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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.<\/jats:p>","DOI":"10.3390\/molecules31091394","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:04:42Z","timestamp":1776945882000},"page":"1394","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plant-Derived Modulators of Tumor Metabolism as Novel, Efficacious, and Low-Toxicity Therapeutic Agents for Cancer Treatment"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7072-7542","authenticated-orcid":false,"given":"Tania Mmapule","family":"Maphoso","sequence":"first","affiliation":[{"name":"Department of Surgery, Level 7, Bridge E, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6196-6739","authenticated-orcid":false,"given":"Dakalo Portia","family":"Ramali","sequence":"additional","affiliation":[{"name":"Department of Surgery, Level 7, Bridge E, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4071-3905","authenticated-orcid":false,"given":"Thanyani","family":"Mulaudzi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Level 7, Bridge E, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6512-304X","authenticated-orcid":false,"given":"Vinesh","family":"Maharaj","sequence":"additional","affiliation":[{"name":"Biodiscovery Centre, Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathryn Helena Stanford","family":"Driver","sequence":"additional","affiliation":[{"name":"Nuclear Medicine Research Infrastructure NPO, Level 4, Steve Biko Academic Hospital, Pretoria 0001, South Africa"},{"name":"Department of Nuclear Medicine, Level 5, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"},{"name":"South African Nuclear Energy Corporation, Elias Motsoaledi St., R104 Pelindaba, Brits Municipality, Pretoria 0240, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3060-5572","authenticated-orcid":false,"given":"Botle Precious","family":"Damane","sequence":"additional","affiliation":[{"name":"Department of Surgery, Level 7, Bridge E, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ingole, S., Vasdev, N., Tekade, M., Gupta, T., Pawar, B., Mhatre, M., Prasad, A.G., and Tekade, R.K. 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