KDM4A-Driven Epigenetic Reprogramming as a Central Nexus Linking Metabolic Adaptation, Immune Remodeling, and Therapy Resistance in Cancer.

Cancer progression and treatment failure are driven not only by genetic alterations but also by the remarkable capacity of tumor cells to adapt to metabolic stress, immune surveillance, and therapeutic pressure. Epigenetic plasticity provides a rapid and reversible mechanism that enables such adaptation. Lysine demethylase 4A (KDM4A), a JmjC-domain-containing histone demethylase targeting H3K9me3 and H3K36me3, has emerged as a central epigenetic regulator of cancer adaptability. Recent studies reveal that KDM4A functions beyond a conventional chromatin modifier and instead acts as an epigenetic hub integrating microenvironmental cues, metabolic signals, and stress responses. Through transcriptional and post-translational regulation, KDM4A coordinates chromatin remodeling programs that support metabolic adaptation, including amino acid utilization, mitochondrial quality control, lipid metabolism, and resistance to ferroptosis. In parallel, KDM4A reshapes tumor-immune interactions in a state-dependent manner. In proliferative and stress-tolerant tumor states, KDM4A-associated chromatin remodeling may support metabolic adaptation, replication-stress tolerance, and immune exclusion. By contrast, under conditions of impaired mitochondrial quality control and sustained metabolic stress, KDM4A can promote tumor-cell senescence and enhance responsiveness to immune checkpoint blockade. These divergent outcomes indicate that the consequences of KDM4A activity are determined by the interaction between substrate- and locus-specific chromatin remodeling and the cellular, metabolic, and therapeutic context in which it occurs. KDM4A-driven epigenetic reprogramming also underlies multiple mechanisms of therapy resistance, encompassing enhanced DNA damage repair capacity, metabolic buffering via mitophagy, and lineage plasticity-mediated therapy escape. These adaptive strategies allow cancer cells to survive therapeutic stress without reliance on additional genetic mutations, contributing to disease progression and poor clinical outcomes. In this review, we synthesize current mechanistic and translational evidence to present a unified framework in which KDM4A links metabolic adaptation, immune remodeling, and therapy resistance. We further discuss therapeutic opportunities, rational combination strategies, and the emerging biomarker potential of KDM4A-centered pathways, highlighting their relevance for precision oncology.