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

TL;DR

A new biomimetic nanoplatform combines photothermal therapy and immune activation to effectively treat tumors and boost long-term immunity.

Contribution

A triple-synergistic nanoplatform that integrates photothermal ablation, ICD, and STING activation for enhanced immunotherapy.

Findings

The nanoplatform suppressed both primary and distant tumors in mice with a 4-fold increase in CD8+ T cells.

It reprogrammed the tumor microenvironment to be pro-inflammatory and acted as a nanovaccine for durable protection.

ICD and STING activation synergistically enhanced immune responses and systemic antitumor immunity.

Abstract

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.

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