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

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. Overall design: Mtdh KO and wild type control mice were irradiated to deplete their own immune system. Irradiated mice received donor bone marrow cells from Mtdh KO or wild type control mice, and then developed their new immune system with 4 types of combinations of Mtdh status in immune cells and other non-immune cells. After 8 weeks with bone marrow transfer, the four types of bone marrow transplanted female mice together with Mdth KO and wild type female mice, were used as recipient to engraft Py8119 cells to develop mammary tumors. Four weeks after tumor cell injection, mammary tumors were harvested and processed into single cell suspension. Live CD45+ cells were isolated through FACS sorting. Sorted cells directly processed to scRNAseq.