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

Natural melanin nanoparticles (MNPs) have demonstrated a potential for eliciting antitumor immune responses through inducing immunogenic cell death (ICD); however, the tumor microenvironment (TME) has been shown to inhibit T cell-mediated antitumor immunity. To address this challenge, we designed TME-responsive biodegradable melanin/MnO_x nanohybrids via a biomineralization process. Under near-infrared (NIR) light irradiation, the photothermal property of melanin/MnO_x nanohybrids triggers ICD and release of tumor-associated antigens (TAAs), while Mn²⁺ and TAAs induce dendritic cell (DC) maturation to provoke immune responses. Furthermore, the immunoregulatory properties of the nanohybrids themselves are exploited to reshape immunosuppressive TME and downregulate PD-L1 through alleviation of the hypoxic and acidic TME. Although MNPs demonstrate higher photothermal killing efficiency than the nanohybrids in vitro due to their superior photothermal effect, the melanin/MnO_x nanohybrids exhibit significantly enhanced antitumor and antimetastatic effects in vivo, benefiting from their ability to reverse immunosuppression and induce DC maturation. Transcriptomics analysis confirmed the successful activation of immune responses. This work presents a promising approach for immunomodulation-enhanced cancer therapy through the intrinsic properties of melanin/MnO_x nanohybrids.