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

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.