β2-微球蛋白 (B2M) 是 MHC I 类分子的关键成分，是向 T 细胞呈递肿瘤抗原所必需的。它的缺失导致对免疫检查点阻断（ICB）疗法的获得性抵抗。然而，已有充分记录的 B2M 灭活肿瘤对 ICB 做出反应的案例，这证明了如何对没有表面 MHC I 类的肿瘤产生抗肿瘤免疫反应的研究。我们在三种具有不同基线 MHC 的小鼠模型中敲除了 B2M I 类表达和抗程序性死亡受体 (PD-1) 治疗的敏感性，并分析了免疫反应。没有 B2M 的 MC38 和 YUMMER2.1 单独响应抗 PD-1 或​​与 IL2 激动剂一起响应，这是由 CD4 T 细胞和自然杀伤 (NK) 细胞介导的。不表达 B2M 的更具攻击性的 B16 仅对 IL2 激动剂有部分反应，这取决于 NK 细胞。在分析来自接受 PD-1 阻断疗法的黑色素瘤患者的近 300 例治疗前活检样本时，我们发现 B2M 突变或纯合性丢失不常见，但杂合性 (LOH) 丢失或拷贝数增加则更为常见。 B2M LOH 在对治疗无反应的患者的活检中富集，并且这些活检更频繁地被活化的 NK 细胞浸润。我们的结论是，在缺乏 B2M 的情况下，CD4 T 细胞和 NK 细胞的激活可以介导对 PD-1 阻断疗法的小鼠模型的反应。此外，在人类黑色素瘤中，部分 B2M 缺失后，肿瘤内存在活化的 NK 细胞，可能会通过低表面 MHC I 类表达来选择阻止肿瘤逃逸。

β2-microglobulin (B2M) is a critical component of the MHC class I molecule and is required to present tumor antigens to T cells. Its loss results in acquired resistance to immune checkpoint blockade (ICB) therapies. However, there have been well-documented cases of B2M-inactivated tumors responding to ICB, justifying investigation of how an antitumor immune response can be generated to tumors without surface MHC class I. We knocked-out B2M in three murine models with varying baseline MHC class I expression and sensitivity to anti-programmed death receptor (PD-1) therapy and analyzed the immune responses. MC38 and YUMMER2.1 without B2M responded to anti-PD-1 alone or with an IL2 agonist, and this was mediated by CD4+ T cells and natural killer (NK) cells. The more aggressive B16 without B2M expression only partially responded to the IL2 agonist, and this was dependent on NK cells. When analyzing nearly 300 pretreatment biopsies from patients with melanoma receiving PD-1 blockade-based therapies, we found infrequent B2M mutations or homozygous loss but more frequent loss of heterozygosity (LOH) or copy number gains. B2M LOH was enriched in biopsies from patients without response to therapy, and these biopsies were more frequently infiltrated by activated NK cells. We conclude that in the absence of B2M, activation of CD4+ T cells and NK cells can mediate responses to murine models of PD-1 blockade therapy. Additionally, in human melanoma the intratumoral presence of activated NK cells upon partial B2M loss likely selects against tumor escape through low surface MHC class I expression.