Natural Plant Bioactives as Regulators of Histone Modifications: Bridging Epigenetics and Anticancer Therapy.

Cancer remains a leading cause of global mortality, with tumor heterogeneity, recurrence, metastasis, and drug resistance posing significant challenges to conventional therapies, which are often limited by toxicity and efficacy. Epigenetic regulation, particularly histone modifications such as methylation, acetylation, phosphorylation, and lactylation, plays a pivotal role in orchestrating gene expression and tumor progression, representing promising yet complex therapeutic targets. Bioactive compounds derived from natural plants, characterized by multi-target activity and low toxicity, have emerged as potent modulators of histone modifications, capable of influencing tumor growth, metastasis, and the tumor microenvironment. Here, we provide a comprehensive review of recent advances elucidating how natural products influence cancer progression and reshape the tumor immune microenvironment by regulating histone modifications. We integrate current knowledge of key histone marks, modifying enzymes, and signaling pathways, proposing a unified framework linking natural compounds, epigenetic regulation, and tumorigenesis. By uncovering these molecular mechanisms, we highlight that plant bioactive compounds can reshape the tumor immune microenvironment through histone modifications to inspire the development of novel, safer, and more effective anticancer agents.