The 3.0 Cell Communication: New Insights in the Usefulness of Tunneling Nanotubes for Glioblastoma Treatment

Simple Summary Communication between cells helps tumors acquire resistance to chemotherapy and makes the struggle against cancer more challenging. Tunneling nanotubes (TNTs) are long channels able to connect both nearby and distant cells, contributing to a more malignant phenotype. This finding might be useful in designing novel strategies of drug delivery exploiting these systems of connection. This would be particularly important to reach tumor niches, where glioblastoma stem cells proliferate and provoke immune escape, thereby increasing metastatic potential and tumor recurrence a few months after surgical resection of the primary mass. Along with the direct inhibition of TNT formation, TNT analysis, and targeting strategies might be useful in providing innovative tools for the treatment of this tumor. Abstract Glioblastoma (GBM) is a particularly challenging brain tumor characterized by a heterogeneous, complex, and multicellular microenvironment, which represents a strategic network for treatment escape. Furthermore, the presence of GBM stem cells (GSCs) seems to contribute to GBM recurrence after surgery, and chemo- and/or radiotherapy. In this context, intercellular communication modalities play key roles in driving GBM therapy resistance. The presence of tunneling nanotubes (TNTs), long membranous open-ended channels connecting distant cells, has been observed in several types of cancer, where they emerge to steer a more malignant phenotype. Here, we discuss the current knowledge about the formation of TNTs between different cellular types in the GBM microenvironment and their potential role in tumor progression and recurrence. Particularly, we highlight two prospective strategies targeting TNTs as possible therapeutics: (i) the inhibition of TNT formation and (ii) a boost in drug delivery between cells through these channels. The latter may require future studies to design drug delivery systems that are exchangeable through TNTs, thus allowing for access to distant tumor niches that are involved in tumor immune escape, maintenance of GSC plasticity, and increases in metastatic potential.