Sulfasalazine combined with anti-IL-1β mAb induces ferroptosis and immune modulation in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC), one of the most prevalent and aggressive forms of head and neck squamous cell carcinoma, has a five-year survival rate of about 50% ~ 60%, emphasizing the urgent need for more effective therapeutic strategies. Solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers and represents a potential therapeutic target. Sulfasalazine (SAS), a Food and Drug Administration-approved drug, is a potent inhibiter of SLC7A11. However, SAS can also increase the levels of pro-inflammatory cytokines such as IL-1β, which may suppress the immune response. Here, we investigate the effect of SAS combined with anti-IL-1β monoclonal antibody (anti-IL-1β mAb) as a novel treatment strategy for OSCC. In this study, SLC7A11 was markedly increased in OSCC tissues, and high SLC7A11 expression predicted poor prognosis. SAS treatment was shown to suppress OSCC cell proliferation and trigger ferroptosis, as evidenced by elevated reactive oxygen species, reduced glutathione and enhanced lipid peroxidation. SAS also elevated IL-1β levels, leading to T cell exhaustion. Combining SAS with anti-IL-1β mAb reversed T cell exhaustion and amplified the anti-tumor effects in vitro. In the 4-nitroquinoline-1-oxide-induced oral cancergenisis model, the combination treatment significantly inhibited oral carcinogenesis compared to monotherapy. Our results suggest that combining SAS with anti-IL-1β mAb enhances the anti-tumor efficacy against OSCC through tumor growth inhibition and immune modulation, offering a promising therapeutic strategy.