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

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. [Display omitted] •Integrated analysis systematically demonstrates the ferroptosis heterogeneity in TNBC•LAR subtype of TNBC is hypersensitive to ferroptosis inducers, especially GPX4 inhibitors•AR plays a dual role in regulating ferroptosis of LAR tumors•Combination of GPX4 inhibitors and immunotherapy is an option for LAR tumors Yang et al. systematically demonstrated the ferroptosis heterogeneity in triple-negative breast cancer (TNBC). They found that luminal androgen receptor (LAR) subtype of TNBC was hypersensitive to ferroptosis inducers and revealed that the combination of GPX4 inhibitors and immune checkpoint inhibitors was a novel treatment strategy for LAR TNBCs.