Third-space endoscopy: Current techniques, clinical applications, and future directions

Third-space endoscopy refers to a set of endoscopic techniques that allow access to the submucosal space or "third space" between the mucosa and muscularis propria, enabling therapeutic intervention while preserving mucosal integrity. The unifying concept across all third-space endoscopy procedures is the creation of a submucosal tunnel with a mucosal flap acting as a safety valve, allowing separation of access from therapy. This principle is the key factor underlying its rapid adoption across diverse indications. The evolution of third-space endoscopy began with the submucosal endoscopy with mucosal flap technique, followed by the first porcine per-oral endoscopic myotomy and its clinical application in humans nearly two decades ago. Per-oral endoscopic myotomy has not only transformed the management of achalasia but also established a platform that has since been extended to multiple gastrointestinal disorders, including per-oral endoscopic myotomy for refractory gastroparesis, submucosal tunneling endoscopic resection for sub-epithelial tumors, Zenker's per-oral endoscopic myotomy, and per-oral endoscopic myotomy for epiphrenic diverticula. Although some procedures, such as per-oral endoscopic myotomy and tunneling resection for subepithelial tumors, have matured with well-defined roles in clinical algorithms, others, including per-oral endoscopic myotomy in refractory gastroparesis and Zenker's per-oral endoscopic myotomy, demonstrate promising safety and efficacy but continue to face unresolved questions regarding patient selection, durability, and comparative effectiveness. Despite these limitations, third-space endoscopy has emerged as a minimally invasive alternative for several conditions traditionally managed surgically. Its standardized core principles allow broad adaptability across disease phenotypes. This narrative review discusses the evolution, technical framework, clinical outcomes, and current limitations of key third-space endoscopy procedures.