Affiliation:
1. MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Basic Research Center of Excellence for Functional Molecular Engineering, School of Chemistry, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital Sun Yat-Sen University Guangzhou 510006 P. R. China
2. MOE Key Laboratory of Theoretical Organic Chemistry and Functional Molecule, School of Chemistry and Chemical Engineering Hunan University of Science and Technology Xiangtan 400201 P. R. China
Abstract
AbstractAn optimal cancer chemotherapy regimen should effectively address the drug resistance of tumors while eliciting antitumor‐immune responses. Research has shown that non‐apoptotic cell death, such as pyroptosis and ferroptosis, can enhance the immune response. Despite this, there has been limited investigation and reporting on the mechanisms of oncosis and its correlation with immune response. Herein, we designed and synthesized a Ru(II) complex that targeted the nucleus and mitochondria to induce cell oncosis. Briefly, the Ru(II) complex disrupts the nucleus and mitochondria DNA, which active polyADP‐ribose polymerase 1, accompanied by ATP consumption and porimin activation. Concurrently, mitochondrial damage and endoplasmic reticulum stress result in the release of Ca2+ ions and increased expression of Calpain 1. Subsequently, specific pore proteins porimin and Calpain 1 promote cristae destruction or vacuolation, ultimately leading to cell membrane rupture. The analysis of RNA sequencing demonstrates that the Ru(II) complex can initiate the oncosis‐associated pathway and activate both innate and adaptive immunity. In vivo experiments have confirmed that oncosis promotes dendritic cell maturation and awakens adaptive cytotoxic T lymphocytes but also activates the innate immune by inducing the polarization of macrophages towards an M1 phenotype.