**1. Introduction**

Pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors that arise from the pituitary gland [1]. In recent years, the development of transnasal endoscopic surgery has improved the surgical outcomes in patients with PitNETs. However, PitNETs often invade into the surrounding cavernous sinus (CS), making them difficult to remove entirely. Although radiation therapy including gamma knife is performed for residual tumors [2], it is onerous to protect essential structures including the optic nerve and internal carotid artery around the sella turcica.

The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is a potent activator of angiogenesis that is known to correlate with disease progression and hemorrhage in PitNETs [3,4]. The difference in the status of VEGF/VEGFR signaling remains controversial. Niveiro et al. [3] demonstrated that the lowest protein level of VEGF-A was detected in prolactin-secreting PitNETs and the highest levels were detected in non-functional PitNETs (NF-PitNETs). In contrast, Cristina et al. [4] demonstrated that higher expressions of VEGF-A and VEGFR1 were observed in prolactin-secreting PitNETs than in NF-PitNETs.

Recently, the significance of the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint system in various types of tumors has received attention [5,6]. Anti-PD-1 and PD-L1 antibodies exerted a highly potent effect in the inhibition of tumor growth in melanoma, non-small lung cancer, and kidney cancer [7,8]. Among immune cell types of note, M2 macrophages produce growth factors and anti-inflammatory cytokines to suppress the host immune response [9–11]. Tumor-associated macrophages (TAMs) typically behave as M2 macrophages in the tumor immune microenvironment to induce immunosuppression [12–14]. Regulatory T cells (Tregs) also exert immunosuppression, resulting in the failure of cancer immunotherapy [15,16]. High Foxp3(+) Tregs infiltration was significantly associated with shorter overall survival in most patients with solid tumors including melanomas and cervical, renal, and breast cancers [17]. VEGF-A plays a pivotal role in the development of these immunosuppressive microenvironments by inhibiting the maturation of dendritic cells and stimulating the proliferation of Tregs [18,19]. However, these immunosuppressive microenvironments have not been fully elucidated in PitNETs.

In the present study, VEGF-A/VEGFRs expressions, the tumor immune microenvironment, and their cross interaction were evaluated, leading to the development of novel treatment strategies for patients with NF-PitNETs.
