Immune atlas of pituitary neuroendocrine tumors highlights endocrine-driven immune signature and therapeutic implication.

Whether the tumor microenvironment is shaped by endocrine hormone secretion, as well as its cellular heterogeneity and therapeutic implications in pituitary neuroendocrine tumors (pitNETs), remains poorly understood. We demonstrate that pitNETs exhibit a sparse immune infiltration. Mass cytometry of 97,418 immune cells from 56 pitNETs establishes a high-resolution atlas, with macrophages and T cells comprising the predominant populations. Hormone secretion status dictates the immune composition and cellular phenotype. Functioning pitNETs are enriched with T cells, with robust expression of immune-suppressive markers CD38, programmed death (PD)-1, and PD-L1. The lymphoid-enriched microenvironment is associated with shorter progression-free survival in patients with pitNETs. Integrating PD-1 blockade with tumor-targeted therapy in functioning pitNETs demonstrates synergistic efficacy with enhanced apoptosis, induces cell-cycle arrest, and suppresses hormone secretion using patient-derived primary cell cultures. Altogether, our findings provide an extended resource on the cellular and functional heterogeneity of the pitNET immune microenvironment and offer a conceptual framework for rational therapeutic strategies.