Combination therapy strategies in engineered 177Lu radiopharmaceuticals beyond single modality: design principles and application outlet.

177Lu has attracted substantial attention in recent years as a medical radionuclide. It emits both β-particles (maximum energy 0.497 MeV) and γ-rays (113/208 keV), which provides unique advantages for theranostic applications in oncology. Since the U.S. Food and Drug Administration (FDA) approved [177Lu]Lu-DOTA-TATE in 2018, 177Lu-based radiopharmaceuticals have demonstrated significant clinical value in the targeted treatment of neuroendocrine tumors (NETs) and prostate cancer. However, monotherapy still faces major challenges, including tumor heterogeneity, drug resistance, and dose-related toxicity. These limitations hinder the full therapeutic potential of 177Lu radiopharmaceuticals. Combination therapy has therefore emerged as a promising strategy to address these obstacles. This review provides a systematic overview of the preparation techniques, clinical efficacy, and combination therapy approaches involving 177Lu radiopharmaceuticals, with the aim of offering a theoretical foundation and practical guidance for optimizing therapeutic paradigms.