Mitochondria‐Targeted Pyroptosis Orchestrated by Photodynamic Microneedle Patches Potentiates Melanoma Immunoradiotherapy
Abstract
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.
Article Details
Authors (13)
Ziyao Lu
State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou China
Xinyu He
Yuwei Wang
Shanxi Key Laboratory of Coal-based Value-added Chemicals Green Catalysis Synthesis, School of Chemistry and Chemical Engineering
Hui Chen
Yuxiao Gu
State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou China
Yutong Shi
Borch Department of Medicinal Chemistry and Molecular Pharmacology Purdue University West Lafayette IN 47906 USA
Huiyu Bu
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development Soochow University Suzhou China
Hengte Ke
Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Science Soochow University Suzhou Jiangsu 215021 China
Huabing Chen
Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development College of Pharmaceutical Science Soochow University Suzhou Jiangsu 215021 China
Lu Xu
Kai Yang
Hui He
Zhengqing Guo
State Key Laboratory of Radiation Medicine and Protection School of Radiation Medicine and Protection Jiangsu Key Laboratory of Radiation Injury Prevention and Hazardous Substance Control Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University Suzhou China