Genetically engineered Salmonella, SGN1, as a tumor microenvironment-targeting modality capable of methionine reduction for oral squamous cell carcinoma.

Metabolic reprogramming is a hallmark of cancer, and targeting amino acid metabolism has emerged as a potential promising therapeutic strategy. Herein, we identified through bioinformatic analysis a pronounced methionine metabolic abnormality in the clinical samples of oral squamous cell carcinoma (OSCC), which is strongly associated with poor patient prognosis. In cultured human OSCC cells, methionine deprivation drastically suppressed cell proliferation and migration. Although dietary methionine restriction significantly inhibited tumor growth in OSCC-derived subcutaneous xenograft model, such approach also induced strong systemic toxicity. To overcome this limitation, we deployed SGN1, an attenuated strain of Salmonella typhimurium engineered to overexpress an L-methioninase (METase). Following intravenous delivery, SGN1 highly colonized and specifically reduced methionine levels in the implanted tumor tissues, and produced superior anti-tumor efficacy in orthotopic OSCC model. Though rapidly cleared from non-tumor organs, SGN1 could persistently colonize within the tumor tissue for at least 7 days. Importantly, SGN1 also inhibited cell proliferation in patient-derived organoids (PDOs), further underscoring its clinical relevance. Hematological, biochemical, and histopathological analyses confirmed that SGN1 exhibited a favorable safety profile. Collectively, our study highlights the methionine dependency in human OSCC and establishes SGN1 as a tumor microenrironment-targeting and well-tolerated methionine-depleting therapy with strong translational potential.