PDE5A and colorectal cancer: • Administering ApcMin/+ mice with the receptor GCC agonist linaclotide or the PDE5 inhibitor sildenafil resulted in a noteworthy decrease in the polyp count per individual mouse.• Both PDE5 inhibitors and receptor GCC agonists demonstrate equal capability in inhibiting intestinal tumorigenesis in mice.• This study emphasizes the promising prospect of manipulating cGMP signaling as a strategy for chemopreventing colorectal cancer in human individuals with elevated risk.