Abstract
Despite the potential of photodynamic therapy in breast cancer treatment, inadequate immunogenicity and inefficient pyroptosis induction remain critical limitations. To address this, we developed dissolvable microneedles (MNs) for localized co-delivery of decitabine (DEC) and glutathione (GSH)-responsive photosensitizer nanoparticles (HPPH-ss-NPs), aiming to potentiate immunogenic pyroptosis in breast cancer. The MNs enabled spatiotemporal control of DEC (dissolution-dependent release) and HPPH-ss-NPs (GSH-triggered activation), enhancing tumor drug levels with reduced systemic exposure. Mechanistically, DEC restored pyroptosis executioner gasdermin E (GSDME) expression, while HPPH-ss-NPs depleted intracellular GSH and generated caspase-3-activating ROS under light irradiation. The synergistic action triggered GSDME-dependent pyroptosis, releasing immunostimulatory DAMPs that increased mature dendritic cells and tumor-infiltrating CD8+ T cells. In orthotopic models, (DEC + HPPH-ss-NPs)@MNs suppressed primary tumor growth, while combining with anti-PD-1 synergistically inhibited tumor recurrence and lung metastasis, establishing durable systemic immunity. This MN-based platform establishes a localized photodynamic-epigenetic crosstalk to convert immunologically inert tumors into pyroptosis-driven immunogenic niches, providing a strategy for combinatorial breast cancer therapy.