Targeting Chemo-resistance Mechanisms In Triple-negative Breast Cancer: A Review

Triple-Negative Breast Cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes, characterized by rapid progression, high recurrence, and poor survival outcomes primarily due to chemoresistance. Although targeted agents such as poly(ADP-ribose) polymerase (PARP) inhibitors and Antibody-Drug Conjugates (ADCs) have provided clinical benefit in selected patient populations, the emergence of resistance often diminishes their long-term efficacy. The development of chemoresistance in TNBC is multifactorial, involving restoration of homologous recombination repair, upregulation of drug efflux transporters, Epithelialto- Mesenchymal Transition (EMT), survival of cancer stem cell populations, and modulation by the tumor microenvironment. This review aims to synthesize current insights into the molecular and cellular determinants of both intrinsic and acquired drug resistance in TNBC. Furthermore, it discusses innovative therapeutic strategies aimed at overcoming these challenges, including combination regimens integrating checkpoint blockade with DNA damage response inhibitors such as ATR, WEE1, and CHK1 inhibitors, as well as the use of epigenetic modulators. Interventions targeting the tumor microenvironment and approaches directed at eradicating cancer stem cells are also examined. Particular emphasis is placed on the emerging role of natural products and compounds derived from traditional Chinese medicine, which exhibit promising preclinical activity in reversing resistance through modulation of efflux transporters, reactivation of apoptotic pathways, and inhibition of EMT. By integrating mechanistic understanding with novel therapeutic developments, this review provides a comprehensive outlook on strategies to enhance treatment durability and improve longterm clinical outcomes in TNBC.