Extracellular Vesicle- and Mitochondria-Based Targeting of Non-Small Cell Lung Cancer Response to Radiation: Challenges and Perspectives.

Simple Summary: Radiation therapy stands out as a primary approach for managing individuals with non-small cell lung cancer (NSCLC). Nevertheless, the predominant impediment to achieving successful therapeutic outcomes lies in the resistance exhibited by tumor cells to radiation exposure. Mitochondrial structure abnormality and defects were found to be in high correlation with malignancy and radioresistance. The cytotoxic impact of radiation on cancer cells is most probably dependent on mitochondria; therefore, the exchange of mitochondrial organelles, DNA, or proteins could potentially serve as an effective strategy for modulating their sensitivity to radiation therapy. In this review, we aimed to uncover novel mechanisms for studying NSCLC's response to radiation. During the cell life cycle, extracellular vesicles (EVs) transport different cargos, including organelles, proteins, RNAs, DNAs, metabolites, etc., that influence cell proliferation and apoptosis in recipient cells. EVs from metastatic cancer cells remodel the extracellular matrix and cells of the tumor microenvironment (TME), promoting tumor invasion and metastatic niche preparation. Although the process is not fully understood, evidence suggests that EVs facilitate genetic material transfer between cells. In the context of NSCLC, EVs can mediate intercellular mitochondrial (Mt) transfer, delivering mitochondria organelle (MtO), mitochondrial DNA (mtDNA), and/or mtRNA/proteinaceous cargo signatures (MtS) through different mechanisms. On the other hand, certain populations of cancer cells can hijack the MtO from TME cells mainly by using tunneling nanotubes (TNTs). This transfer aids in restoring mitochondrial function, benefiting benign cells with impaired metabolism and enabling restoration of their metabolic activity. However, the impact of transferring mitochondria versus transplanting intact mitochondrial organelles in cancer remains uncertain and the subject of debate. Some studies suggest that EV-mediated mitochondria delivery to cancer cells can impact how cancer responds to radiation. It might make the cancer more resistant or more sensitive to radiation. In our review, we aimed to point out the current controversy surrounding experimental data and to highlight new paradigm-shifting modalities in radiation therapy that could potentially overcome cancer resistance mechanisms in NSCLC. [ABSTRACT FROM AUTHOR]