Melanin-Based Immunoregulatory Nanohybrids Enhance Antitumor Immune Responses in Breast Cancer Mouse Model

Natural melanin nanoparticles (MNPs) have demonstrateda potentialfor eliciting antitumor immune responses through inducing immunogeniccell death (ICD); however, the tumor microenvironment (TME) has beenshown to inhibit T cell-mediated antitumor immunity. To address thischallenge, we designed TME-responsive biodegradable melanin/MnO x nanohybrids via a biomineralization process.Under near-infrared (NIR) light irradiation, the photothermal propertyof melanin/MnO x nanohybrids triggers ICDand release of tumor-associated antigens (TAAs), while Mn2+ and TAAs induce dendritic cell (DC) maturation to provoke immuneresponses. Furthermore, the immunoregulatory properties of the nanohybridsthemselves are exploited to reshape immunosuppressive TME and downregulatePD-L1 through alleviation of the hypoxic and acidic TME. AlthoughMNPs demonstrate higher photothermal killing efficiency than the nanohybrids in vitro due to their superior photothermal effect, themelanin/MnO x nanohybrids exhibit significantlyenhanced antitumor and antimetastatic effects in vivo, benefiting from their ability to reverse immunosuppression andinduce DC maturation. Transcriptomics analysis confirmed the successfulactivation of immune responses. This work presents a promising approachfor immunomodulation-enhanced cancer therapy through the intrinsicproperties of melanin/MnO x nanohybrids.

Automated summary

This study designed biodegradable melanin/MnO x nanohybrids to target the tumor microenvironment (TME) and enhance immunomodulation for cancer therapy. Under NIR light irradiation, the nanohybrids trigger immunogenic cell death and release of tumor-associated antigens, while inducing dendritic cell maturation to initiate immune responses. The nanohybrids also possess immunoregulatory properties to reshape the immunosuppressive TME and downregulate PD-L1. In vivo experiments showed significantly enhanced antitumor and antimetastatic effects, confirming the efficacy of melanin/MnO x nanohybrids for immunomodulation-enhanced cancer therapy.