期刊
CELL METABOLISM
卷 35, 期 1, 页码 84-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2022.09.021
关键词
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资金
- National Key Research and Development Project of China [2021YFF1201300, 2020YFA0112304]
- National Natural Science Foundation of China [81922048, 82072922, 82002792, 91959207, 92159301]
- Program of Shanghai Academic/Technology Research Leader [20XD1421100]
- Natural Science Foundation of Shanghai [22ZR1479200]
- Shanghai Key Laboratory of Breast Cancer [12DZ2260100]
- Clinical Research Plan of SHDC [SHDC2020CR4002, SHDC2020CR5005]
- SHDC Municipal Project for Developing Emerging, Frontier Technology in Shanghai Hospitals [SHDC12021103]
- Shanghai Sailing Program [20YF1408600]
By integrating multiomics data, this study revealed the ferroptosis landscape of TNBC and proposed an innovative immunotherapy combination strategy for refractory LAR tumors.
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 utili-zation 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 demon-strated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.
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