Targeting GEM Reprograms Macrophages and Overcomes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to immune checkpoint blockade, highlighting the need to define tumor-intrinsic mechanisms driving resistance to PD-L1 inhibition. Here, we identified GTP-binding protein overexpressed in skeletal muscle (GEM) as a tumor cell-intrinsic regulator associated with poor response to anti-PD-L1 therapy in ESCC. GEM expression in tumor cells drove tumor-associated macrophage (TAM)-mediated immunosuppression, leading to reduced CD8⁺ T cell infiltration and impaired cytotoxic function. Mechanistically, GEM induced SERPINE1 expression that was secreted and acted on macrophage LRP1 to drive alternative activation and suppress antitumor immunity. GEM enhanced SERPINE1 expression through a MKK3-RACK1-p38-MEF2A cascade. GEM signaling was reinforced by a metabolically coupled feedback mechanism. Macrophages exposed to GEM-high tumor cells promoted tumor cell glycolysis and lactate production, which drove AARS1-dependent lactylation of GEM and strengthened its interaction with RACK1 to amplify downstream signaling. Disruption of the SERPINE1-LRP1 axis restored CD8⁺ T cell activity and enhanced response to PD-L1 blockade in vivo. Pharmacological perturbation of GEM-dependent signaling remodeled the tumor immune microenvironment and improved responses to PD-L1 blockade. Together, these findings define a GEM-SERPINE1-LRP1 signaling axis that drives macrophage-mediated immune suppression and suggest that targeting this pathway may enhance the efficacy of PD-L1 blockade in ESCC.