Host MTDH orchestrates liver lipid metabolism and CD8+ T cells to suppress antitumor immunity [Hepatocytes]

Cancer affects the function of distant organs beyond metastasis, conversely, dysfunction in distant organs can also impact tumor progression. However, the mechanisms underlying these interactions remains poorly understood. Here, we uncover that metadherin (MTDH), previously identified as a cancer metastatic gene, expressed in different host tissues, manipulates systemic lipid metabolism to control CD8+ T cell-mediated antitumor immunity. Genetic ablation of MTDH in host tissues significantly suppresses tumor growth and lung metastasis. Mechanistically, MTDH loss in hepatocytes prevents tumor environment-driven dysfunction of lipid metabolism. MTDH deficiency in hepatocytes increases PPARa-mediated lipid oxidation, resulting in reduced systemic lipid levels. Moreover, reduced systemic lipid levels metabolically reprogram MTDH knockout (KO) tumor-infiltrating CD8+ T cells by increasing mitochondrial biogenesis and resistance to lipid peroxidation-induced death. This increased metabolic fitness enhances the effector function of MTDH KO tumor-infiltrating CD8+ T, triggering ASCL4-depedent ferroptosis in tumor cells, contributing to tumor suppression. Targeting host MTDH efficiently synergizes with anti-PD-1 therapy across colorectal and metastatic breast cancer models, providing a promising therapeutic strategy for immunotherapy non-responsive cancers. Thus, our study identifies MTDH as an essential bridge connecting tumor and distant liver communications through metabolic reprogramming, revealing a previously unknown mechanism by which cancer is regulated as a systemic disease.