Glutathione peroxidase 4 (GPX4) is canonically viewed as the primary suppressor of ferroptosis, yet its role in the tumor microenvironment (TME) extends far beyond antioxidant catalysis to encompass immuno-metabolic regulation. In this review, we synthesize recent advances in enzymology, immunology, and cancer metabolism to propose a “lipid peroxidation threshold” framework, wherein GPX4 sets cell-type-specific thresholds that determine susceptibility to ferroptosis across tumor cells, CD8⁺ T cells, dendritic cells (DCs), and myeloid populations. We discuss how these thresholds are dynamically adjusted by post-translational modifications, nutrient competition and intercellular feedback loops, resulting in significant spatial heterogeneity between the tumor core and the tumor invasive front. There is a current selectivity paradox in GPX4 inhibitors, as well as resistance through nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1) that restricts the efficacy of GPX4 inhibitors as monotherapy. We focus on rational combination approaches: GPX4 modulation with immune checkpoint blockade (ICB), chemotherapy, and targeting myeloid-derived suppressor cells (MDSCs); and the pressing need for predictive biomarkers and single-cell spatial profiling. We conclude that successful clinical translation requires moving beyond indiscriminate GPX4 inhibition toward precision “threshold engineering” that selectively lowers tumor lipid peroxidation thresholds while sparing immune cells.

The zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has emerged as a critical regulator of diverse cellular processes, including autophagy, cell cycle progression, and tumorigenesis. Structurally, ZKSCAN3 is characterized by its conserved DNA-binding zinc finger motifs, a SCAN domain mediating protein–protein interaction, and a KRAB repression domain implicated in transcriptional regulation. Post-translational modifications, such as phosphorylation and ubiquitination, dynamically modulate its subcellular localization and activity, enabling context-dependent functional plasticity. Functionally, ZKSCAN3 acts as a master switch in autophagy by repressing the transcription of autophagy-related genes under nutrient-replete conditions, while its nuclear-cytoplasmic shuttling under stress conditions links metabolic reprogramming to cellular survival. Emerging evidence also underscores its paradoxical roles in cancer: it suppresses tumor initiation by maintaining genomic stability yet promotes metastasis through epithelial–mesenchymal transition induction. Furthermore, epigenetic mechanisms, including promoter methylation and non-coding RNA regulation, fine-tune ZKSCAN3 expression, contributing to tissue-specific outcomes. Despite these insights, gaps remain in understanding the structural determinants governing its interaction with chromatin-remodeling complexes and the therapeutic potential of targeting ZKSCAN3 in diseases. Future investigations should prioritize integrating multi-omics approaches to unravel context-specific regulatory networks and explore small-molecule modulators for translational applications. This comprehensive analysis provides a framework for advancing our mechanistic understanding of ZKSCAN3 and its implications in human health and disease. This review synthesizes recent advances in elucidating the regulatory networks and functional complexity of ZKSCAN3, highlighting its dual roles in physiological and pathological contexts.