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; Shuangshuang Wu; Jianqing Wu

doi:10.1038/s41467-025-56002-w

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

Nat Commun. 2025 Jan 13;16(1):630. doi: 10.1038/s41467-025-56002-w.

Authors

Mingjiong Zhang^#¹, Jiahua Cui^#², Haoyan Chen^#¹, Yifan Cheng^#¹, Qiaoyu Chen³, Feng Zong¹, Xiao Lu⁴, Lang Qin⁵, Yu Han¹, Xingwang Kuai⁶, Yuxing Zhang¹, Minjie Chu⁷, Shuangshuang Wu⁸, Jianqing Wu⁹

Affiliations

¹ Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Department of Epidemiology, School of Public Health, Nantong University, Nantong, China.
³ Centre for Assisted Reproduction, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China.
⁵ Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁶ Department of Pathology, Medical School, Nantong University, Nantong, China.
⁷ Department of Epidemiology, School of Public Health, Nantong University, Nantong, China. chuminjie@ntu.edu.cn.
⁸ Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. polariswu7632@njmu.edu.cn.
⁹ Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. jwuny@njmu.edu.cn.

^# Contributed equally.

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.

MeSH terms

Aged
Aging* / immunology
Animals
CD8-Positive T-Lymphocytes / immunology
Carcinoma, Squamous Cell* / genetics
Carcinoma, Squamous Cell* / immunology
Carcinoma, Squamous Cell* / metabolism
Carcinoma, Squamous Cell* / pathology
Cell Proliferation
Cholesterol* / metabolism
Female
Humans
Hydroxymethylglutaryl CoA Reductases
Lung Neoplasms* / genetics
Lung Neoplasms* / immunology
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Male
Mice
Mice, Inbred C57BL
Sterol O-Acyltransferase* / genetics
Sterol O-Acyltransferase* / immunology
Sterol O-Acyltransferase* / metabolism
Sterol Regulatory Element Binding Protein 2 / metabolism
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / metabolism

Substances

Cholesterol
Sterol O-Acyltransferase
Sterol Regulatory Element Binding Protein 2
HMGCR protein, human
SREBF2 protein, human
Hydroxymethylglutaryl CoA Reductases