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This connection reduces the oxidative threshold in MDR cancer cells. Natural or nature-inspired compounds can target this vulnerability and induce collateral sensitivity (CS) by simultaneously modulating the redox balance and ABC transporters\u2019 activity in MDR cancer cells. Moreover, natural-origin compounds can act on multiple targets by combining efflux inhibition, redox modulation, and immune evasion into a unique therapeutic strategy. However, many challenges should be addressed in their characterisation and preclinical validation to ensure their usefulness for clinical application. These include poor bioavailability, pharmacokinetic interactions, safe toxicity windows, and tumour heterogeneity. In perspective, adaptive trial designs employing biomarker-guided patient stratification can translate natural-origin compounds from preclinical promise to precision partners in clinical oncology.<\/jats:p>","DOI":"10.3390\/medicina62071344","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T07:28:27Z","timestamp":1783927707000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural-Origin Compounds as Future Precision Partners in Combination Cancer Therapy"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9045-8239","authenticated-orcid":false,"given":"Milica","family":"Pe\u0161i\u0107","sequence":"first","affiliation":[{"name":"Department of Neurobiology, Institute for Biological Research \u201cSini\u0161a Stankovi\u0107\u201d\u2014National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11108 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7992-8343","authenticated-orcid":false,"given":"Patricia","family":"Rijo","sequence":"additional","affiliation":[{"name":"CBIOS\u2014Research Center for Biosciences & Health Technologies, Universidade Lus\u00f3fona, 1749-024 Lisbon, Portugal"},{"name":"Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1100-5689","authenticated-orcid":false,"given":"Natasa Z.","family":"Djordjevic","sequence":"additional","affiliation":[{"name":"Department of Natural and Mathematical Sciences, State University of Novi Pazar, Vuka Karadzica 9, 36300 Novi Pazar, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41392-026-02583-x","article-title":"Reactive oxygen species (ROS) in cancer: From mechanism to therapeutic implications","volume":"11","author":"Akter","year":"2026","journal-title":"Signal Transduct. 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