From Ferroptotic Stress to Stemness: TNT-Mediated EMT Plasticity in Cancer Progression.

Tumor evolution is shaped by adaptive responses to metabolic and oxidative stress, rather than solely by genetic mutations. Ferroptosis is an iron-dependent mechanism of cell death driven by lipid peroxidation. This process acts both as a tumor suppressive barrier and as a selective pressure for tumor adaptation. Cancer cells that escape ferroptosis undergo metabolic and transcriptional reprogramming, resulting in enhanced antioxidant capacity and increased resistance to oxidative stress. These adaptative changes closely intersect with epithelial-mesenchymal transition (EMT), generating hybrid phenotypes enriched in cancer stem cell (CSC)-like properties. Concurrently, tunneling nanotubes (TNTs) emerge as stress-responsive intercellular communication networks that facilitate the transfer of mitochondria, metabolites and redox regulators, thereby enabling cooperative survival. Through this review, we outline an integrative framework connecting ferroptosis, EMT plasticity, TNT-mediated communication and CSC dynamics, offering insights into novel strategies to overcome therapeutic resistance, prevent metastatic dissemination and limit tumor relapse. It further highlights the current landscape of emerging biomarkers and therapeutic agents that may enable the translation of this integrated network as a target in cancer treatment.