Ferroptosis Inducers Upregulate PD-L1 in Recurrent Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) has a high recurrence rate, with neoadjuvant chemotherapy and anti-PD-L1 immunotherapy showing therapeutic benefits.
• Understanding the interplay between ferroptosis and immune modulation is crucial for improving TNBC treatment strategies.

Purpose of the Study:

• To investigate the effect of ferroptosis inducers on immune-related gene expression in TNBC.
• To develop and validate a ferroptosis-driver score for predicting prognosis and recurrence risk in breast cancer.

Main Methods:

• Integrative omics analyses of TNBC cells treated with ferroptosis inducers (Erastin, RSL3) and single-cell/mass spectrometry data.
• Clinical association analyses using TCGA and METABRIC breast tumor cohorts.
• Protein-level validation of key gene expression in breast cancer stem cells and tumors.

Main Results:

• Ferroptosis inducers upregulated CD274 (PD-L1) in TNBC cells, correlating with overall survival.
• High CD274 expression in tumors was linked to upregulated ferroptosis drivers (IDO1, IFNG, TNFAIP3) and poorer prognosis.
• A CD274 ferroptosis-driver score stratified patients by recurrence risk and was associated with overall survival, independent of clinical factors.

Conclusions:

• Ferroptosis inducers enhance PD-L1 expression in TNBC, suggesting a synergistic potential with anti-PD-L1 immunotherapy for high-risk patients.
• The CD274 ferroptosis-driver score serves as a prognostic biomarker for breast cancer recurrence.
• Targeting ferroptosis alongside immunotherapy may offer a novel strategy for recurrent TNBC.