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Background Programmed death-ligand 1 (PD-L1)-targeted radiopharmaceutical therapy (RPT) combined with immune checkpoint blockade (ICB) represents a promising combinatorial treatment because of the “magic” bystander and abscopal effects of RPT. However, the overall efficacy of this combinatorial approach is often constrained by limited tumor retention and insufficient accumulation of existing radiopharmaceuticals. D-peptides, with their superior metabolic stability, offer a promising modality to overcome these limitations. We previously reported [ 68Ga]/[64Cu]DPA, which exhibited favorable in vivo stability. Nevertheless, its inadequate tumor retention hampers therapeutic efficacy and immune activation, highlighting the need for further optimization to achieve sustained target engagement.Methods Herein, fluorine modification-directed rational design was used to optimize DPA’s target engagement and retention, thereby boosting its immune-activating potential in RPT. Following two rounds of screening, a series of fluorinated D-peptides was synthesized. Their in vivo performance was assessed by positron emission tomography (PET)/CT imaging in tumor-bearing mice and subsequently in patients with cancer. The therapeutic efficacy of the corresponding 177Lu-labeled fluorinated radiopharmaceuticals was further investigated to verify their potential in enhancing antitumor immunity.Results [ 68Ga]D3-6, which incorporates a pentafluorinated phenylalanine residue, exhibited optimal tumor uptake and prolonged retention, achieving 22.43±1.63%ID/g at 4 hours post-injection. A preliminary clinical study further validated its diagnostic efficacy across multiple cancers. Additionally, [177Lu]D3-6 boosted both local and systemic antitumor immunity and, in combination with anti-programmed cell death protein-1 therapy, elicited superior tumor inhibition.Conclusion This study highlights the potential of fluorinated D-peptide radiopharmaceuticals as powerful PD-L1 targeting radiotheranostics, enabling more effective systemic antitumor efficacy in RPT and ICB combination therapy.