Therapy resistance is one of the main obstacles in the treatment of complex diseases such as cancer. As our understanding of the mechanisms involved deepens, exosomes have taken on an increasingly prominent role as key mediators in intercellular communication and in the dissemination of resistant traits within heterogeneous cell populations.
Far from being mere waste vesicles, exosomes act as platforms for the highly regulated transfer of biological information. Their content—which includes miRNAs, proteins and other bioactive components—can significantly alter the behaviour of recipient cells, contributing to adaptation to different types of therapies.
In this context, their role is not limited to passive signalling, but they actively participate in phenotypic reprogramming and the evolution of resistant states.
One of the most significant mechanisms through which exosomes influence therapeutic resistance is the transfer of miRNAs. These small non-coding RNAs have the ability to modulate entire gene expression networks, simultaneously affecting multiple cellular pathways involved in survival, proliferation and stress response.
When cells previously exposed to treatments acquire resistance, they release exosomes enriched in specific miRNAs, and these exosomes, once internalised by sensitive cells, induce functional changes that favour survival in the face of therapy. This process may involve the silencing of pro-apoptotic genes, the attenuation of tumour suppressors, or the activation of signalling pathways associated with growth and resistance, such as PI3K/AKT or NF-κB.
Furthermore, some exosomal miRNAs are involved in the regulation of drug transporters, such as those belonging to the ABC family, increasing the capacity to expel therapeutic agents. In this way, recipient cells not only become more tolerant to treatment but may also acquire a more resilient overall phenotype.
Another relevant aspect is the involvement of these miRNAs in processes such as epithelial-mesenchymal transition (EMT), a cellular programme associated with both increased invasive capacity and therapeutic resistance. The induction of EMT via exosomal signals contributes to increased cellular plasticity and functional heterogeneity within the tumour.
Alongside miRNAs, exosomes carry a functional protein payload that can act directly on recipient cells. Unlike nucleic acids, these proteins do not require transcription or translation processes to perform their function, allowing for a more immediate response.
Among the exosomal proteins implicated in resistance are those related to cell signalling, DNA repair and the regulation of apoptosis. The transfer of anti-apoptotic proteins, molecular chaperones or metabolic enzymes may help stabilise cells subjected to therapeutic stress, promoting their survival.
Furthermore, exosomes can modify the tumour microenvironment by ‘educating’ non-tumour cells, such as fibroblasts or immune system cells. This process creates a more favourable environment for the persistence of resistant cells, partly through the creation of protective niches and the modulation of immune responses.
Taken together, the transfer of proteins not only complements the action of miRNAs but can also synergistically reinforce the acquisition of resistant phenotypes in recipient cells.
The contribution of exosomes to therapeutic resistance is best understood in the context of cellular plasticity. Rather than being viewed as a strictly clonal phenomenon based on genetic mutations, resistance can also emerge through dynamic mechanisms of intercellular communication.
Exosomes enable the transmission of signals that reconfigure the cellular state without the need for permanent alterations to the genome. This type of exchange favours the emergence of cell populations with transient or stable adaptive characteristics, capable of surviving in the presence of therapeutic agents.
In this way, exosomes act as vectors of information that facilitate the collective adaptation of the tumour population, contributing to a more complex and difficult-to-reverse resistance, involving genetic, epigenetic and microenvironmental factors.
Interest in exosomes in the context of therapeutic resistance is not merely conceptual. Their analysis offers significant opportunities in both diagnostic and therapeutic settings. The characterisation of exosomal profiles, including the presence of miRNAs and specific proteins associated with resistance, can provide valuable information for monitoring treatment response and anticipating therapeutic failure.
Furthermore, exosomes themselves represent potential targets for intervening in resistance mechanisms. Strategies aimed at modulating their biogenesis, release or uptake could interfere with communication between resistant and sensitive cells, limiting the spread of adaptive phenotypes.
In parallel, their natural capacity as biological vehicles positions them as promising tools for the development of delivery systems for therapeutic molecules, including miRNAs or targeted drugs, capitalising on their stability, biocompatibility and relative specificity.
Taken together, exosomes represent a fundamental axis in the biology of resistance to therapies, acting as active mediators of intercellular communication capable of transferring miRNAs and functional proteins that reprogramme the behaviour of recipient cells. This mechanism not only promotes survival under therapeutic pressure but also contributes to the emergence and consolidation of resistant phenotypes within heterogeneous cell populations.
A thorough understanding of these processes opens the door to new diagnostic strategies based on exosomal biomarkers and therapeutic approaches aimed at interfering with intercellular communication, which could prove key to improving treatment efficacy and delaying or preventing the emergence of resistance.