B2m, also known as β2-microglobulin, is a crucial subunit of the major histocompatibility complex (MHC) class I. It plays a vital role in presenting tumor antigens to cytotoxic T lymphocytes (CTLs) for anti-tumor effects, and is involved in immune-related pathways [1,3]. It has significance in tumorigenesis and immune control, and its study can be facilitated by genetic models like gene knockout (KO) mouse models [1,2].

In murine models, knocking out B2M in tumors with varying baseline MHC class I expression and sensitivity to anti-programmed death receptor (PD-1) therapy showed that MC38 and YUMMER2.1 without B2M responded to anti-PD-1 alone or with an IL2 agonist, mediated by CD4+ T cells and natural killer (NK) cells. The more aggressive B16 without B2M expression only partially responded to the IL2 agonist, dependent on NK cells. This reveals that in the absence of B2M, CD4+ T cells and NK cells can mediate responses to PD-1 blockade therapy in murine models [2]. In addition, in human melanoma, partial B2M loss with intratumoral activated NK cells may prevent tumor escape through low surface MHC class I expression [2]. Genetic ablation of B2M in syngeneic mouse models causes resistance to PD-1-based immunotherapy, while forced expression of B2M improves the response to immunotherapy, indicating that B2M levels impact treatment outcomes in lung adenocarcinoma [4]. In glioblastoma (GBM) mouse models, inhibition of B2M attenuated GBM stem cell (GSC) survival, self-renewal, and tumor growth [5].

In conclusion, B2m is essential for antigen presentation in the MHC class I-mediated anti-tumor immune response. Studies using KO mouse models have significantly contributed to understanding its role in cancer immunotherapy resistance, such as in melanoma, lung adenocarcinoma, and glioblastoma. These findings provide insights into potential therapeutic strategies targeting B2m to improve cancer immunotherapy efficacy [1,2,4,5].