Hunan Center for Clinical Laboratory, Second People's Hospital of Hunan Province, Changsha, Hunan 410007, P.R. China.
Oncol Rep. 2024 Oct;52(4). doi: 10.3892/or.2024.8796. Epub 2024 Aug 19.
The immune system is integral to the surveillance and eradication of tumor cells. Interactions between the natural killer group 2 member D (NKG2D) receptor and its ligands (NKG2DLs) are vital for activating NKG2D receptor‑positive immune cells, such as natural killer cells. This activation enables these cells to identify and destroy tumor cells presenting with NKG2DLs, which is an essential aspect of tumor immunity. However, tumor immune escape is facilitated by soluble NKG2DL (sNKG2DL) shed from the surface of tumor cells. The production of sNKG2DL is predominantly regulated by metalloproteinases [a disintegrin and metalloproteinases (ADAM) and matrix metalloproteinase (MMP) families] and exosomes. sNKG2DL not only diminish immune recognition on the tumor cell surface but also suppress the function of immune cells, such as NK cells, and reduce the expression of the NKG2D receptor. This process promotes immune evasion, progression, and metastasis of tumors. In this review, an in‑depth summary of the mechanisms and factors that influence sNKG2DL production and their contribution to immune suppression within the tumor microenvironment are provided. Furthermore, due to the significant link between sNKG2DLs and tumor progression and metastasis, they have great potential as novel biomarkers. Detectable via liquid biopsies, sNKG2DLs could assess tumor malignancy and prognosis, and act as pivotal targets for immunotherapy. This could lead to the discovery of new drugs or the enhancement of existing treatments. Thus, the application of sNKG2DLs in clinical oncology was explored, offering substantial theoretical support for the development of innovative immunotherapeutic strategies for sNKG2DLs.
免疫系统对于肿瘤细胞的监测和清除至关重要。自然杀伤细胞组 2 成员 D（NKG2D）受体与其配体（NKG2DLs）之间的相互作用对于激活 NKG2D 受体阳性免疫细胞（如自然杀伤细胞）至关重要。这种激活使这些细胞能够识别和破坏表达 NKG2DL 的肿瘤细胞，这是肿瘤免疫的一个重要方面。然而，肿瘤免疫逃逸是通过肿瘤细胞表面脱落的可溶性 NKG2DL（sNKG2DL）来促进的。sNKG2DL 的产生主要受金属蛋白酶[解整合素和金属蛋白酶（ADAM）和基质金属蛋白酶（MMP）家族]和外泌体调节。sNKG2DL 不仅减少肿瘤细胞表面的免疫识别，还抑制 NK 等免疫细胞的功能，并降低 NKG2D 受体的表达。这个过程促进了肿瘤的免疫逃逸、进展和转移。在这篇综述中，深入总结了影响 sNKG2DL 产生的机制和因素及其对肿瘤微环境中免疫抑制的贡献。此外，由于 sNKG2DL 与肿瘤进展和转移之间存在显著联系，它们作为新型生物标志物具有巨大潜力。通过液体活检可以检测到 sNKG2DLs，可以评估肿瘤的恶性程度和预后，并作为免疫治疗的关键靶点。这可能会导致发现新的药物或增强现有的治疗方法。因此，探讨了 sNKG2DLs 在临床肿瘤学中的应用，为开发创新性 sNKG2DLs 免疫治疗策略提供了重要的理论支持。
