Endophytic actinomycetes as a reservoir of novel chemotherapeutic leads against multidrug-resistant cancer

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–mediated drug efflux, enhanced DNA damage responses, survival-signaling rewiring, tumor-microenvironmental protection and cancer stem cell–driven 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–mesenchymal transition and stemness traits. Finally, translational challenges, such as suboptimal pharmacokinetics, off-target toxicity, herb–drug 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’s 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.