapy via ferroptosis-cGAS-STING synergy. Following intratumoral injection, the hydrogel undergoes rapid thermally and Ca2+-reinforced gelation, forming a stable intratumoral depot that ensures prolonged local retention within stromal-dense pancreatic tumors. Mechanistically, glucose oxidase (GOD)-mediated glucose oxidation disrupts tumor metabolism while generating H2O2, which is further converted into highly reactive oxygen species through Fe3+-mediated Fenton-like reactions, inducing lipid peroxidation and ferroptosis. Comparisons with the Zn-Gel control further support the additional contributions of Fe incorporation and GOD loading to the enhanced ferroptosis-associated responses. In addition, ferroptosis-associated mitochondrial stress and potential DAMP release, including mtDNA, may contribute to enhanced cGAS-STING signaling, with a possible additional contribution from Zn2+ signaling. In a subcutaneous pancreatic cancer model, G@ZnFe-Gel markedly suppressed tumor growth, promotes macrophage reprogramming, enhanced cytotoxic T-cell infiltration, and remodeled the immunosuppressive TME without systemic toxicity. This work establishes a mechanism-driven hydrogel-nanozyme platform that integrates local retention, regulated cell death, and innate-adaptive immune crosstalk, offering a promising strategy for immunologically cold and stroma-rich solid tumors.