GAB3 suppresses lung adenocarcinoma progression by inhibiting the MAPK signaling and potentiating CD8 T cell immunity.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality. Although targeted therapies and immunotherapies have improved outcomes, many patients exhibit limited responses due to primary or acquired resistance, underscoring the need to identify novel molecular targets. The Gab family of scaffolding adapters, including GAB1 and GAB2, are recognized oncogenic regulators, whereas the role of GAB3, implicated in immune cell activation, is poorly defined in solid tumors. Here, we identify GAB3 as a novel tumor suppressor in LUAD. Pan-cancer analysis revealed frequent GAB3 downregulation, with high expression correlating with favorable prognosis in LUAD. Functionally, GAB3 overexpression suppressed LUAD cell proliferation, migration, invasion, and tumor growth in vitro and in vivo. Mechanistically, GAB3 interacted with LYN kinase to inhibit the MAPK signaling pathway and reverse epithelial-mesenchymal transition (EMT). In addition, GAB3 remodeled the tumor immune microenvironment, enhanced CXCL10 secretion, increased CD8 T cell infiltration and effector function, and potently sensitized tumors to anti-PD-1 therapy. Our findings support a dual tumor-suppressive mechanism for GAB3 and propose it as a promising prognostic biomarker and therapeutic target in LUAD.