Hypomethylating agents as emerging therapeutics for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is recognized as the most aggressive subtype of breast cancer. Epigenetic silencing, such as DNA methylation mediated by DNA methyltransferases (DNMTs) plays key roles in TNBC tumorigenesis. Hypomethylating agents (HMAs) such as azacitidine, decitabine, and guadecitabine are key inhibitors of DNMTs, and accumulating evidence has shown their immunogenicity properties. In this review, the efficacy and anti-tumor immune responses triggered by HMAs in TNBC are presented and discussed. Essentially, overexpression of DNMTs is associated with poor prognosis and reduced TNBC survival rates, and these effects are negated by HMAs. In particular, HMAs could reverse epigenetic silencing of tumor suppressor genes and enhance immune recognition of TNBC cells. Clinical trials of HMAs in TNBCs are limited but early-stage trials indicate that HMAs are safe and tolerable. More clinical studies are required to establish the effectiveness of HMAs against the disease, as supported by preclinical data substantiating their effectiveness especially guadecitabine. Future research should focus on optimizing dosing and exploring combinations with immunotherapies to maximize the potential of HMAs in TNBC treatment.