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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Homeobox D9 (HOXD9), a member of the HOX family of transcription factors, plays a driver role in development of multiple cancers. Angiopoietin-2 (ANGPT2) is reportedly to facilitate angiogenesis, growth and metastasis in various cancers, including lung cancer. In addition, blocking ANGPT2 can effectively improve cancer immunotherapy via downregulation of Programmed death ligand-1 (PD-L1). The purpose of this study was to elucidate the role of HOXD9 in NSCLC and whether ANGPT2 is required for HOXD9-mediated malignant behaviors of NSCLC cells. By performing a series of in vitro functional experiments, we found that knockdown of HOXD9 induced proliferative inhibition, cell cycle G1 arrest, apoptosis, migratory suppression and invasive repression of NSCLC cells. Reduced PD-L1 expression in NSCLC cells was observed after HOXD9 silencing. Besides, HOXD9 deletion decreased the expression of ANGPT2 in NSCLC cells. In line with this, HOXD9 overexpression led to opposite alteration in NSCLC cells. Mechanistically, ANGPT2 was transcriptionally activated by HOXD9. Forced expression of ANGPT2 significantly regulated HOXD9-mediated malignant phenotypes, and enhanced PD-L1 expression of NSCLC cells. Our results expressing HOXD9 may function as an oncogene in NSCLC via trans-activation of ANGPT2. [ABSTRACT FROM AUTHOR]