This study uncovers host Metadherin (MTDH) as a pivotal regulator of systemic tumor progression, orchestrating liver metabolism and CD8⁺ T cell immunity. Tumor-derived extracellular vesicles prompt Kupffer cells to release TNFα and TGF-β, which, through MTDH-driven NF-κB signaling, suppress hepatic PPARα activity and lipid oxidation. The resulting systemic lipid accumulation hampers CD8⁺ T cell functionality. Eliminating MTDH in both hepatocytes and CD8⁺ T cells restores lipid metabolism, enhances mitochondrial health, and strengthens antitumor immunity. Proteomic profiling of tumor-infiltrating CD8⁺ T cells highlights increased OXPHOS activity, mitochondrial biogenesis, and diminished ferroptosis markers in MTDH-deficient cells. Combining MTDH inhibition with anti-PD-1 therapy amplifies immunotherapeutic effectiveness, offering a promising metabolic reprogramming strategy.