Background <p>Lung adenocarcinoma (LUAD) is a fatal malignancy all over the world. The KN motif and ankyrin repeat domain-containing protein 3 (KANK3) are critical for regulating LUAD cell proliferation and invasion. However, the molecular mechanism of KANK3 involved in LUAD is poorly defined.</p> Methods <p>KANK3 and GATA-binding protein 2 (GATA2) mRNA level and protein level were determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. The proportion of CD11b⁺CD86⁺ positive cells was detected using flow cytometry. Angiogenesis, cell proliferation, cell cycle progression, apoptosis, migration, and invasion were assessed using tube formation assay, 5-ethynyl-2’-deoxyuridine (EdU) assay, flow cytometry, and transwell assay. Binding between GATA2 and KANK3 promoter was predicted by JASPAR and validated using a dual-luciferase reporter assay. The biological role of GATA2 on LUAD tumor growth was examined by the xenograft tumor model in vivo<i>.</i></p> Results <p>GATA2 and KANK3 were lowly expressed in LUAD tissues and cells. Moreover, KANK3 expedited M1 macrophage polarization and cell apoptosis and suppressed angiogenesis, cell proliferation, migration, and invasion in vitro. At the molecular level, GATA2 was a transcription factor of KANK3 and promoted KANK3 transcription via binding to its promoter regions. GATA2 repressed LUAD tumor growth in vivo by regulating KANK3<i>.</i></p> Conclusion <p>GATA2-activated KANK3 could facilitate M1 macrophage polarization and block LUAD cell malignant behaviors, providing a possible therapeutic target for LUAD treatment.</p>