Methylglyoxal Stress Drives Immune Suppression and Immunotherapy Resistance in Triple-Negative Breast Cancer
核心洞察
University of Liège (搜索) researchers report that methylglyoxal stress, a by-product of tumor glucose metabolism, promotes immunosuppression and metastasis in triple-negative breast cancer (搜索).
The study links methylglyoxal stress to expansion of granulocyte myeloid-derived suppressor cells and identifies a gene signature correlating with their tumor infiltration.
Combining carnosine, which neutralizes methylglyoxal, with anti-PD-1 therapy reduced g-MDSC accumulation and pulmonary metastatic burden in an immunotherapy-resistant preclinical model.
Cancer cell metabolism actively reshapes the tumor immune microenvironment and may underlie resistance to immunotherapy in triple-negative breast cancer (搜索), according to a study from researchers at the University of Liège (搜索) published in the Journal for ImmunoTherapy of Cancer (JITC).
The work, led by Professor Akeila Bellahcène, Director of the National Fund for Scientific Research in the Department of Biomedical and Preclinical Sciences at the University of Liège (搜索), shows that methylglyoxal (MG) stress — a by-product of tumor metabolism — promotes immunosuppression and the formation of metastases and may contribute to immunotherapy resistance. Bellahcène's research focuses on breast cancer metabolism and how it drives tumor progression through cell alteration.
How Tumor Metabolism Generates Methylglyoxal Stress
To sustain rapid proliferation, cancer cells alter their metabolism and consume large quantities of glucose. This activity generates methylglyoxal, a highly reactive molecule already identified as a key factor in tumor progression and metastatic spread in triple-negative breast cancer (搜索). Previous work by teams at the GIGA Institute (搜索) (University of Liège (搜索)) showed that an imbalance between methylglyoxal production and its detoxification by the glyoxalase system — termed "methylglyoxal stress" — promotes metastasis formation.
The new study, conducted by Victoria Mohring and colleagues, sought to determine how this phenomenon influences the tumor's immune environment. Using preclinical breast cancer models and analysis of patient data, the researchers identified a close link between methylglyoxal stress and the accumulation of granulocyte myeloid-derived suppressor cells (g-MDSCs), immune cells known to suppress anti-tumor responses and help tumors evade immune surveillance.
The findings suggest that methylglyoxal stress stimulates the expansion of these immunosuppressive cells, notably through activation of specific inflammatory pathways and upregulation of factors that promote their recruitment. In data from patients with triple-negative breast cancer (搜索), a gene signature associated with methylglyoxal stress correlated with markers of g-MDSC infiltration. According to the researchers, this signature has the potential to help diagnose patients and inform physicians which therapy regimen is optimal for patient care.
A Potential Biomarker of Immunotherapy Response
Beyond breast cancer, the researchers observed that the molecular signature could distinguish between melanoma (搜索) patients who do and do not respond to PD-1 (搜索)-targeting immunotherapy. This observation suggests that the level of methylglyoxal stress could be associated with the efficacy of certain immunotherapy treatments, offering prospects for identifying biomarkers capable of predicting response to immunotherapy and better personalizing patient treatments.
Neutralizing Methylglyoxal to Limit Metastases
The team then explored a therapeutic approach aimed at neutralizing methylglyoxal using carnosine, a naturally occurring molecule capable of trapping it. Carnosine reduces inflammation, can be used to control and stabilize glucose, and is particularly known to combat metabolic dysfunction.
In a model of triple-negative breast cancer (搜索) resistant to immunotherapy, this strategy combined with anti-PD-1 treatment reduced the accumulation of g-MDSCs as well as the pulmonary metastatic burden. Anti-PD-1 immunotherapy works by activating healthy immune cells to recognize and target cancer, giving the combination two arms of tumor control: controlling metabolic instability and enhancing anti-tumor immunity.
"These results highlight a direct link between the metabolic vulnerability of tumor cells and their ability to remodelling their immune microenvironment," Bellahcène said. "They also suggest that combined targeting of tumor metabolism and immune escape mechanisms could constitute a new strategy for combating cancers resistant to immunotherapy."
Implications Beyond Triple-Negative Breast Cancer
The results reinforce the concept that tumor metabolism is not limited to supplying energy to cancer cells but plays an active role in reshaping their immune environment. The researchers conclude that methylglyoxal stress is associated with high g-MDSC infiltration driving tumor metastasis, confirming that tumor metabolism reshapes the tumor microenvironment to enhance cancer progression.
The findings have the potential to be applied to different tumor types and to improve patient care, laying the foundation for an enhanced treatment strategy combining agents that restore healthy metabolic activity with those that activate anti-tumor immunity. The study also highlights the still largely underestimated role of tumor metabolism in treatment response, paving the way for new approaches that combine immunotherapy with metabolic targeting to restore the immune system's defenses against cancer cells and limit metastasis formation.