MLKL/retromer axis controls PD-L1 recycling to compromise antitumor immunity during VCP inhibition–induced necroptosis
Abstract
The activation of the vesicular trafficking system, including endosomal recycling and extracellular vesicle (EV) release, represents an adaptive mechanism in cancer cells to counteract cellular stress or necroptotic death signals, which hampers cancer therapy. However, the underlying mechanisms remain poorly understood. Indeed, our study demonstrate that inhibition of valosin-containing protein (VCPi) induces EV release and necroptosis in colorectal cancer (CRC), but does not achieve a synergistic effect with immunotherapy. Mechanistically, VCPi delays the degradation of mixed lineage kinase domain-like protein (MLKL), a critical regulator of necroptosis and endosomal trafficking. Knockdown of MLKL reduces VCPi-mediated necroptosis, EV release, and programmed death ligand 1 (PD-L1) recycling. VCPi leads to MLKL accumulation, which recruits the retromer complex and GTPase-activating protein TBC1D5 to inactivate Rab7A. This redirects PD-L1-loaded vesicles to the cell surface via the retromer complex, thereby resulting in immunosuppression. Notably, targeting the retromer complex enhances the therapeutic efficacy of combined VCP inhibitors and anti-PD-L1 therapy in CRC, offering a promising immunotherapeutic strategy. Our study elucidates the role of the retromer complex in mediating PD-L1 recycling during VCPi-induced necroptosis and reveals that dual inhibition of VCP and the retromer complex potentiates immunotherapy efficacy in CRC.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (12)
Yang Wang
Zi-Jia Huang
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Nan-Nan Yu
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Jun-Ze Liang
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Yong-Hui Zeng
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Qian Zhao
Zhejiang University , , ,
Yi-Ping Zhou
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Yu-Jie Zeng
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Zheng-Hua Sun
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Shuixing Zhang
Department of Radiology, The First Affiliated Hospital of Jinan University
Qing-Yu He
Ministry of Education Key Laboratory of Tumor Molecular Biology and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, and College of Life Science and Technology, Jinan University
Jing Zhang