Lysine specific demethylase 5B promises to be a new focus of cancer drug-resistance: combination therapy

Drug resistance remains a major obstacle to the long-term efficacy of cancer therapy. Lysine specific demethylase 5B (KDM5B), an epigenetic regulator of H3K4 methylation, has emerged as an important modulator of therapeutic resistance across multiple tumor contexts. In this review, we systematically summarize the mechanisms through which KDM5B contributes to drug resistance, including DNA damage repair, replication stress adaptation, cellular-state plasticity, pro-survival signaling, metabolic reprogramming, and immune regulation. Importantly, the available evidence indicates that KDM5B functions through both catalytic-dependent and catalytic-independent mechanisms, and that the relative contribution of these functions varies according to tumor type, treatment pressure, and cellular context. We further highlight two emerging immunoregulatory mechanisms involving KDM5B-mediated suppression of the cGAS-STING pathway and demethylase-independent cooperation with SETDB1, while distinguishing mechanistic rationale from experimentally validated combination strategies. Building on these findings, we discuss mechanism-guided combination approaches, including catalytic inhibition, protein degradation, disruption of protein-protein interactions, and combinations with DNA-damaging agents, targeted therapies, and immunotherapies. We also summarize candidate biomarkers for patient stratification and discuss major translational challenges, including target selectivity, tumor heterogeneity, pharmacological limitations, and acquired resistance. Collectively, this review provides a context- and mechanism-guided framework for understanding KDM5B-mediated drug resistance and for developing biomarker-informed combination strategies. Clinical trial number: not applicable.