Myeloid PTEN loss affects the therapeutic response by promoting stress granule assembly and impairing phagocytosis by macrophages in breast cancer

Yan Li; Chao Xu; Xiaojun Qian; Gang Wang; Chaoqiang Han; Hui Hua; Menghao Dong; Jian Chen; Haiyang Yu; Rutong Zhang; Xiaoxi Feng; Zhenye Yang; Yueyin Pan

doi:10.1038/s41420-024-02094-0

Myeloid PTEN loss affects the therapeutic response by promoting stress granule assembly and impairing phagocytosis by macrophages in breast cancer

Cell Death Discov. 2024 Jul 30;10(1):344. doi: 10.1038/s41420-024-02094-0.

Authors

Yan Li^#^{1

2}, Chao Xu^#², Xiaojun Qian^{1

2}, Gang Wang², Chaoqiang Han², Hui Hua², Menghao Dong², Jian Chen^{1

2}, Haiyang Yu², Rutong Zhang², Xiaoxi Feng², Zhenye Yang³, Yueyin Pan^{4

5}

Affiliations

¹ Department of Clinical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
² Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
³ Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. zhenye@ustc.edu.cn.
⁴ Department of Clinical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. panyueyin@ustc.edu.cn.
⁵ Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. panyueyin@ustc.edu.cn.

^# Contributed equally.

Abstract

Breast cancer (BRCA) has become the most common type of cancer in women. Improving the therapeutic response remains a challenge. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a classic tumour suppressor with emerging new functions discovered in recent years, and myeloid PTEN loss has been reported to impair antitumour immunity. In this study, we revealed a novel mechanism by which myeloid PTEN potentially affects antitumour immunity in BRCA. We detected accelerated stress granule (SG) assembly under oxidative stress in PTEN-deficient bone marrow-derived macrophages (BMDMs) through the EGR1-promoted upregulation of TIAL1 transcription. PI3K/AKT/mTOR (PAM) pathway activation also promoted SG formation. ATP consumption during SG assembly in BMDMs impaired the phagocytic ability of 4T1 cells, potentially contributing to the disruption of antitumour immunity. In a BRCA neoadjuvant cohort, we observed a poorer response in myeloid PTEN^low patients with G3BP1 aggregating as SGs in CD68+ cells, a finding that was consistent with the observation in our study that PTEN-deficient macrophages tended to more readily assemble SGs with impaired phagocytosis. Our results revealed the unconventional impact of SGs on BMDMs and might provide new perspectives on drug resistance and therapeutic strategies for the treatment of BRCA patients.

Abstract

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