Targeting M3 Muscarinic Receptors with Novel Ligands: Emerging Therapeutic Strategies for Colorectal Cancer

Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Emerging evidence implicates muscarinic acetylcholine receptors, particularly the M3 subtype (M3R), in CRC progression. M3R activation by acetylcholine and bile acids stimulates oncogenic signaling cascades, including EGFR transactivation, MAPK/ERK, PI3K/Akt, and matrix metalloproteinase induction. Elevated M3R expression correlates with poor prognosis, underscoring its potential as a biomarker and therapeutic target. Novel ligands— including orthosteric antagonists, allosteric modulators, and biased ligands—offer promising strategies to selectively disrupt tumorigenic signaling. This review synthesizes mechanistic insights, preclinical and clinical evidence, and translational challenges, highlighting future opportunities for M3R-targeted therapies in CRC.