Src-dependent modulation of IFNγ-induced PD-L1 expression in human breast cancer cell lines.

Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is associated with poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic option for TNBC, but their efficacy remains limited due to resistance. In this study, we investigated whether the non-receptor tyrosine kinase Src (Src tyrosine kinase) regulates interferon-gamma (IFNγ)-induced expression of programmed death-ligand 1 (PD-L1). IFNγ stimulation of TNBC and luminal A breast cancer cell lines induced time-dependent phosphorylation of Src at its activation site (Y419). Pharmacological inhibition of Src significantly suppressed IFNγ-induced PD-L1 mRNA and protein expression, as well as activation of PD-L1-related transcription factors, suggesting transcriptional regulation. In co-culture assays with CD8+ T-cells, TNBC cells were more susceptible to T-cell-mediated cytotoxicity compared with luminal A cells, and Src inhibition further enhanced this cytotoxicity. These findings indicate that Src plays a crucial role in IFNγ-mediated PD-L1 expression and immune evasion in TNBC cell lines. Src inhibition may represent a promising combinatorial strategy to enhance antitumor immunity in TNBC cell lines.