{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:00:41Z","timestamp":1790834441415,"version":"4.1.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Artif. Intell."],"abstract":"<jats:p>Multidrug resistance (MDR) has emerged as a major barrier to effective cancer control, undermining the efficacy of chemotherapy, targeted agents and, increasingly, immunotherapies. This review synthesizes current knowledge on the molecular and cellular bases of MDR in cancer, including ABC transporter\u2013mediated drug efflux, enhanced DNA damage responses, survival-signaling rewiring, tumor-microenvironmental protection and cancer stem cell\u2013driven plasticity. Particular emphasis is placed on endophytic actinomycetes and their metabolites as an underexploited reservoir of MDR modulating chemotypes with potent cytotoxic, resistance-reversal and microenvironment-modulating activities. By integrating recent mechanistic and pharmacological data, the review first delineates the crisis of drug-resistant cancer, then catalogs actinomycete-derived metabolites with documented efficacy against resistant cell lines, including those that inhibit efflux pumps, restore pro-apoptotic signaling or interfere with angiogenesis, epithelial\u2013mesenchymal transition and stemness traits. Finally, translational challenges, such as suboptimal pharmacokinetics, off-target toxicity, herb\u2013drug interactions and the paucity of biomarker-driven clinical trials, are critically examined alongside emerging strategies involving semi-synthetic optimization, nanocarrier delivery and rational combination regimens. A forward-looking discovery pipeline is proposed that couple\u2019s genome mining of endophytic actinomycetes with systematic MDR-mechanism profiling and medicinal chemistry, aiming to prioritize the most promising metabolites for preclinical and clinical development as next-generation MDR-targeted therapeutics.<\/jats:p>","DOI":"10.3389\/frai.2026.1974583","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:40:55Z","timestamp":1790833255000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endophytic actinomycetes as a reservoir of novel chemotherapeutic leads against multidrug-resistant cancer"],"prefix":"10.3389","volume":"9","author":[{"given":"Dhanvee","family":"Ganatra","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Science, Marwadi University","place":["Rajkot, Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahendrapal Singh","family":"Rajput","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Science, Marwadi University","place":["Rajkot, Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaurav","family":"Sanghvi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Science, Marwadi University","place":["Rajkot, Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s12934-025-02759-0","article-title":"Screening of red sea- and Mediterranean sea-derived actinomycetes for antimicrobial and antitumor activities: LC-ESI-HRMS-based metabolomics study","volume":"24","author":"Abdel-Razik","year":"2025","journal-title":"Microb. 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