Increased SOAT2 expression in aged regulatory T cells is associated with altered cholesterol metabolism and reduced anti-tumor immunity

Mingjiong Zhang, Jiahua Cui, Haoyan Chen, Yifan Cheng, Qiaoyu Chen, Feng Zong, Xiao Lu, Lang Qin, Yu Han, Xingwang Kuai, Yuxing Zhang, Minjie Chu (chuminjie@ntu.edu.cn), Shuangshuang Wu (polariswu7632@njmu.edu.cn) and Jianqing Wu (jwuny@njmu.edu.cn)
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Mingjiong Zhang: The First Affiliated Hospital of Nanjing Medical University
Jiahua Cui: Nantong University
Haoyan Chen: The First Affiliated Hospital of Nanjing Medical University
Yifan Cheng: The First Affiliated Hospital of Nanjing Medical University
Qiaoyu Chen: Tongji University School of Medicine
Feng Zong: The First Affiliated Hospital of Nanjing Medical University
Xiao Lu: Changshu No.1 People’s Hospital
Lang Qin: The First Affiliated Hospital of Nanjing Medical University
Yu Han: The First Affiliated Hospital of Nanjing Medical University
Xingwang Kuai: Nantong University
Yuxing Zhang: The First Affiliated Hospital of Nanjing Medical University
Minjie Chu: Nantong University
Shuangshuang Wu: The First Affiliated Hospital of Nanjing Medical University
Jianqing Wu: The First Affiliated Hospital of Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Immune functions decline with aging, leading to increased susceptibility to various diseases including tumors. Exploring aging-related molecular targets in elderly patients with cancer is thus highly sought after. Here we find that an ER transmembrane enzyme, sterol O-acyltransferase 2 (SOAT2), is overexpressed in regulatory T (Treg) cells from elderly patients with lung squamous cell carcinoma (LSCC), while radiomics analysis of LSCC patients associates increased SOAT2 expression with reduced immune infiltration and poor prognosis. Mechanically, ex vivo human and mouse Treg cell data and in vivo mouse tumor models suggest that SOAT2 overexpression in Treg cells promotes cholesterol metabolism by activating the SREBP2-HMGCR-GGPP pathway, leading to enhanced Treg suppresser functions but reduced CD8+ T cell proliferation, migration, homeostasis and anti-tumor immunity. Our study thus identifies a potential mechanism responsible for altered Treg function in the context of immune aging, and also implicates SOAT2 as a potential target for tumor immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-56002-w

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