Epigenetic Dysregulation of Somatostatin Receptors (SSTR) 1-5 and Therapeutic Implications in Neuroendocrine and Non-Neuroendocrine Malignancies.

Somatostatin receptors (SSTR) mediate the antiproliferative, antisecretory, and proapoptotic effects of somatostatin and its synthetic analogs. Their surface expression on neuroendocrine tumor (NET) cells is required for somatostatin analog therapy and radiopharmaceutical therapy (RPT). However, 20%-30% of gastroenteropancreatic NETs and most poorly differentiated neuroendocrine carcinomas show insufficient SSTR expression, limiting therapeutic eligibility. Accumulating evidence indicates that reversible epigenetic mechanisms contribute substantially to SSTR loss, alongside tumor dedifferentiation, lineage-state changes, and clonal evolution with DNA hypermethylation of the SSTR2 promoter representing a central event, complemented by chromatin remodeling and non-coding RNA-mediated regulation. Preclinical studies demonstrate that epigenetic therapies, including DNA methyltransferase and histone deacetylase inhibitors, can restore functional SSTR expression. Notably, the first-in-human LANTana trial provides clinical proof-of-concept that epigenetic priming with oral decitabine/cedazuridine can induce SSTR2 re-expression and enable subsequent RPT in receptor-negative tumors. This review synthesizes current knowledge of epigenetic regulation across all five SSTR subtypes (SSTR1-SSTR5), examines receptor silencing in neuroendocrine and non-neuroendocrine malignancies, and critically evaluates the preclinical and clinical evidence supporting therapeutic strategies that target these mechanisms.