Discussion and Conclusion:
Cancer cells employ a wide range of factors and mechanisms to resist chemotherapy. Among these factors, the triad of CSCs, exosomes, and ncRNAs are particularly prominent. CSCs not only utilize diverse intracellular and extracellular mechanisms to develop chemoresistance but also have a significant role in chemoresistance through their interactions with various components of TME and other cancer cells. Furthermore, It has also been established that CSCs play a crucial role in recurrence after successful chemotherapy. As previously mentioned, exosomes present in the microenvironment have a prominent role in cellular communications and interactions between different components of TME and cancer cells. Additionally, ncRNAs have an important role in intracellular signaling pathways and intercellular communications between CSCs and other factors. Therefore, it can be deduced that ncRNAs are likely to have a significant impact on the function of mentioned factors involved in chemotherapy resistance caused by CSCs. Moreover, CSCs can utilize their high capacity of survival and chemoresistance to stay alive after chemotherapy, as well as employ the combination of exosomes and ncRNAs to spread chemoresistance among other cancerous cells by establishing wide intercellular communications with tumor cells and the tumor microenvironment components, ultimately leading to the exacerbation of chemotherapy resistance and cancer relapse. Indeed, ncRNA can be considered the most prominent factor among other factors in the chemoresistance of CSCs. Therefore, an in-depth understanding of the interactions between CSCs, exosomes, and ncRNAs is very important and vital in achieving the desired chemotherapy results, and research in these three fields is very necessary to understand their precise function in chemotherapy resistance.
In addition, it is recommended that the use of smart nanoparticles as a drug delivery method for small molecules could be an effective approach for delivering a greater and more fruitful amount of small molecules to cancer cells, considering the distinct conditions within the tumor microenvironment (hypoxia, acidity, etc.). One of the challenges in drug delivery is the limited understanding of drug targets. Large-scale screening studies using CRISPR-Cas technology can help to improve our understanding of high-priority drug targets.
On the whole, the application of the following strategies can improve the design and therapeutic outcomes of small molecule drugs as combination therapy for chemotherapy:
1. Focusing more research on interactions between CSCs, exosomes, and ncRNAs as well as their function in chemotherapy resistance for a better and deeper understanding of these areas.
2. Identifying the factors that maintain proper function and favorable interactions between CSCs, exosomes, and ncRNAs to be considered as targets for small molecule drugs so that targeting them causes effective disruption in the function and interactions of these three components.
3. Launching extensive screening studies using CRISPR-Cas technology to identify potential drug targets for the design of effective small molecule drugs.
4. More research on drug delivery systems based on smart nanoparticles to improve and increase their efficiency in the appropriate and sufficient delivery of small molecule drugs to the tumor microenvironment and cancer cells.