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Glutamine Synthetase Loss in β-Catenin-Mutant Hepatocellular Carcinoma Rewires Glutamine Metabolism to Promote Immunosuppressive Macrophage Adaptation [dataset3.scRNAseq]

ABSTRACT: Recent therapeutic strategies using immune checkpoint inhibitors (ICIs) to treat hepatocellular carcinoma (HCC) have shown modest success. Response to ICIs is heterogeneous, and while mutational burden may predict stable responses, some HCCs with poor prognostic markers (e.g., CTNNB1 mutations) may still respond under favorable tumor immune microenvironment (TIME) conditions. We show that β-catenin-mutated HCCs lacking glutamine synthetase (GS) exhibit aggressive disease due to altered glutamate/glutamine (Glu/Gln) availability, driving macrophage adaptation that promotes immunosuppression. Loss of HCC Glul (encoding GS) forces hepatic macrophages to redistribute effort from immunologic to metabolic functions. Notably, depleting macrophages in GS-deficient, β-catenin-mutant HCC models improves survival. Additionally, HCC GS loss results in macrophage GS overexpression that maintains mTOR signaling in tumors, which is targetable. These findings reveal a metabolic dynamic between HCCs and the TIME which suggests that metabolic profiling, including GS expression, may refine patient selection for ICI therapies and improve outcomes under current standards of care.

ORGANISM(S): Mus musculus

PROVIDER: GSE298614 | GEO | 2025/12/10

REPOSITORIES: GEO

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Glutamine Synthetase Loss in β-Catenin-Mutant Hepatocellular Carcinoma Rewires Glutamine Metabolism to Promote Immunosuppressive Macrophage Adaptation [dataset1.Spatial.Transcriptomics]

Project description:Recent therapeutic strategies using immune checkpoint inhibitors (ICIs) to treat hepatocellular carcinoma (HCC) have shown modest success. Response to ICIs is heterogeneous, and while mutational burden may predict stable responses, some HCCs with poor prognostic markers (e.g., CTNNB1 mutations) may still respond under favorable tumor immune microenvironment (TIME) conditions. We show that β-catenin-mutated HCCs lacking glutamine synthetase (GS) exhibit aggressive disease due to altered glutamate/glutamine (Glu/Gln) availability, driving macrophage adaptation that promotes immunosuppression. Loss of HCC Glul (encoding GS) forces hepatic macrophages to redistribute effort from immunologic to metabolic functions. Notably, depleting macrophages in GS-deficient, β-catenin-mutant HCC models improves survival. Additionally, HCC GS loss results in macrophage GS overexpression that maintains mTOR signaling in tumors, which is targetable. These findings reveal a metabolic dynamic between HCCs and the TIME which suggests that metabolic profiling, including GS expression, may refine patient selection for ICI therapies and improve outcomes under current standards of care.

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