Ablation of cancer cell secreted neuropeptide PTHLH/PTHrP provokes anti-tumor immunity in murine tongue squamous cell carcinoma

Intra-tumor nerve infiltration has been correlated with poor prognosis of tumor, particularly in head and neck squamous cell carcinoma (HNSCC). While emerging evidence highlights the critical role of neuroimmune crosstalk in tumor progression and immunosuppression, the molecular mediators of this axis remain poorly understood. This study has identified cancer cell-secreted PTHLH/PTHrP as a key regulator of this neuroimmune network through integrated transcriptomic analysis, CRISPR-mediated knockout, and parallel preclinical models in immunodeficient (BALB/c nude) and immunocompetent (C57BL/6J) mice. Our finding revealed significant higher expression of PTHLH correlated with neuroimmune factors and poor prognosis in immunotherapy outcome. Genetic ablation of PTHLH significantly altered the expression of neurotrophic factors essential for intra-tumoral nerve growth. Strikingly, while PTHLH knockout showed no significant anti-tumor response in vitro and in immunodeficient mice, it dramatically reduced tumor burden in immunocompetent hosts. Comprehensive immune profiling further demonstrated enhanced immunoreactivity (increased CD8 + and CD4 + T cells) alongside reduced immunosuppression (decreased FOXP3 + Tregs and PD-L1 expression) in PTHLH-deficient tumors. Moreover, these tumors also showed lower expression of tumor proliferative and neuron markers. Together these findings established cancer cell secreted PTHLH as a critical mediator of immunosuppression and neuron infiltrations in HNSCC, particularly in tongue tumor.