Prolyl isomerase 1 inhibitor can enhance the efficacy of programmed cell death ligand 1 blockade in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options beyond chemotherapy. Since programmed cell death ligand 1 inhibitors (PD-L1i), a type of immune checkpoint inhibitor, show limited efficacy in TNBC, effective combination strategies are needed. This study evaluated the therapeutic effects of API-1, a prolyl isomerase 1 inhibitor (Pin1i), and the PD-L1i atezolizumab, with or without eribulin, in TNBC models. In vitro assays were conducted using 4T1 and MDA-MB-231 cell lines. In vivo, an orthotopic 4T1 tumor model was established in BALB/c mice. The combination of API-1 and atezolizumab significantly suppressed tumor growth compared with either monotherapy. Notably, the addition of eribulin further enhanced tumor suppression. This triple therapy led to increased CD8⁺ T-cell infiltration and reduced FOXP3⁺ regulatory T cells, and was accompanied by increased IFN-γ expression and increased tumor microvessel density, as assessed by CD31 immunostaining. No significant systemic toxicity or organ damage was observed. Overall, combining Pin1 inhibition and eribulin with PD-L1 blockade was associated with favorable alterations in the tumor immune microenvironment and enhanced antitumor efficacy. These findings support the potential of this combination strategy as a promising therapeutic approach for TNBC. Further preclinical and clinical studies are warranted to validate its efficacy and safety.