A β‑Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer

Triple-negative breast cancer is a highly aggressive
and heterogeneous
breast cancer subtype characterized by early metastasis, poor prognosis,
and high recurrence. Targeting histone citrullination-mediated chromatin
dysregulation to induce epigenetic alterations shows great promise
in TNBC therapy. We report the synthesis, optimization, and evaluation
of a novel series of β-carboline-derived peptidyl arginine deiminase
4 inhibitors that exhibited potent inhibition of TNBC cell proliferation.
The most outstanding PAD4 inhibitor, compound 28, hindered
the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid
tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model.
Furthermore, 28 improved the tumor immune microenvironment
by reshaping neutrophil phenotype, upregulating the proportions of
dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived
suppressor cells. In conclusion, our work offered 28 as
an efficacious PAD4 inhibitor that exerts a combination of conventional
chemotherapy and immune-boosting effects, which represents a potential
therapy strategy for TNBC.