The nutrigenomic-epigenetic axis in cancer: from dietary bioactives to precision oncology.

Abstract

Cancer development and progression are increasingly understood to arise from dynamic interactions between genetic alterations and environmentally driven epigenetic regulation, with dietary exposures representing one of the most biologically influential and modifiable factors. Given the expanding evidence linking nutrition to epigenomic remodeling, a comprehensive synthesis of how specific dietary components influence cancer-relevant epigenetic mechanisms is needed to clarify their preventive and therapeutic relevance. This review brings together mechanistic, epidemiologic, and translational findings to delineate the effects of bioactive dietary constituents, including polyphenols, isoflavones, carotenoids, folate, zinc, vitamin D, sulfur-containing phytochemicals, and microbiome-derived short-chain fatty acids, on DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA regulation. Across these domains, consistent patterns emerge: compounds such as epigallocatechin-3-gallate, resveratrol, quercetin, genistein, and sulforaphane have been shown in preclinical studies to inhibit DNA methyltransferases, modulate histone acetylation and methylation, reprogram microRNA networks, and promote tumor-suppressive transcriptional states; dietary patterns rich in cruciferous vegetables, green tea, grapes, whole grains, marine-derived polyunsaturated fatty acids, and fermentable fibers correlate with reduced cancer incidence; and pro-inflammatory diets high in red meat, processed foods, and added sugars are associated with oxidative stress, inflammation-associated DNA damage, and epigenetic dysregulation. Emerging evidence also highlights the roles of gut microbial metabolites such as butyrate, caloric restriction, and ketogenic regimens in shaping tumor immunometabolism through epigenetically active intermediates, while germline polymorphisms and tumor-intrinsic epigenetic heterogeneity contribute to inter-individual variability in dietary responsiveness. These insights position nutrition as a mechanistically coherent regulator of the cancer epigenome with implications for prevention, prognosis, and integrative oncology, underscoring the need for biomarker-guided dietary interventions and rigorously designed clinical studies to determine the therapeutic potential of personalized nutritional epigenetics.