2. Academic Validation
  3. Fluorination augments tumor engagement and antitumor immunity of a D-peptide-based radiotheranostic agent for combinatorial immune checkpoint blockade therapy

Fluorination augments tumor engagement and antitumor immunity of a D-peptide-based radiotheranostic agent for combinatorial immune checkpoint blockade therapy

  • J Immunother Cancer. 2026 Mar 9;14(3):e013732. doi: 10.1136/jitc-2025-013732.
Siqi Zhang # 1 2,  Can Liu # 1 2,  Qingshuang Lu # 1 2,  Wenhao Liu 1 2,  Jiang Wu 3,  Jianjing Liu 4,  Lina Tong 5,  Kuo Zhao 6,  Qichen Hu 1 2,  Xueyao Chen 1 2,  Linger Li 1 2,  Xuekai Song 1 2,  Feng Wang 7,  Dong Dai 8,  Rui Wang 9,  Kuan Hu 9 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica, Beijing, China.
  • 2 Beijing Key Laboratory of Targeted Radiopharmaceutical Development and Translational Nuclear Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 3 Department of Nuclear Medicine, Nanjing First Hospital, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
  • 5 Department of Nuclear Medicine, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.
  • 6 Department of Daytime Ward, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.
  • 7 Department of Nuclear Medicine, Nanjing First Hospital, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China [email protected] [email protected] [email protected] [email protected].
  • 8 Department of Molecular Imaging and Nuclear Medicine, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China [email protected] [email protected] [email protected] [email protected].
  • 9 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Chinese Academy of Medical Sciences and Peking Union Medical College Institute of Materia Medica, Beijing, China [email protected] [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 41802811 DOI: 10.1136/jitc-2025-013732
Abstract

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.

Keywords

Combination therapy; Radiotherapy/radioimmunotherapy.

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