Role of Tumor Microenvironment in Pituitary Neuroendocrine Tumors: New Approaches in Classification, Diagnosis and Therapy

Simple Summary Pituitary adenomas are highly prevalent intracranial neoplasms that can be locally invasive in up to half of cases. Consequently, using the term "PitNETs" (pituitary neuroendocrine tumors) instead of pituitary adenoma is recommended to highlight their potential aggressiveness. This review aims to present the latest research on PitNETs based on transcriptomic findings and discuss the microenvironment involved in their development and progression. A better understanding of the role of various molecules and non-tumoral cells in PitNET pathogenesis will result in improved diagnosis, monitoring, and treatment of these entities.Abstract Adenohypophysal pituitary tumors account for 10-15% of all intracranial tumors, and 25-55% display signs of invasiveness. Nevertheless, oncology still relies on histopathological examination to establish the diagnosis. Considering that the classification of pituitary tumors has changed significantly in recent years, we discuss the definition of aggressive and invasive tumors and the latest molecular criteria used for classifying these entities. The pituitary tumor microenvironment (TME) is essential for neoplastic development and progression. This review aims to reveal the impact of TME characteristics on stratifying these tumors in view of finding appropriate therapeutic approaches. The role of the pituitary tumor microenvironment and its main components, non-tumoral cells and soluble factors, has been addressed. The variable display of different immune cell types, tumor-associated fibroblasts, and folliculostellate cells is discussed in relation to tumor development and aggressiveness. The molecules secreted by both tumoral and non-tumoral cells, such as VEGF, FGF, EGF, IL6, TNF alpha, and immune checkpoint molecules, contribute to the crosstalk between the tumor and its microenvironment. They could be considered potential biomarkers for diagnosis and the invasiveness of these tumors, together with emerging non-coding RNA molecules. Therefore, assessing this complex network associated with pituitary neuroendocrine tumors could bring a new era in diagnosing and treating this pathology.