免疫检查点抑制剂具有显着的先进肿瘤治疗作用，但其有限的益处和仅对一小部分患者的强烈反应仍然具有挑战性。在本研究中，我们探讨了 contactin-4 (CNTN4) 的免疫调节功能。 CNTN4在肿瘤组织中高表达，表达损害T细胞的抗肿瘤功能。 CNTN4 与 T 细胞上的淀粉样前体蛋白 (APP) 结合，从而减弱癌细胞和 T 细胞之间的结合，并减少 T 细胞受体信号级联。我们开发了抗 CNTN4 抗体 (GENA-104A16) 和抗 APP 抗体 (5A7)，可阻断 CNTN4 和 APP 之间的结合。 GENA-104A16 或 5A7 的施用促进了同基因小鼠模型中的抗肿瘤 T 细胞反应，并增加了体内肿瘤浸润淋巴细胞。此外，CNTN4水平升高与预后不良相关，并与各种细胞毒性免疫相关标志物呈负相关。这些结果表明 CNTN4-APP 是 T 细胞中的抑制性检查点，代表了一种有前途的癌症免疫治疗策略。

Immune checkpoint inhibitors have substantial advanced tumor treatment, but their limited benefits and strong responses in only a subset of patients remain challenging. In this study, we explored the immunomodulatory function of contactin-4 (CNTN4). CNTN4 was highly expressed in tumor tissues, and expression impaired the antitumor function of T cells. CNTN4 bound to amyloid precursor protein (APP) on T cells, which attenuated conjugation between cancer cells and T cells, and diminished T cell receptor signaling cascades. We developed an anti-CNTN4 antibody (GENA-104A16) and an anti-APP antibody (5A7) that blocked the binding between CNTN4 and APP. Administration of either GENA-104A16 or 5A7 promoted antitumor T cell responses in a syngeneic mouse model and increased tumor-infiltrating lymphocytes in vivo. Furthermore, elevated CNTN4 levels were associated with poor prognosis and negatively correlated with various cytotoxic immune-related markers. These results suggest that CNTN4-APP is an inhibitory checkpoint in T cells and represents a promising therapeutic strategy for cancer immunotherapy.