(A) Gastric adenocarcinoma. (i) ACh release from vagal efferents activates M₃ muscarinic receptors (M₃R); vagotomy attenuates neoplasia. (ii) Cancer cells express ChAT, key for non-neuronal ACh synthesis; resulting ACh levels and their autocrine and paracrine impact on tumor progression remain uncertain. M₃R activation induces nerve growth factor (NGF) expression. (B) PDAC. (iii) Treating mice with bethanechol, a non–subtype-selective muscarinic receptor agonist, activates muscarinic receptors. (iv) M₁R activation attenuates PDAC progression by undefined mechanisms involving repressed EGFR signaling. (C) CRC. (v) M₃R signaling transactivates EGFR; this is mediated by MMP7-mediated release of HB-EGF, an EGFR ligand. (vi) Concurrent activation of M₃R and EGFR potentiates target gene expression. (vii) M₃R activation selectively induces MMP1, MMP7, and MMP10 expression. MMP1 and MMP7 facilitate cell invasion. MMP7 also catalyzes the release of EGFR ligands (e.g., HB-EGF). (viii) M₁R expression and activation attenuate colon cancer progression by unknown mechanisms. (ix) Immunocytes and (x) gut flora provide additional sources of non-neuronal ACh. (D) Post-M₃R signaling alters gene expression and cancer cell function by impacting various signaling pathways. APC and/or β-catenin gene mutations free β-catenin from proteasomal destruction, promoting transcription of β-catenin target genes. M₃R activation transactivates EGFR and augments β-catenin signaling. Resulting changes in downstream gene transcription stimulate cancer cell proliferation, survival, migration, invasion, and dissemination. Notably, induction of neurotrophin expression can promote neural growth and tropism, a feedback loop providing additional access to ACh and other neurotransmitters.