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

GEM (GTP-binding protein overexpressed in skeletal muscle) expression in ESCC tumor cells is linked to poor response to anti-PD-L1 therapy and drives macrophage-mediated immunosuppression.

• Why it matters: Immune checkpoint blockade shows heterogeneous benefit in ESCC, and tumor-intrinsic mechanisms behind resistance to PD-L1 inhibition remain unclear.
• What they did: The study mapped a GEM→SERPINE1→LRP1 pathway, showing GEM induces SERPINE1 via an MKK3-RACK1-p38-MEF2A cascade and that SERPINE1 acts on macrophage LRP1 to promote alternative activation.
• The result: Blocking the SERPINE1–LRP1 axis restored CD8+ T cell activity and improved PD-L1 blockade responses in vivo, supporting GEM-pathway targeting to remodel the tumor immune microenvironment.

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