Autophagy in Pituitary Neuroendocrine Tumors (PitNETs): Molecular Mechanisms, Secretory Homeostasis, Therapeutic Resistance, and Translational Perspectives

Abstract

Pituitary neuroendocrine tumors (PitNETs) are usually indolent but may show invasive growth, recurrence, hormonal hypersecretion, and treatment resistance. Autophagy intersects with nutrient sensing, lysosomal homeostasis, mitochondrial quality control, and secretory-granule turnover, but its biological effects in PitNETs are context-dependent. This narrative review synthesizes PitNET-specific and mechanistically relevant evidence on macroautophagy, mitophagy, crinophagy, non-coding RNA and epigenetic regulation, treatment resistance, and pharmacological modulation, emphasizing the distinction between static autophagy markers and dynamic autophagic flux. Evidence is interpreted across human tissue, primary human cells, pituitary tumor cell lines, animal models, and clinical observations, while preserving clear separation between human observations and mechanistic evidence derived from experimental models. Across experimental systems, autophagy activation is associated with antitumor effects in selected settings, whereas completed basal flux may support stress adaptation and late-stage or selective-autophagy inhibition may enhance cytotoxicity. Biological outcome therefore depends on tumor lineage, treatment, the pathway stage affected, and whether flux is completed. Recent studies extend this framework to selective mitophagy, ncRNA/exosomal resistance networks, epitranscriptomic regulation, somatostatin-analogue resistance, and tumor-microenvironmental signaling. Clinical translation remains limited, and no autophagy-modulating strategy is validated for routine PitNET management. Future studies should integrate dynamic flux measurements, lineage-specific biomarkers, pharmacodynamic target engagement, and prospective clinical endpoints.