Metabolic reprogramming is a core hallmark of malignancy, enabling tumor cells to sustain rapid proliferation, evade immune elimination, and develop resistance to therapy. Although a wide range of plant-derived phytochemicals exhibit anticancer activity with comparatively low toxicity, their capacity to disrupt specific metabolic dependencies exploited by tumors has not been comprehensively synthesized. This review brings together current mechanistic evidence showing how major phytochemical classes, including polyphenols, terpenes and terpenoids, glucosinolates, and alkaloids, interfere with pathways central to tumor metabolic fitness, such as aerobic glycolysis, pentose phosphate pathway flux, mitochondrial substrate oxidation, glutamine dependence, and redox homeostasis. It further introduces a pathway-focused framework that links phytochemical mechanisms to quantifiable metabolic outcomes and highlights their potential to remodel the tumor microenvironment by altering nutrient competition, oxidative stress responses, and hypoxia-driven signaling. Key barriers such as poor systemic bioavailability, rapid metabolic degradation, and limited tissue penetration are assessed alongside emerging formulation and delivery strategies designed to enhance therapeutic exposure while preserving low-toxicity profiles. Mapping these mechanistic insights onto clinical development needs allows prioritization of specific phytochemical-metabolic pathway pairs with the strongest potential for translation. This positions plant-derived metabolic disruptors as promising candidates for next-generation, low-toxicity anticancer therapies that strategically exploit defined metabolic vulnerabilities.
Maphoso et al. (Thu,) studied this question.