The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

SIMPLE SUMMARY: The tumor microenvironment (TME) plays a role in promoting tumor progression. Elucidating the relationship between the TME and tumor cells will benefit current therapies. Therefore, this review summarizes the most recent relationship between the TME and tumor characteristics, discusses the differences in the TME at various sites along the digestive tract, and compares the TMEs of neuroendocrine tumors and neuroendocrine carcinomas. Microbial ecological changes in the TME were reviewed. The clinical application of the TME was summarized from bench to bedside. The TME can be used as a tumor drug target for diagnostic value, prognosis prediction, and efficacy evaluation, further revealing the potential of immune checkpoints combined with antiangiogenic drugs. The clinical application prospects of adoptive cell therapy and oncolytic viruses were described. The potential therapeutic approaches and strategies for gastrointestinal neuroendocrine neoplasms are considered. ABSTRACT: Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.