Targeting lineage-specific heterogeneity and hypovascular-fibrotic barriers may enable precision immunotherapy in pituitary neuroendocrine tumors.

The clinical management of refractory pituitary neuroendocrine tumors (PitNETs) remains a formidable challenge due to pervasive resistance to traditional therapies. Current therapeutic failures appear closely associated with lineage-specific immune heterogeneity and the unique "hypovascular-fibrotic" physical barrier that hinders drug delivery. This review critically examines the biological determinants of therapeutic resistance in the tumor microenvironment (TME) to propose a comprehensive framework for precision immuno-oncology. We highlight how immune infiltration profiles and checkpoint expressions are strongly influenced by transcriptional lineages across PIT1-, TPIT-, and SF1-lineage tumors. We elucidate the "hypovascular-fibrotic" barrier, where low microvessel density and dense collagen deposition restrict therapeutic penetration. We also evaluate advanced strategies, including spatial multi-omics for precise patient stratification and focused ultrasound (FUS) for enhanced drug delivery. In the end, we outline potential combinatorial strategies integrating vascular normalization and metabolic reprogramming to synergize with immune checkpoint inhibitors. This mechanism-driven paradigm shift from empirical treatment to precision immuno-oncology may provide critical insights and novel therapeutic strategies for intractable PitNETs.