Protein Post-Translational Modifications in the Regulation of Ferroptosis: New Opportunities and Challenges for Cancer Immunotherapy

Ferroptosis is an emerging form of programmed cell death driven by the excessive accumulation of iron-dependent lipid peroxides, which plays a pivotal regulatory role in suppressing tumor initiation and progression. In recent years, protein post-translational modification (PTM), as a core molecular mechanism regulating protein function, stability, and subcellular localization, occupies a central position in the precise targeted regulation of ferroptosis. This review systematically summarizes and elucidates the core molecular regulatory mechanisms of ferroptosis, focusing on the dynamic regulatory pathways and effects of common protein PTM (including ubiquitination, phosphorylation, acetylation and lactylation) on key ferroptosis regulators. Meanwhile, it deeply analyzes the complex interactive regulatory network between ferroptosis and tumor immunity, and elaborates on the specific pathways by which ferroptosis remodels the tumor immune microenvironment through inducing immunogenic cell death (ICD) and releasing damage-associated molecular patterns (DAMPs). More importantly, this paper systematically discusses the potential application value of ferroptosis-related protein PTM in overcoming tumor immune escape, enhancing the antitumor activity of T cells and natural killer cells, and improving the clinical efficacy of immune checkpoint inhibitors (ICIs). Finally, it summarizes the core challenges existing in this research field and prospects the future development of novel PTM-based combination antitumor strategies targeting ferroptosis and personalized antitumor therapy. This review aims to provide new theoretical references and experimental evidence for the clinical prevention, treatment and intervention of malignant tumors.