Glutamine sequestration promotes tumor growth and immune evasion through elevation of arginine methylation in hepatocellular carcinoma

Abstract Mechanisms underlying the immunosuppressive microenvironment in hepatocellular carcinoma (HCC) extend beyond immune checkpoints to include metabolic competition. Here, we identify a metabolic evasion pathway driven by SLC1A5 overexpression, which enables HCC cells to sequester glutamine from the tumor microenvironment (TME). This influx sustains the intracellular methionine availability, driving pro-tumorigenic arginine hypermethylation, while simultaneously depleting extracellular glutamine required for cytotoxic CD8+ T cell effector function. This creates a dual mechanism of progression: intrinsic epigenetic activation and extrinsic immune starvation. We propose a synergistic strategy co-targeting glutamine transport (V9302) and arginine methylation (AdOx). In vivo, this regimen induced tumor cytotoxicity and restored T cell function, eliciting a robust anti-tumor response. These findings identify a glutamine–arginine methylation axis as a critical link between metabolic reprogramming and immune evasion in HCC, offering a rationale for metabolic-epigenetic co-targeting therapies.