Immune modulation in cancer is a critical strategy aimed at enhancing the immune system to combat tumors and reduce metastasis. One promising approach is immune checkpoint blockade, particularly focusing on the activation of CD8+ T cells. Our research investigates the molecular mechanisms of the metastatic-associated gene, a disintegrin and metalloprotease domain 9 (ADAM9), in regulating the immune response within the tumor microenvironment and its role in cancer progression. ADAM9 overexpression is linked to poor outcomes in cancer patients, specifically in lung and breast cancers.

Through RNA-sequencing analysis comparing control and ADAM9 knockout (KO) lung tumors, we identified genes influenced by ADAM9 that contribute to immune suppression. ADAM9 appears to impact immune cells by modulating cytokine production, interferon response, and lymphocyte activation, thereby influencing the tumor microenvironment and facilitating tumor growth and metastasis. Additionally, we generated recombinant ADAM9 to assess its therapeutic potential.

Our findings showed that knocking out ADAM9 in lung cancer cells alters cytokine profiles, reduces neutrophil infiltration, increases CD8+ T cell presence, and enhances the interferon-gamma (IFN-γ) pathway activity. These changes may explain the smaller tumor sizes and decreased metastasis observed in syngeneic mouse tumor models. Remarkably, the recombinant protein ADAM9 with adjuvants completely inhibited tumor growth in our models, highlighting ADAM9's significance in tumor progression and its potential as a candidate for cancer vaccine development.

In summary, our research underscores the critical role of ADAM9 in shaping the immune landscape of tumors. Targeting ADAM9 may provide new therapeutic approaches, enhancing the effectiveness of existing cancer treatments.