癌症利用不同的机制来逃避 T 细胞免疫监视，包括检查点配体的过度表达、免疫抑制分子的分泌和异常糖基化。在此，我们报道IFNγ是一种在肿瘤微环境中分泌的有效免疫调节剂，可以在源自各种组织学的癌细胞系中诱导α2,6高度唾液酸化。然后，我们关注 Siglec-9（唾液酸部分的受体），并证明 Siglec-9 T 细胞群表现出效应功能降低。我们推测原代人 T 细胞中的 Siglec-9 可以充当检查点分子，并证明使用 CRISPR/Cas9 系统敲除 Siglec-9 可以增强原代人 T 细胞的功能。最后，我们的目标是利用肿瘤高唾液酸化来增强癌症特异性 T 细胞活性。因此，我们设计了几种基于 Siglec-9 的嵌合开关受体 (CSR)，其中包括源自共刺激分子 (CD28/41BB) 的细胞内部分和不同的铰链区。在抗原特异性背景下，用 Siglec-9 CSR 转导的 T 细胞表现出细胞因子分泌增加和激活标记物上调。此外，配备特定 Siglec-9 CSR 的 T 细胞在人类肿瘤异种移植模型中介导强大的抗肿瘤活性。总体而言，这项工作揭示了唾液酸化残基介导的肿瘤逃避机制，并举例说明了一种改进基于工程 T 细胞的癌症治疗的方法。

Cancer exploits different mechanisms to escape T-cell immunosurveillance, including overexpression of checkpoint ligands, secretion of immunosuppressive molecules, and aberrant glycosylation. Herein, we report that IFNγ, a potent immunomodulator secreted in the tumor microenvironment, can induce α2,6 hypersialylation in cancer cell lines derived from various histologies. We then focused on Siglec-9, a receptor for sialic acid moieties, and demonstrated that the Siglec-9+ T-cell population displayed reduced effector function. We speculated that Siglec-9 in primary human T cells can act as a checkpoint molecule and demonstrated that knocking out Siglec-9 using a CRISPR/Cas9 system enhanced the functionality of primary human T cells. Finally, we aimed to augment cancer-specific T-cell activity by taking advantage of tumor hypersialylation. Thus, we designed several Siglec-9-based chimeric switch receptors (CSRs), which included an intracellular moiety derived from costimulatory molecules (CD28/41BB) and different hinge regions. In an antigen specific context, T cells transduced with Siglec-9 CSRs demonstrated increased cytokine secretions and upregulation of activation markers. Moreover, T cells equipped with specific Siglec-9 CSRs mediated robust antitumor activity in a xenograft model of human tumors. Overall, this work sheds light on tumor evasion mechanisms mediated by sialylated residues and exemplifies an approach to improve engineered T cell-based cancer treatment.