Turning off methylglyoxal stress: an alternative approach to inhibit MDSC expansion and metastasis in triple-negative breast cancer

Background: Metabolic reprogramming through enhanced glycolysis is a hallmark of cancer that supports tumor progression and promotes protumor immune responses. Methylglyoxal (MG), a reactive by-product of glycolysis, has recently emerged as an oncometabolite implicated in cancer progression and therapy resistance. Our previous work demonstrated that an imbalance between MG production and detoxification by the glyoxalase system, referred to as MG stress, contributes to progression and metastatic dissemination in triple-negative breast cancer (TNBC). However, the impact of MG stress on the tumor immune microenvironment remains poorly understood. Methods: Using two preclinical breast cancer models, we investigated the relationship between MG stress and immune modulation, with a focus on granulocytic myeloid-derived suppressor cells (g-MDSCs), major mediators of immune evasion. In silico analyses were performed to assess correlations between MG stress-related gene signatures and transcriptional markers of MDSC infiltration in patients with TNBC, as well as associations with anti-programmed cell death protein 1 (PD-1) immunotherapy response in melanoma cohorts. In vivo experiments combined the MG scavenger carnosine with PD-1 blockade in the immunotherapy-resistant 4T1 breast cancer model. Results: MG stress was associated with the expansion of g-MDSCs in breast cancer models. Importantly, MG stress conferred metastatic potential to non-metastatic 67NR breast tumors, potentially through activation of the Nuclear Factor kappa B (NF-κB) pathway, increased granulocyte-macrophage colony-stimulating factor expression, and systemic expansion of g-MDSCs. In silico analyses revealed a positive correlation between MG stress-related gene signature and transcriptional markers of MDSC infiltration in patients with TNBC. Furthermore, this signature distinguished anti-PD-1 responder (low MG stress), from non-responders (high MG stress) in patients with melanoma. Therapeutically, combined targeting of MG stress with carnosine and PD-1 signaling significantly reduced g-MDSC accumulation in tumors, spleens, and lungs, and decreased lung metastatic burden in the 4T1 model. Conclusions: These findings identify MG stress as a driver of an immunosuppressive tumor microenvironment that may impair immunotherapy efficacy and promote metastatic progression in TNBC. Dual targeting of MG stress and PD-1 signaling represents a promising therapeutic strategy to overcome immune suppression and limit metastasis in immunotherapy-resistant breast cancer.