The ferroptosis-tumor microenvironment nexus: bidirectional regulation in cancer pathogenesis and therapeutic opportunities

This review systematically dissects the mechanisms of the bidirectional ferroptosis-tumor microenvironment (TME) regulation. The TME modulates ferroptosis susceptibility in immune cells through metabolic reprogramming and transcriptional regulation, while immune cells induce tumor cells ferroptosis via cytokine signaling and redox disruption. Intercellular crosstalk among immune and stromal cells further shapes ferroptotic responses through multidimensional mechanisms, forming a complex regulatory network. Paradoxically, ferroptosis exerts dual effects on the TME: it enhances antitumor immunity via damage-associated molecular patterns (DAMPs)-mediated dendritic cells (DCs) activation and T cell priming, yet promotes immune evasion through immunosuppressive niche formation and checkpoint upregulation. Current therapeutic strategies focus on glutathione peroxidase 4 (GPX4) inhibitors, synergistic combinations with immune checkpoint inhibitor (ICI), and nanotechnology-enabled targeted delivery systems. Persistent challenges include tumor heterogeneity, off-target toxicity, and deficiency in pharmacokinetics. Future research should prioritize two strategies: ferroptosis biomarker-guided patient stratification and TME-responsive smart drug delivery systems, optimizing personalized therapies to improve survival outcomes. By elucidating the ferroptosis-TME nexus, this review provides novel insights for advancing precision oncology and immunotherapeutic paradigms.