Immune checkpoint blockade (ICB) has achieved groundbreaking results in clinical cancer therapy; however, only a subset of patients experience durable benefits. The aim of this study was to explore strategies for predicting tumor responses to optimize the intervention approach using ICB therapy. Methods: We used a bilateral mouse model for proteomics analysis to identify new imaging biomarkers for tumor responses to ICB therapy. A PET radiotracer was synthesized by radiolabeling the identified biomarker-targeting antibody with ¹²⁴I. The radiotracer was then tested for PET prediction of tumor responses to ICB therapy. Results: We identified galectin-1 (Gal-1), a member of the carbohydrate-binding lectin family, as a potential negative biomarker for ICB efficacy. We established that Gal-1 inhibition promotes a sensitive immune phenotype within the tumor microenvironment (TME) for ICB therapy. To assess the pre-ICB treatment status of the TME, a Gal-1–targeted PET radiotracer, ¹²⁴I-αGal-1, was developed. PET imaging with ¹²⁴I-αGal-1 showed the pretreatment immunosuppressive status of the TME before the initiation of therapy, thus enabling the prediction of ICB resistance in advance. Moreover, the use of hydrogel scaffolds loaded with a Gal-1 inhibitor, thiodigalactoside, demonstrated that a single dose of thiodigalactoside–hydrogel significantly potentiated ICB and adoptive cell transfer immunotherapies by remodeling the immunosuppressive TME. Conclusion: Our study underscores the potential of Gal-1–targeted PET imaging as a valuable strategy for early-stage monitoring of tumor responses to ICB therapy. Additionally, Gal-1 inhibition effectively counteracts the immunosuppressive TME, resulting in enhanced immunotherapy efficacy.

免疫检查点阻断（ICB）在临床癌症治疗中取得突破性成果；然而，只有一小部分患者能够获得持久的益处。本研究的目的是探索预测肿瘤反应的策略，以优化 ICB 治疗的干预方法。方法：我们使用双边小鼠模型进行蛋白质组学分析，以确定肿瘤对 ICB 治疗反应的新成像生物标志物。通过用¹²⁴ I对已识别的生物标志物靶向抗体进行放射性标记来合成 PET 放射性示踪剂。然后测试放射性示踪剂以进行 PET 预测肿瘤对 ICB 治疗的反应。结果：我们确定半乳糖凝集素-1 (Gal-1)（碳水化合物结合凝集素家族的成员）是 ICB 功效的潜在阴性生物标志物。我们确定 Gal-1 抑制可促进 ICB 治疗的肿瘤微环境 (TME) 内的敏感免疫表型。为了评估 TME 的 ICB 治疗前状态，开发了一种 Gal-1 靶向 PET 放射性示踪剂^{124 I-αGal-1。 124} I-αGal-1 PET 成像显示治疗开始前 TME 的治疗前免疫抑制状态，从而能够提前预测 ICB 耐药。此外，使用装载 Gal-1 抑制剂硫双半乳糖苷的水凝胶支架表明，单剂量的硫双半乳糖苷水凝胶通过重塑免疫抑制性 TME 显着增强了 ICB 和过继性细胞转移免疫疗法。结论：我们的研究强调了 Gal-1 靶向 PET 成像作为早期监测肿瘤对 ICB 治疗反应的有价值策略的潜力。此外，Gal-1 抑制可有效抵消免疫抑制 TME，从而增强免疫治疗效果。