Flavonoids in cancer pharmacology: molecular mechanisms, tumor microenvironment regulation, and drug resistance

Flavonoids are structurally diverse polyphenolic compounds that influence multiple processes involved in cancer development and treatment response. This review summarizes the reported effects of structurally defined flavonoids on tumor cell proliferation, regulated cell death, oncogenic and epigenetic signaling, metabolic adaptation, the tumor microenvironment, angiogenesis, and therapy resistance. PubMed, Web of Science, and Scopus were searched for literature published primarily from 2016 to July 2026 using terms related to flavonoids, representative flavonoid compounds, cancer-associated mechanisms, drug resistance, combination therapy, drug delivery, pharmacokinetics, bioavailability, and safety. Earlier landmark and mechanistic studies were included when necessary to provide historical context or support established pathways. Experimental evidence indicates that flavonoids can modulate cell cycle progression, apoptosis and other regulated cell death pathways, inflammatory and immune signaling, tumor metabolism, drug efflux transporters, epithelial to mesenchymal transition, and epigenetic programs associated with resistance. Their effects are nevertheless dependent on compound structure, dose, tumor model, cellular redox state, and treatment context. Combination and nanodelivery strategies may improve experimental activity or exposure, but their interpretation requires consideration of quantitative drug interactions, active metabolites, pharmacokinetic changes, and safety. Most available evidence remains preclinical, and clinical translation is constrained by limited bioavailability, extensive metabolism, heterogeneous tumor responses, and possible interactions with anticancer drugs. Further development should therefore emphasize chemically defined compounds, clinically achievable exposure, functional validation of proposed mechanisms, standardized formulations, and integrated pharmacokinetic and safety assessment.