Targeting Microbiome-Derived Exosomes to Overcome Cancer Therapy Resistance: Mechanisms, Implications, and Opportunities

Despite recent advances in both preclinical and cancer therapies, the growing problem of treatment resistance remains one of the most critical challenges in oncology. To overcome the drawbacks of current oncologic treatments, there is a pressing need for new approaches and potential therapeutic strategies. The interaction between the host microbiome and cancer has recently attracted significant research. Among the various routes of microbiome-cancer interaction, microbiome- derived exosomes also offer an intriguing avenue. Exosomes, which are small extracellular vesicles, originate from several distinct types of cells, including microbiome-associated cells. These vesicles participate in intra- and intercellular communication as well as alteration of the tumour microenvironment. Emphas In light of their possible functions as treatment response modifiers and mediators, this review seeks to explain an intricate link between cancer therapy resistance and exosomes produced from the microbiome. Preclinical studies reveal that microbiome-derived exosomes operate through horizontal transfer of resistance-conferring enzymes and TLR4/MYD88-dependent signalling, demonstrating 2-5 fold upregulation of resistance-associated miRNAs in drug-resistant models. Clinical evidence shows Akkermansia muciniphila improves anti-PD-1 immunotherapy outcomes. Fusobacterium nucleatum- derived vesicles promote oxaliplatin resistance through autophagy activation. We investigate how microbiota-derived exosomes might leverage resistance to conventional cancer treatments and their consequences for these treatments. However, limitations include inter-individual microbiome variability, challenging isolation protocols, and regulatory hurdles under FDA guidelines. We examine the possible applications of microbiome-derived exosomes as therapeutic and diagnostic tools, thereby reflecting the applicability of these findings in clinical practice. This offers an interesting path for new therapeutic approaches meant to solve treatment resistance and raise patient survival.