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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Esophageal squamous cell carcinoma (ESCC) shows variable responses to immune checkpoint blockade (ICB).
• Tumor-intrinsic factors contributing to resistance against PD-L1 inhibition require elucidation.
• Understanding resistance mechanisms is crucial for improving ICB efficacy in ESCC.

Purpose of the Study:

• To identify tumor cell-intrinsic regulators of resistance to anti-PD-L1 therapy in ESCC.
• To elucidate the molecular mechanisms by which these regulators mediate immunosuppression.
• To explore therapeutic strategies targeting identified resistance pathways.

Main Methods:

• GTP-binding protein overexpressed in skeletal muscle (GEM) expression analysis in ESCC.
• Investigated GEM's role in regulating tumor-associated macrophages (TAMs) and T cell infiltration.
• Elucidated the GEM-SERPINE1-LRP1 signaling axis and its downstream effectors.
• Assessed the impact of targeting this axis on anti-PD-L1 therapy response in vivo.

Main Results:

• GEM expression in ESCC cells correlates with poor response to anti-PD-L1 therapy.
• GEM induces SERPINE1, which activates macrophage LRP1, promoting immunosuppression and reducing CD8+ T cell activity.
• A feedback loop involving tumor cell glycolysis and GEM lactylation amplifies GEM signaling.
• Disrupting the SERPINE1-LRP1 axis restores CD8+ T cell function and enhances anti-PD-L1 efficacy.

Conclusions:

• A novel GEM-SERPINE1-LRP1 signaling axis drives macrophage-mediated immune suppression in ESCC.
• This pathway represents a potential therapeutic target to overcome resistance to PD-L1 blockade.
• Targeting GEM-dependent signaling can remodel the tumor immune microenvironment and improve ICB outcomes.