Li Weimiao, Zheng Guoxu, Zhang Shuqun
The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157, Xiwu Road, Xi'an, 710004, China.
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, No.169, Changle West Road, Xi'an, 710032, China.
Breast Cancer. 2025 Jun 23. doi: 10.1007/s12282-025-01738-y.
Killer-cell immunoglobulin-like receptor 2DL4 (KIR2DL4), a member of the killer cell immunoglobulin-like receptors (KIRs) family, plays an important role in the regulation of the immune system, which is expressed primarily on natural killer (NK) cells. Human leucocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is the only known ligand of KIR2DL4. Accumulating evidence has shown that KIR2DL4 has emerged as a potential target for enhancing the antitumor immune response. Elevated expression of KIR2DL4 has been observed in certain tumor types, including melanoma, lung cancer, and ovarian cancer, indicating its role in tumor evasion. Our previous study had shown that blockade of KIR2DL4 interaction in NK cells can re-sensitize breast cancer to trastuzumab treatment, which indicated that KIR2DL4 was a pivotal immune checkpoint of NK cells. Currently, there are several therapeutic approaches targeting KIR in cancer immunotherapy. However, there are no efficient cancer immunotherapy strategy targeting KIR2DL4. In this review, we aim to summarize and discuss the potential role of KIR2DL4 as a target for cancer immunotherapy. A better understanding of KIR2DL4 might be helpful to develop effective KIR2DL4-targeted therapies, which could provide new treatment options for cancer patients.
杀伤细胞免疫球蛋白样受体2DL4（KIR2DL4）是杀伤细胞免疫球蛋白样受体（KIRs）家族的成员之一，主要在自然杀伤（NK）细胞上表达，在免疫系统调节中发挥重要作用。人类白细胞抗原-G（HLA-G）是一种非经典的主要组织相容性复合体（MHC）I类分子，是KIR2DL4唯一已知的配体。越来越多的证据表明，KIR2DL4已成为增强抗肿瘤免疫反应的潜在靶点。在某些肿瘤类型中，包括黑色素瘤、肺癌和卵巢癌，已观察到KIR2DL4表达升高，表明其在肿瘤逃逸中的作用。我们之前的研究表明，阻断NK细胞中的KIR2DL4相互作用可使乳腺癌对曲妥珠单抗治疗重新敏感，这表明KIR2DL4是NK细胞的关键免疫检查点。目前，在癌症免疫治疗中有几种针对KIR的治疗方法。然而，尚无针对KIR2DL4的有效癌症免疫治疗策略。在本综述中，我们旨在总结和讨论KIR2DL4作为癌症免疫治疗靶点的潜在作用。更好地了解KIR2DL4可能有助于开发有效的KIR2DL4靶向疗法，为癌症患者提供新的治疗选择。
