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.

Hypoxia is a key microenvironmental factor shaping tumor cell survival and plasticity, but its cellular consequences depend on the cancer subtype. Here, we compare breast cancer cell lines with varying metastatic potential (MP) in response to CoCl₂-induced hypoxia (100 μM, 20 h), analyzing the results immediately (T0) and after 24 h (T1). Plasma membrane damage was measured by the number of propidium iodide-positive cells. Hypoxia pathway activation was evaluated using HIF-1α immunofluorescence, while phenotypic changes were assessed through quantitative morphometric analysis. Chemically induced hypoxia promoted a delayed increase in membrane failure in low-MP cells, consistent with reduced tolerance to hypoxia-mimetic stress. In contrast, high-MP cultures showed a lower PI-positive fraction at T1, consistent with enhanced survival under these conditions. This divergence was accompanied by higher basal and hypoxia-induced HIF-1α levels in high-MP cells. High-MP cells uniquely demonstrated delayed shape changes after exposure to hypoxia-mimetic conditions, evolving into a more compact and rounded form, suggesting phenotypic plasticity instead of structural deterioration. Together, our findings provide insight into how oxygen deprivation impacts cell destiny and phenotypic plasticity in breast cancer models with varying metastatic risks.