Affiliation:
1. State Key Laboratory of Pharmaceutical Biotechnology Medical School and School of Life Science Nanjing University Nanjing 210093 P. R. China
2. Department of Urology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing 210093 P. R. China
3. Jiangsu Key Laboratory for Nano Technology Nanjing University Nanjing 210093 P. R. China
Abstract
AbstractIn situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria‐targeting modification of fenofibric acid (FFa), a lipid‐lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria‐targeting FFa (Mito‐FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS‐STING‐dependent type I interferon (IFN‐I) secretion. The synchronous CRT exposure and IFN‐I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross‐priming of CD8+ T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito‐FFa injection turns immune‐cold tumors into hot ones and elicits systemic tumor‐specific CD8+ T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD‐L1 blockade and good bio‐safety of i.t. Mito‐FFa administration suggest the great translational potential of Mito‐FFa in tumor immunotherapy.
Funder
National Key Research and Development Program of China
Natural Science Foundation of Jiangsu Province
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)
Cited by
4 articles.
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