ADAM9 Regulation of CXCL12 ‐Dependent Myeloid‐Derived Suppressor Cells Shifting the Immune Landscape of Lung Adenocarcinoma

ABSTRACT Lung cancer‐mediated myeloid‐derived suppressor cell (MDSC) inhibits antitumour immunity for tumour progression and is a promising target. Here, we present the ADAM9‐targeting therapeutic strategy to unleash anticancer immunity. We identified a novel role for ADAM9 in promoting lung cancer immunosuppression through the upregulation of cytokines that drive the recruitment and expansion of MDSCs, with CXCL12 serving as one of the major mediators. This ADAM9–CXCL12–MDSC axis significantly impairs the function of cytotoxic CD8+ T cells. Disrupting the ADAM9–CXCL12 axis suppresses oncogenic signalling pathways, including EGFR and IL‐6 signalling. Therapeutically, the developed ADAM9 inhibitors significantly reduced primary tumour growth and metastasis in syngeneic mouse models of lung tumours, concurrent with remodelling of the immune microenvironment. This study demonstrates that ADAM9 promotes cancer‐mediated MDSC function by enhancing CXCL12 production. Targeting ADAM9 represents a novel and effective strategy to reverse the immunosuppressive tumour microenvironment and suppress lung cancer progression.