Title: The Surprising Biology of Metadherin: Lessons from a Dispensable but Evolutionarily Conserved Cancer Fitness Gene
Abstract: Metadherin (MTDH) exemplifies a quintessential cancer fitness gene—a gene largely dispensable during normal physiological development that play key roles in supporting malignant transformation, progression, metastasis and treatment response. Our earlier work established that MTDH promotes the survival of tumor-initiating cells (TICs) under stress through its essential interaction with SND1, while simultaneously orchestrating tumor-intrinsic immune evasion by downregulating antigen-presentation machinery, such as TAP1 and TAP2. Extending its tumor-intrinsic functions, our recent work revealed a systemic, non-cell-autonomous role of MTDH: primary tumors release extracellular vesicles that hijack host hepatocyte MTDH to trigger hepatic lipid reprogramming. This systemic increase in circulating lipids induces metabolic exhaustion and functional suppression of tumor-infiltrating CD8 T cells. Importantly, genetic deletion or pharmacologically targeting both hepatocyte and T cell MTDH restores systemic lipid homeostasis, rescues CD8 T cell dysfunction, and sensitizes tumors to checkpoint immunotherapy.
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