Intracellular bacterial LPS drives pyroptosis and promotes aggressive phenotype in oral squamous cell carcinoma.

Intracellular bacterial components represent an emerging tumor element that has recently been documented in multiple cancer types, yet their biological functions remain poorly understood. Oral squamous cell carcinoma (OSCC) is a particularly aggressive malignancy lacking highly effective targeted treatments. Here, we explored the functional significance of intracellular bacterial lipopolysaccharide (LPS) in OSCC. Normal human oral keratinocytes (HOKs), HPV-transformed oral keratinocytes (IHGK), and three OSCC cell lines were transfected with ultrapure bacterial LPS. Cytotoxicity was assessed via lactate dehydrogenase (LDH) release assays. Production of interleukin (IL)-1β and IL-18 was measured using ELISA. Impact on tumor progression was evaluated using cell proliferation, migration, invasion, and tubulogenesis assays. Intracellular LPS-induced significant LDH release and increased secretion of IL-18 and IL-1β in IHGK and cancer cells, but not in normal HOKs, indicating selective cytotoxicity and pyroptosis. Notably, metastatic cancer cells exhibited enhanced invasive and vessel-like structures upon LPS exposure, while IHGK cells exhibited increased proliferation without changes in migration. Our findings suggest that intracellular LPS may not merely reside passively within the tumor milieu, but could contribute to OSCC progression by triggering noncanonical inflammasome activation and pyroptosis. This process may enhance pro-inflammatory signaling and more aggressive cellular phenotypes, especially in metastatic settings. Targeting intracellular LPS or its downstream inflammasome pathways may thus represent a promising therapeutic strategy for OSCC, warranting further in vivo and clinical investigations.