Combination immunotherapy targeting LAG-3, PD-1 and STING suppresses hepatocellular carcinoma as monitored by LAG-3 targeted PET imaging

作者：Zhen Quan, Yu Gao, Bo Sun, Yiwan Guo, Ziwei Jin, Na Hao, Dawei Jiang, Chuansheng Zheng, Xin Li, Quan Chen · 发表于：Biomarker Research · 年份：2025 · DOI：10.1186/s40364-025-00820-z · 被引用次数：11 · 研究领域：Cancer Immunotherapy and Biomarkers、interferon and immune responses、Hepatocellular Carcinoma Treatment and Prognosis

Abstract Background The low response rate of anti-PD-1 monoclonal antibodies (mAbs) in hepatocellular carcinoma (HCC) requires the development of combination immunotherapy strategies to improve their efficacy. This study aimed to use LAG-3-targeted PET imaging to monitor the efficacy of anti-PD-1 mAb, a stimulator of interferon genes (STING) agonist, and anti-LAG-3 mAb, both individually and in combination. Furthermore, we evaluated the potential of a triple immunotherapy regimen (anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb) to improve HCC treatment. Methods The LAG-3 inhibitor C25 based on a cyclic peptide was chelated with NOTA, radiolabeled with [ 68 Ga]GaCl 3 . The resulting [ 68 Ga]Ga-NOTA-C25 underwent in vivo PET imaging and ex vivo biodistribution examination in Hepa1-6 tumor-bearing mice. [ 68 Ga]Ga-NOTA-C25 PET was used to monitor the efficacy of monotherapy and dual immunotherapy with anti-PD-1 monoclonal antibody (mAb) and STING agonists. The tumor uptake of [ 68 Ga]Ga-NOTA-C25, tumor response, and survival rates were measured following different treatments. The therapeutic efficacy, molecular mechanisms, and safety of triple immunotherapy were validated using histopathological analysis and flow cytometry. Results [ 68 Ga]Ga-NOTA-C25 PET imaging effectively and noninvasively detected LAG-3 + tumor-infiltrating lymphocytes (TILs) in Hepa1-6 tumor-bearing mice. In mice treated with anti-PD-1 mAb, STING agonist, or a combination immunotherapy, [ 68 Ga]Ga-NOTA-C2...