Programmed cell death and metastatic evolution in breast cancer: the role of anoikis, necroptosis, and ferroptosis.

Metastatic breast cancer (MBC) remains the leading cause of breast cancer-related mortality, driven by the ability of disseminated tumor cells to survive a series of intrinsically lethal stresses encountered during systemic progression, including loss of extracellular matrix attachment, oxidative damage, and immune-mediated cytotoxicity. While resistance to apoptosis has long been considered central to tumorigenesis, it is now evident that metastatic competence depends on coordinated modulation of multiple regulated cell death (RCD) pathways, notably anoikis, necroptosis, and ferroptosis. In this review, we synthesize current mechanistic and translational evidence describing how breast cancer cells reprogram these pathways across the metastatic cascade. We first delineate the molecular basis of anoikis and the adaptive mechanisms that enable anchorage-independent survival. We then examine how circulating tumor cells withstand oxidative and inflammatory stress through redox adaptation and modulation of necroptotic signaling. Within distant organ niches, microenvironmental factors-including metabolic constraints, inflammatory cues, and iron availability-govern susceptibility to ferroptosis and necroptosis, thereby influencing dormancy and metastatic outgrowth. We further introduce the concept of cell death plasticity, defined as the dynamic and context-dependent capacity of tumor cells to modulate, switch between, or simultaneously regulate multiple RCD pathways in response to microenvironmental and therapeutic pressures. This adaptive property underlies both metastatic persistence and therapy resistance, while simultaneously generating context-specific vulnerabilities. Finally, we critically evaluate emerging therapeutic strategies and biomarker frameworks aimed at exploiting these vulnerabilities. Despite strong preclinical rationale, clinical translation remains limited, underscoring the need for biomarker-driven and combinatorial approaches. Collectively, understanding the dynamic interplay among RCD pathways provides a conceptual and translational foundation for targeting metastatic and treatment-resistant breast cancer.