Through establishing a co‐culture system of THP‐1 macrophages and NSCLC cells, we observed a significant decrease in the expression of M2 macrophage markers; and an increase of M1 macrophage markers of TAMs after co‐cultured with supernatant of HHLA2‐deficient NSCLC cells. Here, HHLA2 is linked to non-small cell lung carcinoma.