Matrix-modulating pH-gated hydrogel for coordinated regulation of cancer-associated fibroblast phenotype and Mn²⁺-STING activation for enhanced tumor immunotherapy.

Abstract

The tumor microenvironment (TME), particularly its cancer-associated fibroblast (CAF)-driven fibrotic stroma and immunosuppressive components, forms intertwined physical and immune barriers that impede the efficacy of immunotherapy. To address this challenge, we developed a pH-gated hydrogel platform to modulate CAF-resulted TME barriers and activate potent antitumor immunity. This dynamic network, constructed by Schiff base crosslinking between carboxymethyl chitosan and aldehyde-functionalized hyaluronic acid, was utilized for the co-delivery of pirfenidone (PFD) and manganese-curcumin nanoparticles (MC). In the acidic TME, PFD was released rapidly from hydrogel to modulate CAF phenotype, thereby attenuating the formation of fibrotic stroma. The internalized MC orchestrated three synergistic therapeutic functions: (1) suppressing VEGF-mediated angiogenesis via curcumin, (2) generating reactive oxygen species through Mn²⁺-catalyzed Fenton-like reactions, and (3) promoting dendritic cell maturation by activating the cGAS-STING pathway with Mn²⁺. Upon 808 nm NIR laser irradiation, MC exhibited potent photothermal conversion efficacy, inducing localized hyperthermia that further amplified ROS production, and triggered immunogenic cell death. This coordinated cascade thereby elicited robust antitumor immunity, as evidenced by the upregulated expression of proinflammatory cytokines (TNF-α, IFN-γ, IL-6) and enhanced CD8⁺ T cell infiltration. Notably, this strategy achieved marked tumor regression in B16F10 melanoma-bearing mice. Thus, this work established a TME-responsive platform that coordinated barrier modulation with multimodal therapeutic synergy, providing a promising paradigm for solid tumor immunotherapy. STATEMENT OF SIGNIFICANCE: Modulating the tumor microenvironment (TME) by targeting cancer-associated fibroblasts (CAFs) represent a promising strategy to enhance the efficacy of immunotherapy. Here, we develop a pH-gated hydrogel platform that enables the controlled delivery of pirfenidone and manganese-curcumin nanoparticles (MC), thereby facilitating the regulation of CAF-mediated fibrotic barriers followed by the activation of antitumor immunity. The released MC integrate antiangiogenic activity, ROS amplification, STING pathway activation, and photothermal ablation into a unified therapeutic system. Moreover, the photothermal effect further amplifies ROS generation and STING signaling, resulting in remodeling of the TME. This coordinated cascade elicits robust T-cell activation and cytokine secretion, achieving marked tumor eradication in murine melanoma models. Overall, this study establishes a therapeutic paradigm that integrates stromal barrier modulation with immune activation to achieve more effective tumor treatment.