Advances in Somatostatin Receptor-Targeting Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors: Biological Rationale, Combination Strategies, and Clinical Perspectives

Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are the most common subtype of NETs, and their incidence continues to increase worldwide. Many NETs express somatostatin receptors (SSTRs), enabling molecular imaging and treatment with radiolabeled somatostatin analogs (SSTAs). [177Lu]Lu-DOTATATE is an established treatment for advanced SSTR-positive NETs, but complete and durable responses remain uncommon. This review summarizes current clinical experience with [177Lu]Lu-DOTATATE and emerging SSTR-targeting radiopharmaceuticals and examines strategies to improve PRRT efficacy. Treatment may be enhanced at several interconnected steps, including increasing receptor availability and tumor targeting, improving radiopharmaceutical uptake and absorbed dose, preventing repair of radiation-induced damage, suppressing cellular stress adaptation and survival, and promoting tumor cell elimination. These approaches include radiation priming and fractionation, somatostatin analog pretreatment, epigenetic modifiers, inhibitors of DNA repair and cellular survival pathways, immunotherapy, and chemotherapy-based combinations. PARP, DNA-PK, and HSP90 inhibitors and chemotherapy-based combinations have shown particularly strong preclinical or clinical evidence, whereas mTOR inhibitors, tyrosine kinase inhibitors, Hedgehog inhibitors, immunotherapy, NAMPT inhibitors, p53 stabilization, and epigenetic modifiers remain under investigation. Ongoing development of novel radiopharmaceuticals, personalized dosimetry, retreatment strategies, and rational combinations is expected to refine PRRT and improve outcomes for patients with NETs.