BackgroundRadioimmunotherapy with cetuximab and conjugates with various radioisotopes is a feasible treatment option for different tumor models. Scandium-47 (47Sc), one of several β−-particle-emitting radioisotopes, displays favorable physical and chemical properties for conjugation to monoclonal antibodies. However, the therapeutic efficacy of47Sc in preclinical and clinical studies is largely unknown. Given that intrinsic alterations in tumors greatly contribute to resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy, research on overcoming resistance to radioimmunotherapy using cetuximab is required.Methods47Sc was produced by irradiation of a CaCO3target at the HANARO research reactor in KAERI (Korea Atomic Energy Research Institute) and prepared by chromatographic separation of the irradiated target. Cetuximab was conjugated with47Sc using the bifunctional chelating agent DTPA. Radiochemical purity was determined using instant thin-layer chromatography. The immunoreactivity of47Sc-DTPA-cetuximab was evaluated using the Lindmo method and an in vitro cell-binding assay. The inhibitory effects of cetuximab and47Sc-DTPA-cetuximab were confirmed using cell growth inhibition and BrdU cell proliferation assays. Differences in protein expression levels between cetuximab- and47Sc-DTPA-cetuximab-treated cells were confirmed using western blotting. Complex formation between RUNX3 and DNA repair components was confirmed using immunoprecipitation and western blotting.ResultsCetuximab induces cell cycle arrest and cell death in EGFR-overexpressing NSCLC cells. Radiolabeling of cetuximab with47Sc led to increased therapeutic efficacy relative to cetuximab alone. Application of47Sc-DTPA-cetuximab induced DNA damage responses, and activation of RUNX3 significantly enhanced the therapeutic efficacy of47Sc-DTPA-cetuximab. RUNX3 mediated susceptibility to EGFR-targeted NSCLC therapy using47Sc-DTPA-cetuximab via interaction with components of the DNA damage and repair machinery.Conclusions47Sc-DTPA-cetuximab promoted cell death in EGFR-overexpressing NSCLC cells by targeting EGFR and inducing DNA damage as a result of β irradiation emitted from the conjugated47Sc. Activation of RUNX3 played a key role in DNA damage and repair processes in response to the ionizing radiation and inhibited cell growth, thus leading to more effective tumor suppression. RUNX3 can potentially moderate susceptibility to47Sc-conjugated cetuximab by modulating DNA damage and repair process mechanisms.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-023-11161-1.