Hypochlorous Acid-Responsive Prodrug Nanoplatform for Synergistic Cancer Immunotherapy

Immunotherapy offers a promising paradigm for cancer treatment, but its efficacy is often constrained by tumor heterogeneity and the immunosuppressive tumor microenvironment. Herein, we constructed a multifunctional nanoplatform (termed MD1a NP) designed to elicit personalized antitumor immunity and overcome tumor immunosuppression by co-assembling a hypochlorous acid (HOCl)-responsive methylene blue (MB)-doxorubicin (DOX) dimer prodrug with a stimulator of interferon genes (STING) agonist (1a). Following intravenous administration, elevated intratumoral HOCl triggers the activation and release of MB and DOX, inducing nanoparticle disassembly and facilitating the liberation of 1a. Upon near-infrared laser irradiation, MB-mediated photodynamic therapy synergizes with DOX-induced chemotherapy to eradicate tumor cells and amplify immunogenic cell death, thereby enhancing the release of tumor antigens and damage-associated molecular patterns. This cascade promotes dendritic cell maturation, which is further reinforced by 1a-mediated STING activation. Moreover, MD1a NP treatment decreases regulatory T-cell populations, alleviates T-cell suppression, and promotes memory T-cell formation. Consequently, MD1a NP combined with laser irradiation remodels the immunosuppressive tumor microenvironment and effectively inhibits both primary and distant tumor growth while preventing lung metastasis in orthotopic 4T1 breast cancer models. This study provides insights into the design of tumor-activatable nanoplatforms for multimodal therapy against immune-desert cancers.