Molecular basis of cancer chemoresistance: biochemical insights

Chemoresistance remains a major barrier in cancer therapy, frequently resulting in treatment failure and reduced patient survival. This multifaceted phenomenon arises from the interplay of well-established mechanisms such as genetic mutations, non-genetic adaptations, and tumor microenvironment (TME) mediated influences as well as newly emerging findings from recent research (2020-present). Key biochemical contributors include diminished intracellular drug accumulation through altered uptake or efflux, dysregulation of drug metabolism and bioactivation involving multiple Phase I and Phase II enzymes, genomic instability affecting DNA repair pathways, disruption of cell cycle control, and evasion of apoptosis. In addition, recent evidence highlights the roles of epigenetic reprogramming, metabolic reconfiguration, and TME-derived signaling in amplifying chemoresistance. This review integrates both foundational concepts and recent advancements in understanding drug resistance, with particular emphasis on updated insights into drug-metabolizing enzymes and their impact on therapeutic failure. It also evaluates current and emerging strategies to overcome resistance including targeting metabolic enzymes, modulating the TME, and implementing polytherapy's that address multiple resistance pathways. By synthesizing established knowledge with recent discoveries, this review highlights promising directions for improving the efficacy of cancer treatments and enhancing patient outcomes.