Abstract
Pituitary neuroendocrine tumors (PitNETs) are pathologically characterized by dysregulation of neuroendocrine function and systemic disruption of hormonal homeostasis, yet their regulatory effects on peripheral immune networks remain poorly characterized. Here, we systematically analyzed bulk RNA sequencing (RNA‑seq) from 883 PitNET tumors, 108 PitNET‑associated peripheral blood mononuclear cells (PBMC) samples, and 175 healthy PBMC controls, combined with 69 single‑cell RNA sequencing (scRNA-seq) samples covering tumors, normal pituitaries, as well as tumor‑derived and normal PBMCs. We identified a systemic immune disequilibrium in PitNET patients, characterized by increased circulating lymphocyte proportions, accompanied by upregulated cytokine-receptor interaction signatures. Notably, tumor resection reversed this imbalance, as supported by the normalization of monocyte and neutrophil counts, validated by flow cytometry and routine blood data from 600 samples (200 healthy controls and 200 PitNET patients with paired pre- and post-surgery follow‑up). Trajectory analysis identified terminally differentiated, secretory-specialized cell populations with lineage-specific hormone and cytokine hypersecretion. Ligand-receptor inference suggested these tumor-derived factors potentially engage circulating immune cell receptors. A random‑forest classifier based on PBMC transcriptomes distinguished PitNET subtypes, underscoring the diagnostic potential of peripheral immune signatures. Furthermore, in an estrogen-induced rat model, elevated PRL level coincided with the same peripheral immune skewing. Overall, our work provides a valuable resource and demonstrates PitNETs can be systemic immune modulators, where intrinsic hormone secretory activity and monocyte-lymphocyte imbalance collectively drive peripheral immune dysfunction.