Programmed cell death in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a particularly aggressive and therapeutically challenging subtype of breast cancer, defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This absence of actionable molecular targets contributes to its resistance to conventional treatments. This review provides an overview of the mechanistic functions, interrelated processes, and therapeutic implications of several programmed cell death (PCD) pathways-including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis-in the context of TNBC pathogenesis and treatment. A conceptual framework is proposed for leveraging these interconnected cell death pathways as a basis for novel targeted interventions. Given the complex interplay among various PCD forms characterized by shared features such as inflammation, mitochondrial dysfunction, and overlapping molecular mediators, this integrated network offers promising opportunities for combinatorial therapeutic strategies. Modulation of one cell death pathway may influence others, potentially amplifying therapeutic efficacy. Furthermore, these PCD pathways are highly relevant to immunotherapy outcomes, offering a foundation for synergistic treatment modalities. This review provides an in-depth analysis of the crosstalk between immune-based therapies and PCD, along with a comprehensive discussion of derived therapeutic approaches. However, tumor diversity, resistance mechanisms, and discrepancies between preclinical models and human physiology pose major challenges in applying these findings clinically. The overarching goal is to present innovative insights and strategies to enhance the clinical management of TNBC and ultimately improve patient outcomes.