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While natural orifice transluminal endoscopic surgery provided early conceptual groundwork, third-space endoscopy builds upon it by maintaining interventions within the submucosal layer, offering improved precision and reduced risk. The creation of a controlled submucosal working space enables precise therapeutic interventions while potentially reducing the morbidity associated with traditional surgical approaches. 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While natural orifice transluminal endoscopic surgery provided early conceptual groundwork, third-space endoscopy builds upon it by maintaining interventions within the submucosal layer, offering improved precision and reduced risk. The creation of a controlled submucosal working space enables precise therapeutic interventions while potentially reducing the morbidity associated with traditional surgical approaches. Among its most impactful applications are the peroral endoscopic myotomy techniques, including cricopharyngeal, esophageal, gastric, and Zenker’s myotomies. These procedures have redefined the management of cricopharyngeal bar, achalasia, gastroparesis, and Zenker’s diverticulum, respectively. These techniques offer durable symptom relief with reduced recovery times. Over the past five years, refinements in technique, advancements in instrumentation, technology, and improved patient selection have expanded indications and enhanced safety. However, challenges remain, including the limited standardization and accessibility to specialized training. This review provides a comprehensive analysis of the evolution, technical refinements, and clinical outcomes of thirdspace endoscopy, with a focus on its expanding role in foregut surgery. By consolidating current evidence and highlighting future directions, we aim to provide a critical perspective on the impact of intramural surgery and its potential to further transform the management of complex gastrointestinal disorders.  \nKey Words: Third-space endoscopy; Cricopharyngeal; Esophageal; Gastric; Zenker  \n WJGE  [https://www.wjgnet.com](https://www.wjgnet.com) 1 December 16, 2025  Volume 17  Issue 12   \nRestrepo-Rodas G et al. Mastering the third space  \n©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.  \nCore Tip: Third-space endoscopy has redefined the management of complex foregut disorders through techniques such as cricopharyngeal, esophageal, gastric, and Zenker’s myotomies. These procedures offer effective, less invasive alternatives to traditional surgery, with growing evidence of durable outcomes. This review ","cbCaiqObZ6tYIlKH","https://ap.wps.com/l/cbCaiqObZ6tYIlKH","pdf",806360,12,"English","# Introduction\n## Concept of the three anatomical spaces for endoscopic procedures\n## Development of third-space endoscopy (TSE) and submucosal tunnel techniques\n## Clinical rationale and early feasibility evidence","[{\"question\":\"What is third-space endoscopy and how does it differ from earlier minimally invasive GI approaches?\",\"answer\":\"Third-space endoscopy (intramural surgery) keeps interventions within the submucosal layer rather than breaching the serosal surface. It builds on natural orifice transluminal endoscopic surgery by using a natural orifice for access while remaining inside the GI wall.\"},{\"question\":\"Which procedures are highlighted as major applications of third-space endoscopy?\",\"answer\":\"The document highlights peroral endoscopic myotomy techniques, including cricopharyngeal, esophageal, gastric, and Zenker’s myotomies. These are linked to management of conditions such as cricopharyngeal bar, achalasia, gastroparesis, and Zenker’s diverticulum.\"},{\"question\":\"What advantages and remaining challenges are described for third-space endoscopy?\",\"answer\":\"The review describes improved precision and potentially reduced morbidity, along with durable symptom relief and reduced recovery times. It also notes ongoing challenges such as limited standardization and restricted accessibility to specialized training.\"}]","Mastering the third space - Innovations in intramural endoscopic surgery for gastrointestinal disorders | PDF",1790565845]