Siglecs play a key role in mediating cell–cell interactions via the recognition of different sialylated glycoconjugates, including tumor-associated MUC1, which can lead to the activation or inhibition of the immune response. The activation occurs through the signaling of Siglecs with the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins, while the inhibition signal is a result of the interaction of intracellular immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing receptors. The interaction of tumor-associated MUC1 sialylated glycans with Siglecs via ITIM motifs decreases antitumor immunity. Consequently, these interactions are expected to play a key role in tumor evasion. Efforts to modulate the response of immune cells by blocking the immune-suppressive effects of inhibitory Siglecs, driving immune-activating Siglecs, and/or altering the synthesis and expression of the sialic acid glycocalyx are new therapeutic strategies deserving further investigation. We will highlight the role of Siglec’s family receptors in immune evasion through interactions with glycan ligands in their natural context, presented on the protein such as MUC1, factors affecting their fine binding specificities, such as the role of multivalency either at the ligand or receptor side, their spatial organization, and finally the current and future therapeutic interventions targeting the Siglec–sialylated MUC1 immune axis in cancer.
Siglecs通过识别不同的唾液酸化糖缀合物（包括肿瘤相关MUC1）在介导细胞间相互作用中发挥关键作用，这一过程可导致免疫反应的激活或抑制。激活作用通过含有胞质免疫受体酪氨酸激活基序（ITAM）的Siglecs信号传导实现，而抑制信号则源于携带细胞内免疫受体酪氨酸抑制基序（ITIM）受体的相互作用。肿瘤相关MUC1唾液酸化聚糖通过ITIM基序与Siglecs相互作用会降低抗肿瘤免疫力，因此这些相互作用预计在肿瘤免疫逃逸中起关键作用。通过阻断抑制性Siglecs的免疫抑制效应、驱动免疫激活型Siglecs和/或改变唾液酸糖萼的合成与表达来调节免疫细胞反应，是值得深入探索的新型治疗策略。本文将重点阐述Siglec家族受体在天然环境中通过与糖蛋白配体（如MUC1）相互作用介导免疫逃逸的作用机制，探讨影响其精细结合特异性的因素（包括配体或受体侧的多价性作用、空间构象等），并综述当前及未来针对癌症中Siglec-唾液酸化MUC1免疫轴的治疗干预策略。
肿瘤(癌症)患者之家