Marine Actinomycete-Derived Secondary Metabolites for Overcoming Chemoresistance in Cancer Treatment: Focus on Mechanisms and Biosynthetic Pathway

Chemoresistance remains a major limitation of cancer chemotherapy, leading to therapeutic failure, tumour relapse, and poor clinical outcomes. The development of agents capable of sensitising resistant cancer cells or modulating resistance-associated pathways is therefore of considerable pharmaceutical interest. In recent years, marine actinomycetes have emerged as a promising source of structurally diverse secondary metabolites with the potential to interfere with key mechanisms underlying chemoresistance, including drug efflux transporters, dysregulated apoptosis, altered epigenetic regulation, proteasome function, cancer stem cell maintenance, and tumour microenvironment-mediated protection. This review critically summarises current evidence on marine actinomycete-derived secondary metabolites that exhibit chemosensitising or resistance-modulating properties, with emphasis on experimentally validated mechanisms and emerging predictive studies. In addition, the biosynthetic pathways of secondary metabolites, including polyketide synthases, non-ribosomal peptide synthetases, and their hybrids, as well as other unusual enzymes in marine actinomycetes, have been discussed in relation with their cytotoxic potential. Furthermore, recent advances in developing the technologies to identify the available metabolites through genome mining, regulatory engineering, and fermentation optimisation, are highlighted. Key challenges, including intrinsic and translational limitations, are addressed and future perspectives focusing on adapting integrated pharmacological strategies are proposed. Overall, this review has been outlining the broad scope of developing next-generation anti-chemoresistance drugs from the potential substances derived from marine actinomycetes.