Study links methylglyoxal stress to immunotherapy resistance in triple-negative cancer

The metabolism of cancer cells may play a key role in their ability to evade the immune system. This is demonstrated by a new study conducted by researchers at the University of Liège, which reveals how methylglyoxal stress – a by-product of tumor metabolism – promotes immunosuppression and the formation of metastases, and may contribute to resistance to immunotherapy and the progression of triple-negative cancer.

In order to grow rapidly, cancer cells alter their metabolism and consume large quantities of glucose. This activity generates, in particular, methylglyoxal (MG), a highly reactive molecule already identified as a key factor in tumor progression and metastatic spread in triple-negative breast cancer.

Previous work, carried out by teams at the GIGA Institute (University of Liège), had shown that an imbalance between the production of methylglyoxal and its detoxification by the glyoxalase system – known as 'methylglyoxal stress' – promotes the formation of metastases. This time, the researchers sought to understand how this phenomenon influences the tumor's immune environment.

An immune environment hijacked for the benefit of the tumor

Using preclinical breast cancer models and the analysis of patient data, Victoria Mohring and her colleagues have identified a close link between methylglyoxal stress and the accumulation of granulocyte-derived myeloid-derived suppressor cells (g-MDSCs). These immune cells are 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 the activation of specific inflammatory pathways and the upregulation of factors that promote their recruitment. In data from patients with triple-negative breast cancer, a gene signature associated with methylglyoxal stress also correlates with markers of g-MDSC infiltration.

A potential indicator of response to immunotherapy

The researchers also observed that this molecular signature could be used to distinguish between melanoma patients who do and do not respond to PD-1-targeting immunotherapy. This observation suggests that the level of methylglyoxal stress could be associated with the efficacy of certain immunotherapy treatments.

These results reinforce the idea that tumor metabolism is not limited to supplying energy to cancer cells, but that it plays an active role in reshaping their immune environment.

Targeting methylglyoxal to limit metastases

The team then explored a therapeutic approach aimed at neutralising methylglyoxal using carnosine, a molecule capable of trapping it. In a model of triple-negative breast cancer resistant to immunotherapy, this strategy, combined with anti-PD-1 treatment, reduced the accumulation of g-MDSCs as well as the pulmonary metastatic burden.

These results highlight a direct link between the metabolic vulnerability of tumor cells and their ability to remodelling their immune microenvironment. They also suggest that combined targeting of tumor metabolism and immune escape mechanisms could constitute a new strategy for combating cancers resistant to immunotherapy. "

Professor Akeila Bellahcène

Towards new therapeutic strategies

Beyond triple-negative breast cancer, this study highlights the still largely underestimated role of tumor metabolism in the response to treatment. It paves the way for the development of new approaches combining immunotherapy and metabolic targeting to restore the immune system's defences against cancer cells and limit the formation of metastases.

This research also offers new prospects for identifying biomarkers capable of predicting response to immunotherapy and, ultimately, of better personalising patient treatments.