Abstract
<jats:p>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. Two complementary approaches are emphasized: increasing tumor uptake through modulation of SSTR expression and enhancing radiation response through radiosensitization. SSTR upregulation has been investigated using radiation priming, somatostatin analog pretreatment, epigenetic modifiers, and selected pharmacological agents. Radiosensitization strategies include inhibition of DNA repair, cellular stress-response and oncogenic signaling pathways, tumor metabolism, and immune checkpoint signaling. 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, 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.</jats:p>