Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is intricately linked with oxidative stress through shared regulatory nodes and reciprocal amplification loops. Although ferroptosis and oxidative stress have each been extensively investigated, their bidirectional crosstalk, together with its consequences for the tumor microenvironment, has yet to be systematically elucidated. On this basis, this review proposes and systematically dissects a “ferroptosis-oxidative stress-tumor microenvironment” triad, focusing on its bidirectional interaction network and therapeutic translational value. We analyze the driving mechanisms underlying the mutually amplifying loop between the two processes, including iron metabolism, lipid peroxidation cascades, antioxidant defense, and organelle function. Within the tumor microenvironment, this interplay drives context-dependent remodeling of immune cell function, cancer-associated fibroblast activity, angiogenesis, and tumor heterogeneity. Furthermore, this review evaluates emerging therapeutic strategies that target ferroptosis and oxidative stress within the TME, and outlines the obstacles hindering clinical translation and future directions. A deep understanding of the “ferroptosis-oxidative stress-tumor microenvironment” triad will advance our fundamental understanding of the execution and regulatory mechanisms of ferroptosis, and lay a theoretical foundation for the future development of precision therapeutic strategies centered on ferroptosis.

Glioblastoma (GBM) is the most lethal primary brain tumor, with minimal therapeutic progress over the past two decades. A defining feature of GBM is its intrinsic resistance to apoptosis, prompting interest in activating alternative cell death pathways such as ferroptosis, an iron-dependent process driven by lipid peroxidation. In GBM, ferroptosis represents a context-dependent vulnerability that arises directly from tumor specific lipid metabolic reprogramming. Here, we outline a unifying framework in which ferroptosis sensitivity is governed by three interdependent axes: availability of oxidizable lipids, redox buffering, and iron handling. Genetic alterations common in GBM, such as CDKN2A loss, EGFR amplification or mutation, and PTEN loss, reshape these axes to either suppress or promote ferroptotic cell death. This susceptibility is further modulated by cellular state and the tumor microenvironment. Effective therapeutic targeting will require biomarker-driven patient stratification, rational combination strategies, and the development of brain-penetrant agents with tumor-selective activity. Together, this framework positions ferroptosis not as a universally inducible death pathway in GBM, but as a context-dependent vulnerability that can be therapeutically exploited in tumors already poised near the ferroptosis threshold.