Development of PD-L1 Targeting Small-Molecule Immunotheranostic Agents for Personalized Antitumor Immunotherapy

  • J Med Chem. 2026 Feb 26;69(4):4602-4612. doi: 10.1021/acs.jmedchem.5c03238.
Gaochao Lv  1  2 ,  Junyi Zhu  1  2 ,  Nan Zhang  1  2 ,  Rui Tang  1  2 ,  Huan Peng  1 ,  Ying Peng  1 ,  Xin Hu  1  2 ,  Ling Qiu  1  2 ,  Jianguo Lin  1  2
Affiliations
  • 1. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China.
  • 2. Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
PMID: 41678291 DOI: 10.1021/acs.jmedchem.5c03238
Abstract

Immune checkpoint blockade targeting PD-1/PD-L1 has transformed Cancer treatment but faces challenges such as low response rates and a lack of reliable biomarkers. To address these issues, we developed a novel small-molecule immunotheranostic agent, [18F]LG-8, and its therapeutic counterpart LG-8, which share identical structures to ensure consistent biodistribution. [18F]LG-8 PET specifically quantified PD-L1 in murine melanoma (B16-F10) and lung carcinoma (LLC) models. LG-8 exhibited potent antitumor efficacy in B16-F10 tumors with high PD-L1 uptake but not in LLC models with low PD-L1 expression, confirming the predictive value of the diagnostic scan. Furthermore, we implemented an individualized chemo-immunotherapy strategy guided by [18F]LG-8 PET imaging, where cisplatin pretreatment enhanced PD-L1 expression in a subset of LLC tumors, enabling effective LG-8 treatment only in mice with elevated PD-L1 levels. This theranostic approach integrates precise diagnosis and immunotherapy within a unified molecular platform, significantly improving response prediction and advancing personalized Cancer Immunotherapy.

Products