Triple-synergistic biomimetic nanoplatform orchestrates photothermal immunotherapy through coordinated ICD and STING...

The immunosuppressive tumor microenvironment (TME) impedes conventional cancer immunotherapies. To overcome this barrier, we engineer DDT-HM nanoparticles (NPs), a biomimetic nanoplatform cloaked in a hybrid membrane fused from cancer cells and macrophages. This dual-functional coating combines macrophage-mediated immune evasion for prolonged circulation with cancer cell-directed homologous targeting for precise tumor accumulation. DDT-HM NPs co-deliver a rationally designed NIR-II photothermal agent (TPT-Se) and a STING agonist (DMXAA). Under 808 nm irradiation, TPT-Se generates localized hyperthermia that directly ablates tumors and triggers immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs), including cytosolic DNA. Simultaneously, tumor-localized DMXAA potently activates the STING pathway. Crucially, ICD and STING signaling exhibit potent reciprocal reinforcement: ICD-derived DAMPs amplify dendritic cell (DC) maturation, which is further potentiated by STING-driven type I interferon responses, while STING activation amplifies ICD-initiated systemic antitumor immunity. In 4T1 tumor-bearing mice, this strategy achieves remarkable suppression of both primary and distant tumors, accompanied by a 4-fold increase CD8⁺ T cells and a pro-inflammatory TME reprogramming. Furthermore, DDT-HM NPs function as a potent nanovaccine, expanding central and effector memory T-cell pools and conferring durable protection against tumor rechallenge. This work establishes a "triple-threat" biomimetic platform that unifies precision photothermal ablation, synergistic dual-pathway immune activation, and nanovaccine functionality for durable cancer immunotherapy.