B2m, also known as β2-microglobulin, is a crucial subunit of the major histocompatibility complex (MHC) class I. It plays a fundamental role in presenting tumor antigens to cytotoxic T lymphocytes (CTLs), thus having a significant impact on tumor-immune interactions and the anti-tumor immune response [1,5]. It is also involved in other biological processes such as synaptic function [3] and the regulation of pulmonary hypertension in heart failure with preserved ejection fraction [4].

In murine models, knocking out B2M in three murine models with different baseline MHC class I expression and sensitivity to anti-programmed death receptor (PD-1) therapy showed 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 [2]. In glioblastoma, inhibition of B2M in GBM stem cells (GSC) attenuated GSC survival, self-renewal, and tumor growth, indicating its role in maintaining stem-like neoplastic populations [7]. In syngeneic mouse models, genetic ablation of B2M in tumor cells led to resistance to PD-1-based immunotherapy, and B2M knockdown also decreased the therapeutic efficacy [6].

In conclusion, B2m is essential for antigen presentation in the anti-tumor immune response. Gene knockout and knockdown mouse models have revealed its critical role in cancer immunotherapy resistance, synaptic function, and pulmonary hypertension-related heart failure. These findings contribute to understanding the underlying mechanisms of these diseases and provide potential therapeutic targets.

References:

1. Wang, Hanbing, Liu, Baorui, Wei, Jia. 2021. Beta2-microglobulin(B2M) in cancer immunotherapies: Biological function, resistance and remedy. In Cancer letters, 517, 96-104. doi:10.1016/j.canlet.2021.06.008. https://pubmed.ncbi.nlm.nih.gov/34129878/

2. Torrejon, Davis Y, Galvez, Mildred, Abril-Rodriguez, Gabriel, Comin-Anduix, Begoña, Ribas, Antoni. . Antitumor Immune Responses in B2M-Deficient Cancers. In Cancer immunology research, 11, 1642-1655. doi:10.1158/2326-6066.CIR-23-0139. https://pubmed.ncbi.nlm.nih.gov/37801341/

3. Gao, Yue, Hong, Yujuan, Huang, Lihong, Xu, Huaxi, Wang, Xin. . β2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function. In Cell, 186, 1026-1038.e20. doi:10.1016/j.cell.2023.01.021. https://pubmed.ncbi.nlm.nih.gov/36868208/

4. Jheng, Jia-Rong, DesJardin, Jacqueline T, Chen, Yi-Yun, Simon, Marc A, Lai, Yen-Chun. 2024. Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction. In Arteriosclerosis, thrombosis, and vascular biology, 44, 1570-1583. doi:10.1161/ATVBAHA.123.320270. https://pubmed.ncbi.nlm.nih.gov/38813697/

5. Han, Xiaowen, Zhang, Jiayi, Li, Weidong, Gao, Lei, Chen, Hao. 2025. The role of B2M in cancer immunotherapy resistance: function, resistance mechanism, and reversal strategies. In Frontiers in immunology, 16, 1512509. doi:10.3389/fimmu.2025.1512509. https://pubmed.ncbi.nlm.nih.gov/40191187/

6. Zhao, Yu, Cao, Yuejiao, Chen, Yiqi, Jiang, Chenxia, Zhou, Xiaorong. 2021. B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy. In Immunology, 164, 507-523. doi:10.1111/imm.13384. https://pubmed.ncbi.nlm.nih.gov/34115389/

7. Li, Daqi, Zhang, Qian, Li, Lu, Rich, Jeremy N, Wang, Xiuxing. . β2-Microglobulin Maintains Glioblastoma Stem Cells and Induces M2-like Polarization of Tumor-Associated Macrophages. In Cancer research, 82, 3321-3334. doi:10.1158/0008-5472.CAN-22-0507. https://pubmed.ncbi.nlm.nih.gov/35841593/