Immunotherapy aimed at inhibiting the negative co-stimulatory molecule programmed cell death-ligand 1 (PD-L1) has limited effectiveness, with clinical response rates remaining below 10%–15%. Therefore, new immune checkpoints need to be explored. Our study focused on human endogenous retrovirus H long terminal repeat–associating protein 2 (HHLA2), a highly glycosylated member of the B7 family that is widely expressed in colorectal cancer. HHLA2 expression negatively correlates with the prognosis of colorectal cancer. Glycosylation of HHLA2, which is regulated by the glycosyltransferase STT3 oligosaccharyltransferase complex catalytic subunit A (STT3A), is crucial for protein stability and expression in cell membranes. Additionally, the binding of HHLA2 to the receptors killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) and transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) is dependent on N-glycosylation. Moreover, N-glycosylation of HHLA2 promotes immune evasion in colorectal cancer by suppressing the immune response of NK cells. Notably, the STT3A inhibitor NGI-1 enhances the anti-tumor immune response of NK cells. Our findings provide new insights and a molecular basis for targeting HHLA2 in immunotherapy for colorectal cancer.

中文翻译：

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药理学抑制 HHLA2 糖基化可恢复结直肠癌的抗肿瘤免疫力

旨在抑制负性共刺激分子程序性细胞死亡配体 1 (PD-L1) 的免疫疗法效果有限，临床反应率仍低于 10%–15%。因此，需要探索新的免疫检查点。我们的研究重点是人内源性逆转录病毒 H 长末端重复关联蛋白 2 (HHLA2)，它是 B7 家族的高度糖基化成员，在结直肠癌中广泛表达。 HHLA2表达与结直肠癌的预后呈负相关。 HHLA2 的糖基化由糖基转移酶 STT3 寡糖转移酶复合物催化亚基 A (STT3A) 调节，对于细胞膜中的蛋白质稳定性和表达至关重要。此外，HHLA2 与受体杀伤细胞免疫球蛋白样受体、三个免疫球蛋白结构域和长胞质尾 3 (KIR3DL3) 以及包含跨膜和免疫球蛋白 (Ig) 结构域 2 (TMIGD2) 的结合依赖于 N-糖基化。此外，HHLA2 的 N-糖基化通过抑制 NK 细胞的免疫反应来促进结直肠癌的免疫逃避。值得注意的是，STT3A抑制剂NGI-1增强了NK细胞的抗肿瘤免疫反应。我们的研究结果为结直肠癌免疫治疗中靶向 HHLA2 提供了新的见解和分子基础。