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Purpose: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225Ac or 131I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB). Methods: We studied the biodistribution and tumour uptake of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [225Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [225Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB. Results: The biodistribution showed high tumour uptake of [131I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [225Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [131I]I-GMIB-4AH29 or [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [225Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy. Conclusion: [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [225Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy. [ABSTRACT FROM AUTHOR]