Immune modulation in cancer aimed at strengthening the immune system to treat cancers and reduce cancer metastasis, such as immune checkpoint blockade in CD8+ T cell activation. We intend to investigate the molecular mechanism of the metastatic-associated gene, a disintegrin and metalloprotease domain 9 (ADAM9) in regulating the immune response of tumor microenvironment for cancer progression. Overexpression of ADAM9 is associated with poor outcomes of cancer patients, e.g., lung and breast cancers. Recently, we find that ADAM9 knockout in lung cancer cells can reprogram cytokine profiles, reduce neutrophils infiltration, increase CD8+ T cells infiltration as well as IFN-g pathway in the tumor environment, that may provide clues to explain the small tumor size and low metastases in syngeneic mouse tumor models. By comprehensive analysis of ADAM9-mediated genes involved in immune suppression via RNA-sequencing analysis of control and ADAM9 KO lung tumors, we found that ADAM9 in cancer cells might influence immune cells by regulating cytokine production, response of interferon, and lymphocyte activation, thereby probably manipulate cells in the microenvironment for contributing to tumor development, progression, and metastasis. We further generated recombinant ADAM9 to ealuate the potential therapeutic properties. We found that recombinant ADAM9 could completely inhibit tumor growth. These results indicated that ADAM9 is important in tumor progressing and could be a good candidate for cancer vaccine.