Epigenetic Biomarkers for Predicting Nucleoside Analog Drug Response and Resistance in Cancer

Nucleoside analogs (NAs) play a central role in cancer therapy, either through direct cytotoxicity or epigenome reprogramming. They are clinically effective but have shortcomings in their long-term effectiveness because of variable patient responses and the emergence of resistance. There is growing evidence that DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs (ncRNAs) are key factors that determine sensitivity and resistance to NAs. This review summarizes existing evidence on the epigenetic control of cytotoxic and epigenetic nucleoside analogs, discusses predictive biomarkers of human Equilibrative Nucleoside Transporter 1 (hENT1) and deoxycytidine kinase (dCK) promoter methylation, histone modifications, and ncRNA signatures, and assesses the emerging strategies of multi-omic integration. Improvements in detection methods, such as high-resolution sequencing, single-cell profiling, and liquid biopsy, are addressed, along with the issues of reproducibility, tumor heterogeneity, and clinical translation. Epigenetic biomarkers are promising for patient stratification in clinical trials, although a lack of uniformity in technical and methodological approaches currently constrains their full potential. The future focus will be on standardized panels of biomarkers, real-time monitoring, rational combination strategies, and biomarker-directed clinical trial designs. Overall, epigenetic biomarkers are capable of changing nucleoside analog therapy into a more precise, durable, and personalized treatment approach.