Multi-Organ Orchestration of the Hepatic and Immune Axis by Host MTDH Promotes Systemic Tumor Progression [ATAC-Seq]

Here, we identify host Metadherin (MTDH) as a critical regulator of tumor-induced immunosuppression and metabolic reprogramming via tumor-liver interactions. Using Mtdh knockout (KO) mouse models, we show that concurrent MTDH loss in hepatocytes and CD8⁺ T cells enhances effector T cell function and suppresses tumor growth and metastasis.

Mechanistically, tumor-derived extracellular vesicles (EVPs) activate Kupffer cells to secrete TNFα and TGF-β, which suppress hepatic PPARα-mediated lipid oxidation via NF-κB signaling. MTDH loss restores hepatic lipid catabolism and promotes mitochondrial metabolic reprogramming in CD8⁺ T cells in response to a lipid-reduced environment , thereby boosting anti-tumor immunity. Genetic or pharmacological targeting of MTDH synergizes with anti-PD-1 therapy in murine cancer models.