Bioinformatics Screening of Tumor-Derived Neuropeptides Mediating Neuroimmune Axis of Head and Neck Cancer

<b>Background/Objectives:</b> Emerging studies have indicated the importance of intra-tumoral neuronal signals in tumor progression and immune modulation. However, there is limited insight into neuroimmune crosstalk, and the molecules involved are largely unknown. This study investigates the relationship between tumor-derived neuropeptides and immune modulation in head and neck squamous cell carcinoma (HNSC). <b>Methods:</b> By utilizing neuropeptide databases and web tools leveraging TCGA data, neuropeptides' expression and their associations with neurotrophic factors, immune cell infiltration, and immune checkpoints were analyzed, followed by survival analysis. <b>Results:</b> Over half of the neuropeptides were expressed in HNSC, with 16% exhibiting differential expression compared to normal counterparts. Notably, differentially expressed neuropeptides showed significant correlations with neurotrophic factors, immune cell infiltration, and checkpoint genes. Further, their expression was significantly different in responder and non-responder patient samples subjected to immune checkpoint therapy. Neuropeptide genes-PTHLH, NMB, GAST, APLN, and LYNX1-were identified and emerged as crucial mediators in neuroimmune crosstalk. Additionally, the neurotrophic gene NTRK1 exhibited extensive correlation with immune checkpoint genes, underscoring the prevalence of neuroimmune crosstalk in HNSC. <b>Conclusions:</b> These findings shed light on the role of tumor-derived neuropeptides in neuroimmune regulation in HNSC, offering valuable insights for future studies to decode the cancer neuroscience of HNSC progression and therapy.