Ferroptosis-centered strategies: redefining therapeutic resistance & adaptation in modern oncology

Ferroptosis is a new regulated cell death process, independent of apoptosis, necroptosis, and pyroptosis, which offers a promising therapeutic opportunity characterised by iron-dependent lipid peroxidation and mitochondrial membrane condensation. This has the advantage of being able to bypass the caspase-independent mechanism, thus avoiding apoptosis resistance in heterogeneous and drug-refractory tumours. Sensitivity to ferroptosis varies with factors of iron metabolism, redox balance, general environmental cues like hypoxia, acidification, nutrition, and involvement of fibroblast-associated alterations in the microenvironment and the immunosuppressive niche. Nanocarrier-based technology, which involves iron delivery systems, GPX4 inhibitors, ROS-amplifying polymers, and dual or multi-responsive platforms, results in some form of selective induction into ferroptosis and avoids off-target toxicity. Possible therapeutic combinations with chemotherapy, radiotherapy, photodynamic therapy, and immunotherapy could improve the antitumor efficiency. Yet, despite preclinical promise, there are indeed challenges such as the absence of an in vivo standardised biomarker, biosafety concerns, and regulatory bottlenecks. Future directions will potentially include smart self-amplifying nanocarriers, AI-guided theranostic systems, and predictive biomarkers to strategically position ferroptosis as an oncologic precision strategy overcoming resistance, heterogeneity, and immune modulation.