Histone lysine demethylase (KDM) 5A can specifically remove the dimethyl and trimethyl groups on histone H3 lysine 4 (H3K4me2/3). This activity enables KDM5A to modulate chromatin structure and gene transcription, thereby influencing fundamental cellular processes such as proliferation, differentiation, and apoptosis. Notably, KDM5A is frequently dysregulated across a wide spectrum of malignancies. This review aims to provide a comprehensive and updated synthesis of the multifaceted roles of KDM5A in tumor biology, encompassing its molecular mechanisms in cancer progression, its contribution to therapy resistance, its complex interplay with tumor immunotherapy, and the current landscape of targeted pharmacological inhibition. The core content of this review systematically dissects the oncogenic functions of KDM5A. Structurally, KDM5A possesses multiple functional domains that facilitate chromatin recruitment and enzymatic activity. Biologically, it exerts context-dependent dual roles in regulating cell cycle and differentiation, often promoting tumorigenesis by silencing tumor suppressors. The molecular mechanisms driving cancer progression are elaborated across several key pathways. KDM5A promotes tumor proliferation and migration by modulating the PI3K/AKT signaling axis through targeting regulators like ROCK1/PTEN and FXYD3. It facilitates epithelial-mesenchymal transition (EMT), a critical step in metastasis, by repressing epithelial markers and activating mesenchymal markers. Furthermore, KDM5A enhances tumor cell survival by downregulating pro-apoptotic genes and cell cycle inhibitors. Its role extends to suppressing anti-tumor immunity by downregulating antigen-presentation genes. A particularly significant section addresses KDM5A′s central role in fostering drug tolerance and resistance to chemotherapeutic agents and targeted therapies, often through epigenetic silencing of key sensitivity genes. Paradoxically, emerging evidence also implicates KDM5A in potentiating response to immune checkpoint blockade (ICB) therapy. By repressing PTEN, KDM5A can activate the PI3K-AKT-S6K1 pathway, leading to upregulated PD-L1 expression and enhanced recruitment of CD8+ T cells, suggesting a complex, context-dependent interaction with the tumor immune microenvironment. Given its prominent oncogenic functions, KDM5A has emerged as a compelling therapeutic target. We review the development and preclinical application of various KDM5A inhibitors. These compounds have shown efficacy in inhibiting tumor growth, overcoming drug resistance, and synergizing with existing therapies in model systems. In conclusion, KDM5A is a master epigenetic regulator deeply involved in tumor initiation, progression, metastasis, and therapy resistance. Its dual roles in immune modulation present both challenges and opportunities. Future research should develop highly selective inhibitors of KDM5A, understand the determinants of its oncogenic or tumor-suppressive effects in specific environments, utilize advanced spatial omics techniques to clarify its exact role in the tumor microenvironment, and verify its clinical effectiveness as a biomarker and therapeutic target in human clinical trials or translating KDM5A biology into effective personalized cancer therapies.
Liu et al. (Mon,) studied this question.