For decades, scientists and patients alike have believed that cutting off a tumor’s supply of glucose — its primary energy source — could starve cancer cells into submission. Low-carbohydrate diets and drugs that block glucose metabolism have been widely explored as anticancer strategies.
But a new study published in Cell challenges this long-standing assumption, revealing that while glucose restriction can slow down primary tumor growth, it can also unintentionally promote cancer spread to the lungs.
Researchers led by Cai-Yuan Wu and Dong-Ming Kuang at Sun Yat-sen University discovered that low-glucose conditions trigger a chain reaction in tumor cells that reshapes the body’s immune defenses, creating what scientists call a “pre-metastatic niche” — an environment in the lungs that invites cancer cells to settle and grow.
The Hidden Danger Behind Glucose Deprivation
The team found that glucose restriction, whether caused by diet or tumor metabolism, leads to endoplasmic reticulum (ER) stress inside cancer cells. This stress activates a key enzyme known as HMG-CoA reductase degradation protein 1 (HRD1).
HRD1 then modifies a protein called TRAIL through K63-linked ubiquitination, tagging it for packaging into tiny vesicles known as exosomes. These exosomes are then released into the bloodstream, carrying TRAIL to distant organs like the lungs.
Once there, the exosomal TRAIL interacts with PVR⁺ macrophages, reprogramming them into a state that suppresses the body’s first line of defense — the natural killer (NK) cells. Exhausted and depleted, these NK cells can no longer recognize or destroy early cancer cells that arrive in the lungs.
In other words, glucose deprivation — meant to weaken cancer — paralyzes the immune system’s sentinels, turning the lungs into a fertile ground for metastasis.
From Promise to Paradox
“Glucose restriction has been celebrated as a universal cancer therapy strategy, but our findings reveal a serious caveat,” said lead author Yuan Wei. “It’s not only about starving the tumor — it’s about protecting the immune system from collateral damage.”
The study shows that low-carbohydrate diets and metabolic inhibitors, while effective against the primary tumor, may inadvertently assist the spread of cancer by sabotaging innate immunity.
To counter this effect, the team tested TIGIT blockade, an immunotherapy that reactivates NK cells. The combination of TIGIT inhibition and glucose restriction prevented metastasis entirely, while still reducing tumor growth — offering a possible path forward for safer metabolic-based cancer therapies.
A Biomarker for Early Detection
The researchers also identified a powerful clinical biomarker: plasma exosomal TRAIL. Elevated levels of this molecule in the blood accurately predicted early postoperative lung metastasis, outperforming traditional indicators such as α-fetoprotein (AFP) and tumor size.
Across a dataset covering 15 different cancer types, patients with low tumor glucose metabolism experienced a significantly higher rate of recurrence within two years after surgery — underscoring the risks of metabolic restriction when used in isolation.
Balancing Metabolism and Immunity
This discovery forces oncologists and researchers to rethink the simple “starve the tumor” model. Cancer metabolism and immune surveillance are deeply intertwined; targeting one can destabilize the other.
Future therapies may need to combine dietary or metabolic interventions with immune checkpoint blockade, ensuring that the immune system remains active even when tumors are deprived of glucose.
The Takeaway
This landmark study reframes how we understand cancer metabolism and metastasis. The fight against cancer, it seems, is not only about denying energy to tumors — it’s also about preserving the energy of the immune system itself.
