Delphinidin, a dietary anthocyanidin, modulates PD-L1 and STING/TBK1 signaling and reprograms the immune microenvironment in triple-negative breast cancer

Triple-negative breast cancer (TNBC) exhibits genomic instability and rapidly upregulates PD-L1. This study investigated whether delphinidin, the dietary anthocyanidin, could modulate both intrinsic PD-L1 signaling and STING/TBK1/IRF3 pathway in TNBC. MDA-MB-231 and 4 T1 cells were mainly treated with 90 μM and 85 μM delphinidin, respectively, followed by LC-MS/MS proteomics, Western blotting, RT-qPCR, siRNA knockdown, immunoprecipitation, ELISA, and immunofluorescence for in vitro mechanistic exploration. An in vivo study was performed in a 4 T1 syngeneic tumor model established in female BALB/c mice. Mice received delphinidin (50—100 mg/kg) oral gavage, and tumor tissues were analyzed by immunohistochemistry, RT-qPCR, ELISA, immunofluorescence, and flow cytometry. In vitro, delphinidin reduced p65 abundance, suppressing PD-L1 transcription and protein expression. It enhanced STING/TBK1/IRF3 signaling with increased IFN-β levels. In vivo, delphinidin inhibited tumor growth and promoted a more immune reactive microenvironment. The findings provide a mechanistic rationale for incorporating delphinidin or structurally related nutraceuticals into immunotherapeutic strategies.