Abstract
G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and play a critical role as pharmacological targets. An improved understanding of GPCRs' involvement in tumor microenvironment may provide new perspectives for cancer therapy. This study used machine learning to classify head and neck squamous cell carcinoma (HNSCC) patients into two GPCR-based subtypes. Notably, these subtypes showed significant differences in prognosis, gene expression, and immune microenvironment, particularly CD8+ Tcell infiltration. S1PR4 emerged as a key regulator distinguishing the subtypes, positively correlated with CD8+ Tcell proportion and cytotoxicity in HNSCC. It was predominantly expressed in CX3CR1+CD8+ Tcells among Tcells. Upregulation of S1PR4 enhanced Tcell function during CAR-T cell therapy, suggesting its potential in cancer immunotherapy. These findings highlight S1PR4 as an immune modulator for favorable prognosis in HNSCC, and offer a potential GPCR-targeted therapeutic option for HNSCC treatment.
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