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The development of MTX resistance contributes to the reduced efficacy and development of adverse reactions, forcing clinicians to withdraw treatment early. This drawback requires combinational approaches to combat the resistance and enhance the efficacy and safety of MTX. To provide a brief overview of MTX resistance and strategies to mitigate its aftereffects in cancer therapy, a literature\u2010based search was conducted using keywords such as cancer pathology, MTX mechanism and resistance, S100A4, folate uptake, folate efflux, P\u2010glycoprotein, beta\u2010catenin and anticancer properties of Vitamins A, D, E and K. Investigations encompassing in vitro studies, in vivo studies and clinical trials were reviewed to identify the mechanisms of resistance induced by MTX and the potential benefits of coadministering fat\u2010soluble vitamins with existing anticancer drugs. Derivates of Vitamin A could target cancer stem cells and increase chemotherapy sensitivity in non\u2013small cell lung cancer. Similarly, calcitriol and cytotoxic medications exhibit additive or synergistic effects. Existing research revealed that fat\u2010soluble vitamins can inhibit drug transporters, such as P\u2010glycoprotein, which inhibit drug efflux, improving chemotherapy efficacy in cancer. As personalised medicine continues to evolve, incorporating combination approaches with MTX and fat\u2010soluble vitamins holds promise for enhancing treatment efficacy, which can counteract MTX resistance via multiple pathways and improve the safety profile.<\/jats:p>","DOI":"10.1155\/sci5\/8259470","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T02:05:17Z","timestamp":1744855517000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Combating Methotrexate Resistance in Cancer Treatment: A Review on Navigating Pathways and Enhancing Its Efficacy With Fat\u2010Soluble Vitamins"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3687-5193","authenticated-orcid":false,"given":"Muhsina","family":"Kakkadath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Naidu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2655-846X","authenticated-orcid":false,"given":"S. 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