Epigenetics and the Tumor Microenvironment in Neuroendocrine Tumors

Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies arising from neuroendocrine cells and are most commonly localized in the gastroenteropancreatic and pulmonary systems. Overall, most NENs are characterized by a low mutational burden. Consequently, increasing research attention has focused on epigenetic mechanisms and the tumor microenvironment, which may actively contribute to tumor pathogenesis. Moreover, epigenetic modifications represent plausible mediators of communication in the crosstalk between neuroendocrine cancer cells and components of the tumor microenvironment, as observed in other non-neuroendocrine malignancies. Objectives: The aim of this review is to summarize current knowledge on the role of epigenetic regulation and the tumor microenvironment in the pathogenesis of neuroendocrine tumors and to discuss their potential as targets for more effective therapeutic strategies. Methods: We reviewed research articles published over the past decades that investigated the involvement of epigenetic mechanisms and the tumor microenvironment in NENs. Results: Several studies highlight the pivotal role of epigenetic alterations and tumor microenvironment interactions in NEN biology, influencing tumor development, progression, and therapeutic response. Conclusions: Further studies are warranted to deepen understanding in this field, as this may lead to the development of more effective therapies and improved clinical outcomes for patients with neuroendocrine neoplasms.