Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy

Fan Yang; Yi Xiao; Jia-Han Ding; Xi Jin; Ding Ma; Da-Qiang Li; Jin-Xiu Shi; Wei Huang; Yi-Ping Wang; Yi-Zhou Jiang; Zhi-Ming Shao

doi:10.1016/j.cmet.2022.09.021

Ferroptosis heterogeneity in triple-negative breast cancer reveals an innovative immunotherapy combination strategy

Cell Metab. 2023 Jan 3;35(1):84-100.e8. doi: 10.1016/j.cmet.2022.09.021. Epub 2022 Oct 17.

Authors

Fan Yang¹, Yi Xiao², Jia-Han Ding¹, Xi Jin¹, Ding Ma¹, Da-Qiang Li³, Jin-Xiu Shi⁴, Wei Huang⁴, Yi-Ping Wang⁵, Yi-Zhou Jiang⁶, Zhi-Ming Shao⁷

Affiliations

¹ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
² Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: yixiao11@fudan.edu.cn.
³ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁴ Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai (CHGC) and Shanghai Institute for Biomedical and Pharmaceutical Technologies (SIBPT), Shanghai 201203, China.
⁵ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Medical Epigenetics, International Co-Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; Shanghai Key Laboratory of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁶ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: yizhoujiang@fudan.edu.cn.
⁷ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: zhimingshao@fudan.edu.cn.

PMID: 36257316
DOI: 10.1016/j.cmet.2022.09.021

Abstract

Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n = 465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.

Keywords: fatty acid metabolism; ferroptosis; heterogeneity; immunotherapy; treatment; triple-negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ferroptosis* / physiology
Humans
Immunotherapy / methods
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / metabolism
Triple Negative Breast Neoplasms* / pathology