| Summary: | Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in the field of tumor hypoxia in non-small cell lung cancer (NSCLC), including biology, biomarkers, in vitro and in vivo studies and also hypoxia imaging and detection. While classic two-dimensional (2D<i>)</i> in vitro research models reveal some hypoxia dependent manifestations, three-dimensional (3D) cell culture models more accurately replicate the hypoxic TME. In this study, a systematic review of the current NSCLC 3D models that have been able to mimic the hypoxic TME is presented. The multicellular tumor spheroid, organoids, scaffolds, microfluidic devices and 3D bioprinting currently being utilized in NSCLC hypoxia studies are reviewed. Additionally, the utilization of 3D in vitro models for exploring biological and therapeutic parameters in the future is described.
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