Researchers at Ludwig Princeton have discovered that tumors can manipulate distant organs to evade the immune system, according to a study published in Cell Metabolism. Led by Yibin Kang and Yong Tang, the research demonstrates how cancer cells send signals across the body to alter fat metabolism in the liver and immune responses in CD8⁺ T cells, shielding the disease from therapeutic attacks.
How Tumors Co-Opt Systemic Lipid Metabolism
For decades, cancer research focused primarily on genetic mutations and the immediate microenvironment surrounding a tumor. However, the new findings published in Cell Metabolism show that tumors actively reach across the body to tweak physiological processes governed by distant organs. According to Yibin Kang, cancer co-opts an ancient metabolic program that normally helps organisms store energy during fluctuating food availability.
The study reveals that a protein called metadherin—encoded by the MTDH gene—mediates this metabolic and immune crosstalk. While MTDH helps regulate normal fat metabolism in healthy tissues, tumors exploit this pathway to suppress anti-tumor immunity. Through a series of bone marrow-transplantation experiments conducted alongside Ludwig Princeton Director Joshua Rabinowitz’s laboratory, the team found that host cells rather than cancer cells control systemic lipid metabolism in tumor-bearing mice.
Targeting MTDH in Liver and T Cells
Disrupting the MTDH gene in just one location is not enough to stop the disease. According to Yong Tang, blocking MTDH in both liver cells and CD8⁺ T cells enhances anti-tumor immunity, curtails tumor growth and metastasis, and improves the effectiveness of immunotherapy. When MTDH is lost in hepatic cells, the liver restores its normal breakdown of fats, maintaining a low-lipid systemic environment.
This coordinated loss makes tumor-infiltrating CD8⁺ T cells more metabolically fit, less prone to programmed cell death, and more efficient at destroying cancer cells. Furthermore, the researchers demonstrated that this disruption enhances the effects of anti-PD-1 checkpoint blockade immunotherapy.
Did you know? Previous work by Kang’s group showed that mice lacking the MTDH gene are resistant to diet-induced obesity and fatty liver disease while otherwise developing and living normally. This suggests that healthy tissues can largely do without the pathway that tumors rely on.
Implications for Future Cancer Therapy
The discovery adds a crucial dimension to the broader understanding of cancer as a systemic disease rather than a localized mass. As outlined in companion perspectives examining the hallmarks of cancer, elucidating how tumors interact with distant organs remains vital for improving patient survival rates, which have risen from 35% in the 1950s to 69.7% by 2017 according to the SEER Cancer Statistics Review.
Because healthy tissues can function normally without MTDH, the protein represents an attractive therapeutic target. Therapeutics that simultaneously block MTDH in the liver and immune cells could offer a fresh strategy to overcome the resistance mechanisms that often blunt current treatments.
Frequently Asked Questions
What is metadherin (MTDH)?
Metadherin is a protein encoded by the MTDH gene that regulates fat metabolism and helps organisms store energy. Research shows that cancer co-opts this protein to support tumor growth and suppress immune attacks.
How do tumors protect themselves from the immune system?
According to the Cell Metabolism study, tumors manipulate physiological processes in distant organs like the liver to alter systemic lipid metabolism, which in turn impairs the function of CD8⁺ T cells.
Why must MTDH be blocked in both liver and T cells?
Preclinical models show that disrupting MTDH in both liver cells and CD8⁺ T cells is necessary to restore fat breakdown, create a low-lipid environment, and make immune cells effective killers of cancer.
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