Combating Chemoresistance in Breast Cancer: Exploring Tumor Microenvironment, Combination Therapies, and Drug Repurposing Strategies

Chemoresistance in Breast Cancer is a challenge that remains paramount in its treatment. Chemoresistance mechanisms in this heterogeneous disease are complicated and have never been fully elucidated. Since the current therapies are insufficient to address chemoresistance, more potent strategies are urgently required to enhance current treatment plans. Chemoresistance in cancer can arise from a variety of molecular mechanisms, including active drug expulsion (drug efflux), decreased drug uptake, enhanced DNA repair mechanisms, the ability of cancer cells to evade programmed cell death (apoptosis), the diversity in the population of cancer cells within a tumor (tumor heterogeneity), and significant alterations in the tumor microenvironment (TME), where interactions between cancer cells, cancer-associated fibroblasts, immune cells, and the extracellular matrix contribute to a supportive environment that allows tumors to survive treatment and escape therapy. The available therapeutic strategies include combinations with new drugs, immunotherapies, epigenetic modulators, and drug delivery systems based on nanoparticles-a few of the many promising strategies garnering attention toward overcoming chemoresistance. Drug repurposing provides a practical and economical means to combat resistance through FDA-approved anticancer agents. Second, the incorporation of immune checkpoint inhibitors (ICIs), PARP inhibitors, and metabolic modulators enhances the efficacy of treatments even further. Here in this article, we have reviewed the latest developments in the management of chemoresistance with a focus on innovative therapeutic approaches, innovative therapies targeting the tumor microenvironment, strategic drug repurposing, and meticulously designed clinical trials in the treatment of Breast Cancer.