Mitochondria‐Targeted Pyroptosis Orchestrated by Photodynamic Microneedle Patches Potentiates Melanoma Immunoradiotherapy

ABSTRACT The lethality of melanoma stems from its high metastatic propensity, intrinsic apoptosis resistance, and a profoundly immunosuppressive microenvironment, which collectively undermine conventional radiotherapy and immunotherapy. Here, we develop a spatiotemporally precise therapeutic strategy using mitochondria‐targeted photodynamic microneedles ( mito TPS‐MNs) to orchestrate GSDME‐mediated pyroptosis and potentiate systemic immunoradiotherapy. Upon transdermal photoactivation, mito TPS induces intense, mitochondria‐confined reactive oxygen species (ROS) bursts, triggering a caspase‐3/GSDME‐dependent pyroptotic cascade while simultaneously disrupting mitochondrial respiration to alleviate tumor hypoxia. This dual‐action mechanism sensitizes melanoma to x‐ray irradiation, achieving near‐complete regression of primary tumors and remodeling “cold” tumor microenvironments into immunologically “hot” niches. The explosive release of damage‐associated molecular patterns (DAMPs) from pyroptotic cells functions as an in situ cancer vaccine, promoting dendritic cell maturation, the systemic recruitment of CD8 + cytotoxic T lymphocytes, and potent abscopal responses against untreated distant metastases. Our work establishes mitochondria‐directed pyroptosis as a mechanistic switch to bypass the inherent apoptotic resistance of melanoma, providing a clinically translatable strategy to convert localized interventions into systemic immunity against advanced melanoma.