Macrophage lipid efflux regulates the tumour microenvironment in early‐stage lung adenocarcinoma
9 affiliations
- 1Department of Pulmonary and Critical Care Medicine, AI+ Lung Cancer Prevention and Treatment CenterZhongshan HospitalFudan UniversityShanghai China
- 2Institute of Science and Technology Fudan University Shanghai China
- 3Department of Pathology Zhongshan Hospital Fudan University Shanghai China
- 4Department of Physiology and Pathophysiology, School of Basic Medical Sciences Fudan University Shanghai China
- 5Department of Anatomy, Histoembryology, School of Basic Medical Sciences Fudan University Shanghai China
- 6Global Institute of Future Technology Shanghai Jiao Tong University Shanghai China
- 7Department of Pulmonary, Critical Care and Sleep Medicine Icahn School of Medicine at Mount Sinai New York New York USA
- 8Tisch Cancer Institute Center for Thoracic Oncology Mount Sinai Health System New York New York USA
- 9Department of Thoracic Surgery Zhongshan Hospital Fudan University Shanghai China
Abstract
Background Metabolic rewiring influences macrophage functions in tumours. However, metabolic heterogeneity of macrophages in early‐stage lung adenocarcinoma (LUAD) has not been fully understood. Methods Based on single‐cell transcriptomic analysis on lung tissues from human subsolid pulmonary nodules and from KrasG12Dand KrasG12DTgfbr2−/− mice, we unveiled alterations of macrophage states in LUAD. We applied cell migration and invasion assays to examine effects of ATP binding cassette subfamily A member 1 (ABCA1) in macrophages on tumour progression. In addition, using coculture system, we explored its role in macrophage polarisation. Results Major macrophage subsets underwent shifts during tumourigenesis, as alveolar macrophages reduced sharply and their interstitial counterparts increased. Of note, tumour‐associated macrophages (TAMs) are metabolically rewired, with a subset enhancing lipid efflux predominated in both human and murine tumour. It was characterised by high expression of the lipid transporter, ABCA1. Targeting ABCA1 by its inhibitor probucol suppressed TAM capacity to induce tumour cell migration and invasion. In addition, inhibiting ABCA1 was associated with dampened immunosuppression of TAMs by shifting them to a M1‐like phenotype. Conclusions We uncovered TAM heterogeneity in early‐stage LUAD and proposed ABCA1 as a potential target for metabolic rewiring, which manipulated macrophage polarisation states and its effects on tumour aggressiveness.
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BibTeX
@article{zheng2026macrophage,
title = {{Macrophage lipid efflux regulates the tumour microenvironment in early‐stage lung adenocarcinoma}},
author = {Yujie Zheng and Yuan Wang and Yalin Wang and Yue Shi and Hui Kong and Shaohua Lu and Yong Zhang and Jie Hu and Jian Zhou and Xiangdong Wang and Meng Xiang and Qiong Liu and Hongyi Xin and Charles A. Powell and Fred R. Hirsch and Chunxue Bai and Yuanlin Song and Jun Yin and Dawei Yang},
journal = {Clinical and Translational Discovery},
year = {2026},
month = oct,
doi = {10.1002/ctd2.70199},
url = {https://doi.org/10.1002/ctd2.70199},
note = {CC BY},
}
RIS
TY - JOUR
TI - Macrophage lipid efflux regulates the tumour microenvironment in early‐stage lung adenocarcinoma
AU - Yujie Zheng
AU - Yuan Wang
AU - Yalin Wang
AU - Yue Shi
AU - Hui Kong
AU - Shaohua Lu
AU - Yong Zhang
AU - Jie Hu
AU - Jian Zhou
AU - Xiangdong Wang
AU - Meng Xiang
AU - Qiong Liu
AU - Hongyi Xin
AU - Charles A. Powell
AU - Fred R. Hirsch
AU - Chunxue Bai
AU - Yuanlin Song
AU - Jun Yin
AU - Dawei Yang
PY - 2026
DA - 2026/10/26
JO - Clinical and Translational Discovery
DO - 10.1002/ctd2.70199
UR - https://doi.org/10.1002/ctd2.70199
AB - Background Metabolic rewiring influences macrophage functions in tumours. However, metabolic heterogeneity of macrophages in early‐stage lung adenocarcinoma (LUAD) has not been fully understood. Methods Based on single‐cell transcriptomic analysis on lung tissues from human subsolid pulmonary nodules and from KrasG12Dand KrasG12DTgfbr2−/− mice, we unveiled alterations of macrophage states in LUAD. We applied cell migration and invasion assays to examine effects of ATP binding cassette subfamily A member 1 (ABCA1) in macrophages on tumour progression. In addition, using coculture system, we explored its role in macrophage polarisation. Results Major macrophage subsets underwent shifts during tumourigenesis, as alveolar macrophages reduced sharply and their interstitial counterparts increased. Of note, tumour‐associated macrophages (TAMs) are metabolically rewired, with a subset enhancing lipid efflux predominated in both human and murine tumour. It was characterised by high expression of the lipid transporter, ABCA1. Targeting ABCA1 by its inhibitor probucol suppressed TAM capacity to induce tumour cell migration and invasion. In addition, inhibiting ABCA1 was associated with dampened immunosuppression of TAMs by shifting them to a M1‐like phenotype. Conclusions We uncovered TAM heterogeneity in early‐stage LUAD and proposed ABCA1 as a potential target for metabolic rewiring, which manipulated macrophage polarisation states and its effects on tumour aggressiveness.
SN - 2768-0622
ER -