Self-reinforced photothermal-immunomodulation potentiating ISR-ICD cascade against postoperative relapse.

Abstract

Postoperative liver cancer relapse remains a formidable clinical challenge. Photothermal therapy (PTT) holds promise by eliminating residual malignancies and activating antitumor immunity; notably, tumor cells persistently reconstitute proteostasis and survive by integrated stress response (ISR)-mediated heat shock protein 90 (HSP90) activation to constrain PTT efficacy. To address this limitation, we engineered a self-reinforced photothermal-immunomodulation strategy based on electrospun nanofiber scaffolds co-loaded with black phosphorus nanosheets (BPNSs) and the HSP90 inhibitor 17-DMAG. These nanofiber scaffolds exhibited robust hydrophobicity, efficient photothermal conversion, and near-infrared (NIR) responsive controlled drug release. Under NIR irradiation, the nanofiber scaffolds leveraged BPNSs to generate stable PTT while liberating 17-DMAG to amplify proteotoxicity, forcibly redirecting the ISR from pro-survival adaptation toward robust apoptosis and immunogenic cell death (ICD). Consequently, prominently exposed damage-associated molecular patterns potentiated tumor immunogenicity and remodeled immune microenvironment by dendritic cells maturation, cytotoxic T lymphocytes (CTLs) priming, and immunosuppressive populations reprogramming. Crucially, subsequent synergy with anti-PD-L1 reinvigorated CTLs and established durable immune memory. Systematic validation confirmed this localized strategy uniquely integrates precision photothermal energy conversion with potent ISR-ICD cascade, effectively synergizing with anti-PD-L1 to suppress postoperative liver cancer relapse and metastasis, thereby holding substantial translational potential for clinical oncology.