Researchers have discovered that tumors release microscopic particles that reprogram liver fat metabolism, creating a systemic lipid-rich environment that disarms CD8+ T cells. Published in Cell Metabolism and reported by Ludwig Princeton scientists, the findings reveal a sophisticated mechanism of immune evasion.
Scientists exploring how cancers grow and spread have uncovered a mechanism that allows tumors to alter physiological processes far from their origin. The findings show that cancer acts as a systemic disease by establishing lines of communication with distant, noncancerous organs according to Yibin Kang. A study led by Ludwig Princeton’s Yibin Kang and Yong Tang adds a new dimension to this emerging portrait of the tumor in its context.
Our study adds to the growing body of evidence showing how cancer can act as a systemic disease by establishing lines of communication between its tumors and distant, noncancerous organs, Kang
Targeting metabolic-epigenetic-immune axis in cancer
In their quest to understand how cancers take root, grow and spread, scientists have for the past half-century explored the genetic aberrations and microenvironmental peculiarities of tumors and their constituent cells. Such studies continue to yield discoveries that are today fueling a revolution in cancer therapy. Meanwhile, new technologies have in recent years enabled a more granular examination of how tumors interact biochemically with the rest of the body to support their own growth and survival.
How Extracellular Particles Alter Liver Fat Metabolism
The remote control mechanism relies on tiny particles released into the bloodstream by tumors. These deliver molecular messengers to resident immune cells in the liver. That delivery triggers the production of factors that disrupt normal fat-processing functions.
The net effect is an accumulation of fat in the liver and higher lipid levels in the blood, establishing an environment that undermines the functional capabilities of the body’s primary anti-tumor forces.
What Is Cancer
We found that small particles released by tumors reprogram fat metabolism in the liver to further undermine the function of CD8+ T cells, the primary anti-tumor forces of the immune system, Kang
The MTDH Gene and Immune System Evasion
At the center of this metabolic crosstalk is metadherin—a protein encoded by the MTDH gene that, among other things, helps regulate fat metabolism—which mediates this metabolic-immune crosstalk. While previous work showed that high MTDH expression in breast cancer cells drives metastasis and thwarts immunity, the recent study demonstrates that MTDH expressed by noncancerous liver cells and T cells also supports tumor growth.
The researchers also demonstrate that in liver and CD8+ T cells, metadherin mediates this metabolic-immune crosstalk. After investigation, the research team found that blocking MTDH in both liver cells and CD8⁺ T cells—but, notably, not just one of them—enhances anti-tumor immunity, reduces the growth and metastasis of tumors and improves the effectiveness of immunotherapy.
Cancer's Malignant Remote Control
Our findings reveal how a gene that is normally useful for physiological function can become a vulnerability in cancer,
said Tang.
When MTDH is disrupted in both hepatic and T cells, the breakdown of fats in the liver is restored, maintaining a low-lipid environment in tumor-bearing mice researchers observed. This suggests that therapeutically targeting MTDH may offer a new strategy for cancer therapy.
Implications for Immunotherapy and Future Treatment
The coordinated loss of MTDH in liver and T cells also enhances the effects of immunotherapy. By showing that host cells outside the tumor microenvironment actively contribute to immune evasion through systemic metabolic changes, the study points toward therapeutic strategies that target MTDH alongside existing immunotherapies.
