Immunogenic Cell Death Augmented by Manganese Zinc Sulfide Nanoparticles for Metastatic Melanoma Immunotherapy

Both T-cell deprivation and insufficient tumor immunogenicity seriously hinder the efficacy of immune mediated tumor destruction in melanoma. In this work, an amphiphilic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) copolymer with a thermally sensitive flowable core (mPEG-b-PHEP) was chosen to incorporate IR780 dye and manganese zinc sulfide nanoparticles (ZMS) to form polymer micelles (denoted PPIR780-ZMS), which precisely controlled the release of ZMS after being triggered by near infrared light (NIR). Mn2+-mediated chemodynamic therapy (CDT) by photothermal trigger boosted the generation of reactive oxygen species (ROS), making the PPIR780-ZMS smart bomblets in vivo. It was demonstrated that PPIR780-ZMS could maximize immunogenic cell death (ICD) in cancer, which is characterized by abundant damage-associated molecular pattern (DAMP) exposure. As a result, the cytotoxic T cells (CD8+) and helper T cells (CD4+) expanded and infiltrated the neoplastic foci, which further reprogrammed the suppressive tumor microenvironment (TME) against the primary tumor and pulmonary metastases with safe systemic cytokine expression. In addition, Mn2+-mediated cGAS-STING signaling pathway activation enhanced the antitumor immunity of this nanocomposite, providing a practical strategy for expanding the use of Mn-based nanostructures.

Automated summary

In this study, a smart micelle system was developed using an amphiphilic copolymer to encapsulate manganese zinc sulfide nanoparticles and triggered release by near infrared light. The micelles effectively enhanced reactive oxygen species generation, leading to immunogenic cell death and improved antitumor immunity in melanoma.