<p>Metastatic non-small cell lung cancer (mNSCLC) cells carry heterogeneity, not only among different subtypes but also within a single tumor. Most evidence suggests that mNSCLC exploits specific molecular drivers and mechanisms to maintain physiology, metabolism, and immune evasion during tumorigenesis. Genome-wide association studies also revealed particular mutations in the oncogenic drivers supporting tumor cell proliferation and survival, resulting in aggressive and drug-resistant phenotypes of mNSCLC. While significant progress has been made in understanding mNSCLC at the genetic and molecular levels, a considerable gap remains in understanding the dynamic interplay between intrinsic factors—particularly key tumor-associated cells—and tumor immune microenvironment (TIME) during metastasis. Hence, this review highlights histological and genetic characteristics, emphasizes the clinical relevance of metastasis, and the roles of tumor-associated cells in shaping the immunosuppressive tumor microenvironment (TME) in mNSCLC. Understanding these intricate features and mechanisms is crucial for identifying novel therapeutic targets and improving strategies to combat mNSCLC progression in diagnosed patients.</p> Graphical Abstract <p></p>