Abstract 2362: Bitter taste receptors detect oral dysbiosis and trigger oral cancer cell death via β-arrestin-biased NLRP3 activation

Bitter taste receptors (taste 2 receptors, T2Rs) are a family of G protein-coupled receptors (GPCRs) that transduce bitter taste signals in the taste buds via the gustatory G protein α-gustducin. Recently, T2Rs have emerged as novel regulators in various extraoral physiological processes, including microbial interactions and carcinogenesis. Notably, T2R4 and T2R14 can recognize bacterial quorum sensing (QS) molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12). Reanalysis of oral microbiome datasets from oral squamous cell carcinoma (OSCC) patients, a major subtype of head and neck squamous cell carcinoma (HNSC), revealed an upregulation of bacterial QS pathways associated with oxo-C12 synthesis. Lower expression levels of T2R4 or T2R14 correlated with poor outcomes and impaired bacterial defense responses in OSCC/HNSC patients. We hypothesized that T2R4 and T2R14 mediate the interplay between oral microbial dysbiosis and OSCC in response to the bacterial QS molecule oxo-C12. Our results showed that oxo-C12 induces pyroptosis and apoptosis in human OSCC cells, unlike other T2R agonists such as quinine and apigenin. Unexpectedly, T2R4 and T2R14 mediated oxo-C12-induced cell death independently of α-gustducin, instead activating the NLRP3 inflammasome via β-arrestin-1/2 (β-ARR1/2). This indicates that oxo-C12 acts as a β-ARR1/2-biased ligand, triggering OSCC cell death through the T2R-β-ARR1/2-NLRP3 axis. A positive correlation between β-ARR2 and T2R4, T2R14, or NLRP3 in HNSC patient datasets supports this signaling pathway. Taken together, T2R4 and T2R14 function as crucial interkingdom sensors that detect oral microbiome dysbiosis and trigger defensive cell death mechanisms in OSCC via β-ARR1/2-biased NLRP3 activation. These findings suggest the potential of T2Rs as chemotherapeutic targets, particularly through ligand-specific biased pathways involving either G protein- or β-ARR1/2-dependent signaling. Citation Format: Sungmin Joo, Seong Yu, Jeong-Mu Shin, Yeshin Kwon, Na-Young Song. Bitter taste receptors detect oral dysbiosis and trigger oral cancer cell death via β-arrestin-biased NLRP3 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2362.