EVs deliver functional molecules through cell-to-cell interaction, and alter physiological and pathological functions of recipient cells(Valadi et al., 2007). To cite, EVs have been the crucial mediators of cancer progression by regulating/altering the biochemistry of tumor microenvironment (TME)(Li et al., 2007; Milane et al., 2015), and contributing to oncogenesis, metastasis, and resistance to therapy(Kogure et al., 2020; Kosaka et al., 2016). Lung cancer mortality is expected to be the highest among cancer mortality rates with 2.08-fold-increase (WHO 2016-2060 projection data)(Thandra et al., 2021). Non-small cell lung cancer (NSCLC) is a most common epithelial lung cancer, accounting for around 85% of all lung cancer types(Padinharayil et al., 2022b; “Pathology Outlines - WHO classification (n.d.)). According to the American Cancer Society's (ACS) Surveillance, Epidemiology, and End Result Program (SEER) database, distant stage lung cancer has a larger percentage of diagnosis (56%) and the lowest relative five-year survival (6.3%) than local and regional stages(“Cancer Statistics (n.d.)). These seminal statistics emphasizes the importance diagnostic technologies for the early detection and novel management strategies(Mattiuzzi and Lippi, 2019). Interestingly, NSCLC specific exosome-derived-molecules such as, oncogenic mRNAs, lipids, DNA fragments, and lncRNA are emerging as clinical biomarkers(Xu et al., 2018). Exosomes as a speculum of parental cells, and their potential to carry neo-antigens such as tumor specific nucleotides, proteins and lipids make them an essential clinical target for use as disease biomarkers(Jalalian et al., 2019; Yokoi et al., 2015). Nonetheless, high-throughput technologies for obtaining high-quality exosomes using nanotechnology have emerged(Tang et al., 2020). Exosomes have the potential to use as an effective therapeutic agent, as they can carry and deliver biochemical molecules with potential therapeutic significance(Johnsen et al., 2014; Wu et al., 2019). The heterogeneity of EVs and presence of non-vesicular components complicate the understanding of their functions and molecular composition(Jeppesen et al., 2019). Interestingly, origin- or condition specific EVs are now used to study pathways involved in cancer progression(Ruivo et al., 2017). The metastatic ability of hypoxia-exposed cell-derived EVs(Shao et al. (n.d.)), and the malignant phenotype of highly metastatic cells-derived EVs(Kosaka et al., 2016; Yokoi et al., 2017) are an example.

This review focuses on advances in fundamental understanding of EVs from the aspect of EV heterogeneity and highlights the role of exosomes in NSCLC in the various steps from oncogenesis to the processes behind resistance. We summarize recent advancements and the current knowledge of exosome-based NSCLC progression and their potential in cancer therapy.