Arecoline upregulates CD155 expression to facilitate immune evasion in oral squamous cell carcinoma

Background: Areca nut is the fourth most addictive substance worldwide and is a known Group 1 carcinogen. Chronic areca nut chewing has been strongly associated with the development of oral squamous cell carcinoma (OSCC), although the underlying carcinogenic mechanisms remain unclear. Methods: Employing spatial multiomics technology, we recently mapped the immune microenvironment of areca nut-associated OSCC and identified a marked upregulation of the immune checkpoint molecule CD155 in these tumors. Further quantitative reverse transcription-PCR, western blotting, immunofluorescence, animal experiments, etc, explored and verified the reasons for the upregulation of CD155 caused by arecoline and the results of immune escape in OSCC. Results: The investigation revealed that arecoline, a bioactive component of areca nut, induces CD155 expression in OSCC cells. Through interaction with its receptor, TIGIT, CD155 suppresses CD8+ T cell function and activity, facilitating immune evasion in OSCC. Mechanistically, arecoline upregulates CD155 via activation of muscarinic acetylcholine receptors on the surface of OSCC cells, leading to RhoA-mediated inhibition of YAP phosphorylation. This promotes YAP nuclear translocation and phase separation, driving CD155 transcription. In both in vitro and in vivo models, blockade of the CD155-TIGIT signaling axis significantly enhanced the efficacy of immunotherapy in OSCC. Conclusion: This study unveils a novel mechanism by which arecoline promotes immune evasion in OSCC and highlights promising immune therapeutic targets and strategies for the treatment of areca nut-associated OSCC.