Necrotic tumor cells contribute to pro-tumoral responses and inflammatory mediator production via NF-κB activation in oral squamous cell carcinoma.

Although tumor necrosis has traditionally been regarded as a passive consequence of rapid tumor growth, current evidence suggests that necrotic tumor cells actively modulate the behavior of surrounding viable cancer cells. In this study, we investigated whether necrotic tumor cells promote pro-tumoral activation of oral squamous cell carcinoma (OSCC) cells and aimed to elucidate its underlying mechanisms. Human OSCC cell lines were exposed to necrotic tumor cells under both direct and indirect co-culture conditions. Necrotic cells significantly enhanced proliferation, migration, and invasion of viable OSCC cells independent of direct cell-cell contact, which indicates the involvement of soluble factors. Necrotic cell stimulation induced the nuclear accumulation of NF-κB p65 and increased the expression of downstream inflammatory mediators, including CXCL8. Pharmacological inhibition of NF-κB signaling attenuated necrotic cell-induced pro-tumoral phenotypes and reduced CXCL8 secretion. These findings suggest that necrotic tumor cells induce pro-tumoral phenotypic changes in OSCC cells by activating canonical NF-κB signaling and subsequent pro-inflammatory responses. Additionally, this study provides a mechanistic insight into the role of tumor necrosis in establishing a tumor-favorable microenvironment.