Mitochondrial Redox Vulnerabilities in Triple-Negative Breast Cancer: Integrative Perspectives and Emerging Therapeutic Strategies

Abstract

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC, an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities.