Multiomics identifies a cholesterol–TFEB–PLD3–TLR9 axis driving immunosuppressive tumor-associated macrophage polarization in esophageal squamous cell carcinoma
Abstract
Tumor-associated macrophages (TAMs) reshape the tumor immune microenvironment and promote tumor progression, yet the underlying mechanisms remain largely unclear. Through integration of single-cell RNA (scRNA) sequencing datasets from esophageal squamous cell carcinoma (ESCC), we identified a distinct protumoral macrophage population with elevated expression of phospholipase D3 (PLD3). Multiomics investigations revealed that high infiltration of these PLD3-high macrophages was associated with poor clinical outcomes in ESCC patients. Mechanistically, tumor cells secreted cholesterol to modulate the microenvironment. Upon the uptake by TAMs, cholesterol triggered the nuclear translocation of transcription factor EB (TFEB), which directly bound to the PLD3 promoter region and activated its transcription. The overexpressed PLD3 localized to lysosomes, enzymatically degrading single-stranded nucleic acids, thereby suppressing the activation of the toll-like receptor 9 (TLR9) pathway. This cascade ultimately impaired effector T cell function and sustained an immunosuppressive tumor microenvironment (TME). Notably, therapeutic intervention using ODN2216-siPLD3 in murine models enhanced CD8 T cell infiltration and significantly inhibited tumor growth. Our findings highlight PLD3-high macrophages as a promising diagnostic biomarker and a therapeutic target for ESCC, paving the way for potential clinical translation.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (21)
Licheng Tan
College of Chemistry and Chemical Engineering/Film Energy Chemistry for Jiangxi Provincial Key Laboratory (FEC), Nanchang University, Nanchang, China.
Hongyu Zhou
Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University
Baifeng Zhang
Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Dora Lai Wan Kwong
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Yongxu Jia
Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University
Jiayi Huang
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Kin To Hugo Siu
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Shuang Zhang
Jiao Huang
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Jie Luo
Yuma Yang
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Qin Liu
Yingchen Lyu
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Liuxian Ban
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Ziyang Qi
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Nanzhou Yu
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Chaohui He
Department of Cardiovascular Surgery, Songshan Lake Central Hospital of Dongguan City
Weiguang Zhang
School of Chemistry
Yanru Qin
Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University
Beilei Liu
Department of Biomedical Sciences, Tung Biomedical Sciences Centre, City University of Hong Kong
Xinyuan Guan
Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong