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Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. The tumor immune microenvironment (TIME) significantly influences ferroptosis sensitivity in both cancer and immune cells. Recent years have witnessed major advances in understanding how multi-level regulatory mechanisms control ferroptosis in tumors, encompassing epigenetic modifications and post-translational protein regulation. Epigenetic mechanisms include DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, while post-translational modifications (PTMs) involve phosphorylation, glycosylation, ubiquitination, acetylation, methylation, and lactylation of key ferroptosis proteins. This review examines the intricate relationship between the TIME, ferroptosis, and these dual regulatory networks. We focus particularly on how epigenetic processes and PTMs synergistically control ferroptosis mediators in the TIME, exploring how ubiquitination controls protein stability, and how metabolic modifications like lactylation link cellular metabolism to ferroptosis regulation. These multilevel interactions create a complex regulatory landscape that influences cancer progression, immune evasion, and therapeutic resistance. The crosstalk between epigenetic and post-translational regulation determines ferroptosis susceptibility across different cellular contexts within tumors, with distinct modification patterns observed in cancer cells versus immune infiltrates. Additionally, we discuss emerging therapeutic strategies that simultaneously target both epigenetic and post-translational regulation of ferroptosis, including combination approaches that modulate specific modification enzymes to enhance ferroptosis induction. Understanding these complex multilevel regulatory relationships provides valuable insights for developing novel precision cancer treatment approaches that leverage the therapeutic potential of ferroptosis modulation with potentially significant clinical impact.
Du et al. (Mon,) studied this question.