# Epigenetics and the Tumor Microenvironment in Neuroendocrine Tumors

## TL;DR

This review explores how epigenetic changes and the tumor environment contribute to neuroendocrine tumors and treatment resistance.

## Contribution

The paper provides a comprehensive review of epigenetic mechanisms and tumor microenvironment interactions in neuroendocrine tumors.

## Key findings

- Epigenetic modifications play a key role in neuroendocrine tumor pathogenesis and therapy resistance.
- Tumor microenvironment interactions influence tumor development and treatment response.
- Further research is needed to develop more effective therapies for neuroendocrine neoplasms.

## Abstract

The incidence of neuroendocrine neoplasms is increasing over the years, and therapy effectiveness is still relatively limited by the development of resistance mechanisms. Given the low rate mutation of these neoplasia, there is evidence of an emerging role of epigenetic modifications in neuroendocrine tumor pathogenesis and therapy resistance, leading to a need to investigate more deeply how these mechanisms are altered in these tumor types, how they can affect therapeutic efficacy, and if they can mediate the crosstalk between tumor cells, tumor microenvironment components, and tumor-stroma crosstalk that support tumoral development and progression. In this review we aim to describe all the recent evidence involving epigenetic mechanisms and the tumor microenvironment components that support tumor onset, development and resistance to treatment in the context of neuroendocrine neoplasm. The goal is to highlight potential new path to improve treatment response and outcomes in patients affected by neuroendocrine neoplasms.

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.