Radionuclide‑drug conjugates in lung cancer: advances in precision therapy and clinical translation

Lung cancer is the leading cause of cancer‑related mortality worldwide. Current therapies continue to face challenges such as drug resistance and tumour heterogeneity. Radionuclide‑drug conjugates (RDCs) represent an emerging theranostic platform designed to precisely irradiate tumours. This review aims to systematically outline the landscape of advances in RDCs for lung cancer, and provides a forward‑looking perspective on next‑generation RDCs.

This analysis was based on preclinical and clinical data retrieved from PubMed and ClinicalTrials.gov, with all records reviewed up to January 2026. Studies were exhaustively surveyed across most radionuclides relevant to RDCs in lung cancer, following the periodic table to ensure comprehensive coverage.

In lung cancer, a total of 66 RDCs have been screened, with 30 having entered early‑phase clinical trials. Among completed trials, RDCs underwent a transition from initial ¹³¹I/⁹⁰Y‑labelled antibodies toward ¹⁷⁷Lu‑labelled somatostatin receptor (SSTR)‑targeting peptides. SSTR remains the dominant target, with a notable shift from agonists to antagonists. Meanwhile, fibroblast activation protein (FAP), epidermal growth factor receptor (EGFR), and programmed death‑ligand 1 (PD‑L1) are receiving growing attention. Peptides and antibodies are equally employed, with bispecific antibodies (bsAbs), single‑domain antibodies (sdAbs), and cyclic peptides advancing rapidly. Furthermore, nanoparticles (NPs) offer versatile platforms, and pretargeting or dual‑targeting strategies are being developed to improve both efficacy and safety. Crown chelators and bipyridine derivatives provide more stable chelating options. Although ¹⁷⁷Lu remains the mainstay, α emitters and emerging mixed‑decay radionuclides like ¹⁶¹Tb are gaining ground. Combination therapies are also being investigated to enable first‑line application.

Despite recent progress in RDC development, challenges such as off‑target toxicity, radiation resistance, and radionuclide production remain. Next‑generation RDCs hold promise to overcome these barriers by novel radionuclides, personalised dosimetry, multifunctional delivery platforms, and multidrug combination strategies. Collectively, these innovations will propel RDCs into a personalised, precision theranostic platform for lung cancer.