Necrostatin-1 attenuates oral squamous cell carcinoma by modulating tumour immune response in mice

Necroptosis has been shown to play an important role in various pathologies, including pancreatic cancer (PDAC). However, its role in the progression of oral cancer (OSCC) remains unclear.

To determine the expression of key necroptosis pathway markers in an OSCC mouse model and evaluate the therapeutic effect of a necroptosis inhibitor on the progression of OSCC.

4-NQO-induced OSCC in mice resembles very closely to human OSCC. The expression of RIPK-1, RIPK-3, MLKL and their respective phosphorylation was increased in OSCC tissues of cancer-bearing mice. In the analysis of the necroptosis pathway in human OSCC with the TCGA database, we found similar overexpression of RIPK-1 in human cancer, which correlated with the severity of cancer in terms of different cancer grades and stages. Pharmacological blockade of necroptosis with necrostatin-1 (NEC-1) reduced the progression and development of OSCC, characterized by reduced number and severity of tumour lesions, improved histology with reduced hyperplasia, dysplasia and invasive carcinoma. Immune profiling of blood, spleen and tumour tissues demonstrated suppressed expression of MDSCs (CD11b⁺Gr-1⁺) and M2-macrophages (CD11b⁺F4/80⁺CD206⁺), while M1-macrophages (CD11b⁺F4/80⁺MHCII⁺) were elevated in the treatment group. The ratio of M2/M1 was reduced in the treated group, suggesting the promotion of anti-tumour immune response. Expression of Arg-1, YM1/2, IL-10 and TGF-β was reduced in tumour tissues in the treated group.

In summary, blocking the necroptosis pathway alters the tumour microenvironment (TME) and inhibits the progression of OSCC. Targeting necroptosis could be an effective therapy for treating OSCC in a clinical setup.