Thermosensitive Hydrogel-Mediated Chemo-Photothermal Combined Immunotherapy for Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains clinically challenging due to the lack of therapeutic targets and an immunosuppressive microenvironment. Despite its targeted potential, photothermal therapy (PTT) faces limitations in clinical applications due to tumor thermotolerance, insufficient immunogenic cell death (ICD) induction, and unpredictable nanodrug metabolism. Herein, we developed a chitosan/β-glycerophosphate thermosensitive hydrogel (CS/GP@MTO Gel) using clinical tracer mitoxantrone hydrochloride (MTO). Under physiological temperature, the system enables precise in situ delivery of MTO nanocrystals via a sol-gel phase transition. Under 660 nm laser irradiation, the photothermal effect generated by MTO enhances chemosensitivity, while MTO downregulates heat shock protein 70 (HSP70) expression through DNA damage signaling, thereby reducing the thermal resistance effect and establishing synergistic chemo-photothermal therapy. This strategy significantly triggers the release of damage-associated molecular patterns (DAMPs), remodeling the immunosuppressive niche. Furthermore, in combination with PD-1/PD-L1 inhibitors (anti-PD-L1), it effectively inhibits primary and metastatic tumor progression. This study provides an innovative TNBC treatment strategy with targeting capabilities and immunomodulatory functions.