SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-β1 promotes abnormal glycosylation of SEMA7A via induction of epithelial–mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8⁺ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

SEMA7A 属于信号蛋白家族，参与肿瘤发生和肿瘤进展。异常的糖基化与免疫逃逸和肿瘤生长有着复杂的联系。 SEMA7A 是一种高度糖基化的蛋白质，具有五个糖基化位点。 SEMA7A 糖基化的潜在机制及其对免疫抑制和肿瘤发生的贡献尚不清楚。在这里，我们鉴定了头颈鳞状细胞癌中 SEMA7A 的过度表达和异常 N-糖基化，并阐明岩藻糖基转移酶 FUT8 通过 a直接的蛋白质-蛋白质相互作用。 SEMA7A 的糖基化状态对于其从细胞质到细胞膜的细胞内运输是必需的。细胞因子 EGF 通过增加 SEMA7A 对 FUT8 的结合亲和力触发 SEMA7A N-糖基化，而 TGF-β1 通过诱导上皮-间质转化促进 SEMA7A 的异常糖基化。 SEMA7A 的异常 N-糖基化导致 CD8 ⁺ T 细胞沿着衰竭状态的轨迹分化，从而形成免疫抑制微环境并抵抗免疫原性细胞死亡。 SEMA7A 的去糖基化可显着改善 EGFR 靶向和抗 PD-L1 免疫疗法的临床结果。最后，我们还将剪接调节因子 RBM4 定义为糖基化 SEMA7A 的下游效应子和 PD-L1 选择性剪接的关键介质。这些发现表明，靶向 FUT8-SEMA7A 轴可能是改善头颈鳞状细胞癌患者抗肿瘤反应的有前途的策略。