Pan-cancer neurotransmitter receptor alterations define neuroregulatory subtypes with prognostic significance.

Cancer neuroscience highlights the critical role of neural signaling in tumors, yet a pan-cancer understanding of neuroregulatory dysregulation is lacking. We systematically characterized 130 neurotransmitter receptor (NTR) genes across 9,125 tumors from 33 cancer types. Our analysis revealed heterogeneous NTR mutations, with 17 cancer types showing elevated rates. Notably, amplification of the muscarinic receptor gene CHRM2 exhibited mutual exclusivity with the clinically actionable gene ERBB2, suggesting its potential as a therapeutic target. NTR expression was widely dysregulated and associated with altered DNA methylation, microRNA (miRNA) expression, and patient prognosis. Unsupervised clustering identified five recurrent neuroregulatory subtypes with distinct clinical and molecular features across cancers. Using low-grade glioma and liver cancer as examples, we validated that the S4 and S1 subtypes were consistently correlated with aggressive disease and poor outcomes in these two cancers, respectively. This study establishes a foundational framework for advancing cancer neuroscience and targeting neuroregulatory signaling in cancer therapy.