PhotoPyro‐Induced cGAS‐STING Pathway Activation Enhanced Anti‐Melanoma Immunotherapy via a Manganese‐Coordinated Nanomedicine

Abstract Malignant melanoma is an aggressive skin cancer with a high metastatic and mortality rate. Owing to genetic alterations, melanoma cells are resistant to apoptosis induction, which reduces the efficacy of most adjuvant systemic anticancer treatments in clinical. Here, a noninvasive strategy for anti‐melanoma immunotherapy based on a manganese‐coordinated nanomedicine is provided. Supplemented with photoirradiation, photon‐mediated reactive oxygen species generation by photosensitizer chlorin e6 initiates photon‐controlled pyroptosis activation (PhotoPyro) and promotes antitumor immunity. Simultaneously, photoirradiation‐triggered double‐stranded DNA generation in the cytosol would activate the Mn 2+ ‐sensitized cyclic GMP–AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway, which further augment the PhotoPyro‐induced immune response. The syngeneic effect of these immunostimulatory pathways significantly benefits dendritic cell maturation by damage‐associated molecular patterns and proinflammatory cytokines secretion, thereby activating T cells and remarkably eliciting a systemic antitumor immune response to inhibiting both primary and distant tumor growth. Collaboratively, the photoirradiation‐triggered PhotoPyro and cGAS‐STING pathway activation by nanomedicine administration could enhance the antitumor capacity of immunotherapy and serve as a promising strategy for melanoma treatment.