AUGUST 28, 2026, NEW YORK – 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.
A study led by Ludwig Princeton’s Yibin Kang and Yong Tang now adds a new dimension to this emerging portrait of the tumor in its context. Reported in the current issue of Cell Metabolism, its findings reveal how tumors reach out across the body and tweak physiological processes governed by a distant organ to indirectly shield themselves from immune attack.
“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,” said Kang. “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.”
The researchers also demonstrate that in liver and CD8+ T cells, metadherin-a protein encoded by the MTDH gene that, among other things, helps regulate fat metabolism-mediates this metabolic-immune crosstalk.
“Our findings reveal how a gene that is normally useful for physiological function can become a vulnerability in cancer,” said Tang. “We have also demonstrated in preclinical models 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. This suggests that therapeutically targeting MTDH may offer a new strategy for cancer therapy.”
Metadherin is not new to the world of cancer. Kang’s group discovered years ago that MTDH is highly expressed in breast cancer cells, where it drives metastasis, supports malignant cells under various stresses, such as chemotherapy, and helps thwart anti-tumor immunity. His team also demonstrated in mouse models that the inhibition of MTDH in tumor cells suppresses the growth and metastasis of breast, prostate, lung and colorectal cancers. The current study shows that the MTDH expressed by noncancerous liver and CD8+ T cells also supports tumor growth and metastasis, but by a very different mechanism-through its effects on systemic physiology.
Initial experiments had revealed to Kang, Tang and colleagues that the tumor suppression observed in mice lacking the MTDH gene stemmed in part from changes in the immune response. What precisely those changes were, however, proved hard to pin down. After puzzling for two years over the problem, the researchers discovered through a crucial series of bone marrow-transplantation experiments that the effect depended on MTDH being disrupted in both CD8+ T cells and liver cells.
Kang, Tang and their colleagues collaborated with the laboratory of Ludwig Princeton Director Joshua Rabinowitz, a leader in the large-scale, dynamic analysis of systemic metabolism, to find out why this is the case. Together, the researchers found that MTDH expressed by host cells, not cancer cells, controls systemic lipid metabolism in mice bearing tumors.
Their studies revealed that extracellular vesicles/particles (EVPs), tiny membrane-bound packages released into the bloodstream by tumors, deliver molecular messengers to certain resident immune cells in the liver, inducing their production of factors that disrupt the normal fat-processing function of the liver. That disruption relies on a signaling cascade in liver cells that is dependent on MTDH, and its net effect is an accumulation of fat in the liver and higher lipid levels in the blood. This creates a systemic lipid-rich environment to undermine the fitness and functional capabilities of CD8+ T cells, which favors tumor growth.
MTDH loss in hepatic cells restores the breakdown of fats in the liver and maintains a low-lipid systemic environment in tumor-bearing mice-and, interestingly, appears to have no detrimental effects.
“With the coordinated loss of MTDH in T cells and liver cells, tumor-infiltrating CD8⁺ T cells were more metabolically fit, less prone to programmed death and more efficient killers of cancer cells,” Tang said. “And we saw enhanced anti-tumor immunity and suppression of tumor growth and metastasis with MTDH loss across multiple models of cancer.”
The researchers also demonstrate that disruption of MTDH in liver and T cells in mice enhances the effects of anti-PD-1 checkpoint blockade immunotherapy, which stimulates the CD8+ T cell response to cancer.
“MTDH appears to be one of those rare genes that evolved to help organisms adapt to fluctuating food availability by promoting efficient energy storage,” said Kang. “Previous work showed that mice lacking MTDH are resistant to diet-induced obesity and fatty liver disease but otherwise develop and live normally. Cancer has coopted this ancient metabolic program to support its own growth and suppress anti-tumor immunity. This is why MTDH could be an attractive therapeutic target: tumors rely on a pathway that healthy tissues can largely do without.”
This study was supported by the Ludwig Institute for Cancer Research, the New Jersey Commission on Cancer Research, the U.S. National Science Foundation, the U.S. National Institutes of Health, Stand up to Cancer, the Paul Allen Distinguished Investigator program, the Breast Cancer Research Foundation, the Brewster Foundation, American Cancer Society, Weil Cancer Hub East, and the Susan G. Komen Foundation.
Aside from his post as a Member of the Princeton Branch of the Ludwig Institute for Cancer Research, Yibin Kang is Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton University and an Associate Director of Rutgers Cancer Institute of New Jersey.
