当前基于抗体的免疫检查点阻断（ICB）疗法的低反应和适应性耐药的百分比需要开发新的免疫治疗策略。在这里，我们开发了一种针对唾液酸结合免疫球蛋白样凝集素-15（Sigelc-15）的适体辅助免疫检查点阻断（Ap-ICB），Sigelc-15是一种新型免疫抑制剂，在癌细胞/肿瘤浸润性骨髓细胞上广泛上调，并且相互排斥程序性细胞死亡配体 1 (PD-L1)。通过蛋白质适体选择，我们鉴定了对 Sigelc-15 蛋白质/Sigelc-15 阳性细胞具有高亲和力的 WXY3 适体。我们证明 WXY3 适体在体外和体内挽救了抗原特异性 T 细胞反应。重要的是，针对 Siglec-15 的 WXY3 Ap-ICB 增强了肿瘤微环境中的抗肿瘤免疫力，并抑制了同基因小鼠模型中的肿瘤生长/转移，这可能是由于巨噬细胞和 T 细胞功能增强的结果。此外，通过使用基于适配体的球形核酸，我们开发了多价结合和空间位阻协同的ICB策略，进一步提高了体内抗肿瘤效果。总而言之，我们的结果支持 Ap-ICB 靶向 Siglec-15 作为癌症免疫治疗正常化的潜在策略。© 2023 Wiley-VCH GmbH。

The percentage of low response and adaptive resistance to current antibody-based immune checkpoint blockade (ICB) therapy requires the development of novel immunotherapy strategies. Here, we developed an aptamer-assisted immune checkpoint blockade (Ap-ICB) against sialic acid-binding immunoglobulin-like lectin-15 (Sigelc-15), a novel immune suppressor broadly upregulated on cancer cells/tumor infiltrating myeloid cells and mutually exclusive of programmed cell death ligand 1 (PD-L1). Using protein aptamer selection, we identified WXY3 aptamer with high affinity against Sigelc-15 protein/Sigelc-15 positive cells. We demonstrated that WXY3 aptamer rescued antigen-specific T cell responses in vitro and in vivo. Importantly, the WXY3 Ap-ICB against Siglec-15 amplified anti-tumor immunity in the tumor microenvironment and inhibited tumor growth/metastasis in syngeneic mouse model, which may result from enhanced macrophage and T cell functionality. In addition, by using aptamer-based spherical nucleic acids, we developed a synergetic ICB strategy of multivalent binding and steric hindrance, which further improves the in vivo anti-tumor effect. Taken together, our results support Ap-ICB targeted Siglec-15 as a potential strategy for normalization cancer immunotherapy.© 2023 Wiley-VCH GmbH.