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<p>Granzyme B is a serine protease primarily secreted by cytotoxic T lymphocytes (CTLs), serving as an important immune-related biomarker. Quantifying the expression level of granzyme B in tumors by positron emission tomography (PET) is an ideal strategy for evaluating the tumor-killing effect of CTLs and monitoring immunotherapy response. In this study, two granzyme B responsive self-assembly PET tracers [<sup>68</sup>Ga]CA-M-IEFD and [<sup>68</sup>Ga]CA-H-IEPD were designed utilizing the CBT-Cys bioorthogonal click reaction. Both tracers exhibit high radiochemical purity and favorable stability. <i>In vitro</i> cellular uptake assays confirmed the granzyme B-specific targeting of the tracers, showing significantly higher uptake in MC38 cells co-cultured with activated-T lymphocytes producing granzyme B compared with MC38 cells cultured alone. <i>In vivo</i> PET imaging indicated that the tumor uptake of the tracers in MC38 tumor-bearing mice treated with immune drugs <i>S</i>-(2-boronoethyl)-<i>L</i>-cysteine hydrochloride (BEC) or PD-L1 blocker (LG-12) was markedly increased. Western blotting and immunofluorescence staining assays further validated that the increased uptake of the tracers in tumors was associated with immune activation and upregulated granzyme B expression triggered by immunotherapy. Moreover, we confirmed that the tracer can visualize immune activation in diverse tumor models, showing its broad applicability. This study aims to develop a granzyme B-targeted tracer for real-time detection of granzyme B activity, offering a potential tool for the surveillance of tumor immune activation.</p>

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Granzyme B-responsive self-assembled positron emission tomography tracers for monitoring tumor immune activation

  • 期刊论文

  • 发表日期：

    2026年6月24日

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  • Jichen Yang,
  • Rui Tang,
  • Miao Sun,
  • Xinru Li,
  • Ying Peng,
  • Ke Li,
  • Huijie Jiang,
  • Ling Qiu,
  • Jianguo Lin

摘要

Granzyme B is a serine protease primarily secreted by cytotoxic T lymphocytes (CTLs), serving as an important immune-related biomarker. Quantifying the expression level of granzyme B in tumors by positron emission tomography (PET) is an ideal strategy for evaluating the tumor-killing effect of CTLs and monitoring immunotherapy response. In this study, two granzyme B responsive self-assembly PET tracers [68Ga]CA-M-IEFD and [68Ga]CA-H-IEPD were designed utilizing the CBT-Cys bioorthogonal click reaction. Both tracers exhibit high radiochemical purity and favorable stability. In vitro cellular uptake assays confirmed the granzyme B-specific targeting of the tracers, showing significantly higher uptake in MC38 cells co-cultured with activated-T lymphocytes producing granzyme B compared with MC38 cells cultured alone. In vivo PET imaging indicated that the tumor uptake of the tracers in MC38 tumor-bearing mice treated with immune drugs S-(2-boronoethyl)-L-cysteine hydrochloride (BEC) or PD-L1 blocker (LG-12) was markedly increased. Western blotting and immunofluorescence staining assays further validated that the increased uptake of the tracers in tumors was associated with immune activation and upregulated granzyme B expression triggered by immunotherapy. Moreover, we confirmed that the tracer can visualize immune activation in diverse tumor models, showing its broad applicability. This study aims to develop a granzyme B-targeted tracer for real-time detection of granzyme B activity, offering a potential tool for the surveillance of tumor immune activation.