{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:06:01Z","timestamp":1790193961330,"version":"4.1.0"},"reference-count":142,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NCI\/NIH Intramural Funding","award":["ZIA BC 011899"],"award-info":[{"award-number":["ZIA BC 011899"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of tumors that arise throughout the gastrointestinal tract. These tumors are heterogeneous, with complex clinical symptoms and tumor behaviors, and demonstrate rising incidence rates worldwide. In addition to their nature, GEP-NETs possess limited diagnostic and therapeutic options, which results in poor survival rates for patients with metastatic tumors. Given these findings, a further analysis of these tumors\u2019 biology is needed to determine new therapeutic strategies. The tumor microenvironment (TME) consists of several residual cell populations and non-cellular components whose altered behavior creates a tumor-supportive niche. Studies from other cancers demonstrate the TME\u2019s significance in tumor initiation, progression, and spread. In this review, we discuss efforts to characterize the TME in GEP-NETs. Preliminary studies of the immune system in GEP-NETs have led to several major clinical trials, with limited success. Efforts to target signaling crosstalk between cancer-associated fibroblasts, vascular endothelial cells, and tumor cells has led to major discoveries and multiple approved therapies. Finally, alterations to the extracellular matrix may lead towards an improved understanding of GEP-NET development, behavior, and improved detection methods. While research has rapidly expanded our knowledge within the last decade, further work is needed to bring our understanding of the GEP-NET TME in line with other rare cancers.<\/jats:p>","DOI":"10.3390\/ijms26125635","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T06:42:48Z","timestamp":1749710568000},"page":"5635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Role of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Tumors"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3512-8796","authenticated-orcid":false,"given":"Srujana V.","family":"Yellapragada","sequence":"first","affiliation":[{"name":"Neuroendocrine Cancer Therapy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4099-6642","authenticated-orcid":false,"given":"Steven D.","family":"Forsythe","sequence":"additional","affiliation":[{"name":"Neuroendocrine Cancer Therapy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-3704","authenticated-orcid":false,"given":"James P.","family":"Madigan","sequence":"additional","affiliation":[{"name":"Neuroendocrine Cancer Therapy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7538-9431","authenticated-orcid":false,"given":"Samira M.","family":"Sadowski","sequence":"additional","affiliation":[{"name":"Neuroendocrine Cancer Therapy Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"name":"Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sultana, Q., Kar, J., Verma, A., Sanghvi, S., Kaka, N., Patel, N., Sethi, Y., Chopra, H., Kamal, M.A., and Greig, N.H. 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