CuET Radiosensitizes FAP-Targeted Radioligand Therapy in Lung Cancer by inhibiting DNA Repair

Background The efficacy of fibroblast activation protein (FAP)-targeted radionuclide ligand therapy (RLT) is often limited by the activation of DNA damage repair pathways in tumor cells. This study explores whether bis-(diethyldithiocarbamate)-copper (CuET, a NPL4 inhibitor and also a DNA repair inhibitor) enhances FAP-targeted RLT efficacy. Results While both [ ¹⁷⁷ Lu]Lu-FAP-2286 and CuET monotherapies significantly inhibited tumor growth and prolonged survival compared to vehicle (P < 0.05), their efficacy was limited. Notably, [ ¹⁷⁷ Lu]Lu-FAP-2286 monotherapy markedly upregulated NPL4 expression in tumors. The full-dose combination therapy resulted in profound tumor regression (-65.1% volume change), significantly outperforming monotherapy at day 13 (P < 0.05). This translated into a striking survival benefit, with a 77.8% survival rate at 50 days post-treatment versus 0% for monotherapy (P < 0.001). Mechanistically, the combination led to a significant increase in DNA damage, elevated apoptosis and autophagy, and suppressed proliferation (P < 0.05). Critically, the half-dose combination achieved short-term tumor control superior to full-dose monotherapy and yielded a comparable median survival (41.3 vs. 38.7 days, P = 0.41), demonstrating a significant radiosensitizing effect. Conclusion CuET acts as a potent radiosensitizer for [ ¹⁷⁷ Lu]Lu-FAP-2286 by exacerbating DNA damage and exploiting therapy-induced NPL4 upregulation. This dual-mechanism combination presents a promising strategy to enhance the efficacy of FAP-targeted RLT, with the potential for dose reduction to mitigate toxicity.