Hypoalbuminemia induces immunosuppression through disorder in macrophages and drives resistance to immune checkpoint inhibitors.

Hypoalbuminemia is a common clinical biomarker associated with poor outcomes in cancer patients. While it correlates with resistance to immune checkpoint inhibitors (ICIs), the direct functional role and underlying mechanisms in driving immunotherapy resistance remain unclear. In our study, we demonstrated that hypoalbuminemia directly drives ICIs resistance by orchestrating an immunosuppressive tumor microenvironment (TME) through impaired macrophage arginine metabolism. In a C57/BL model, low-protein diet-induced hypoalbuminemia mice bearing LLC tumors showed poor response to immunotherapy. Comprehensive immune profiling revealed a suppressed TME, characterized by reduced CD8+ T cell infiltration and increased macrophage abundance. Depletion of tumor-associated macrophages (TAMs) alleviated this immunosuppression. Transcriptomic analysis of TAMs from low-protein diet-induced hypoalbuminemia mice revealed a significant downregulation of the arginine biosynthesis pathway, which was consistent with observed reductions in systemic arginine levels. Crucially, dietary arginine supplementation successfully reversed the immunosuppressive phenotype and restored ICIs efficacy. However, this restorative effect of arginine is significantly dependent on its action on macrophages. Our findings establish low-protein diet-induced hypoalbuminemia as a key driver of immunotherapy resistance, unveil a novel metabolic-immune circuit centered on TAM arginine metabolism, and identify arginine replenishment as a potential therapeutic strategy to reverse immune suppression in hypoalbuminemia patients.