Themis2, also known as ICB1 (Induced on contact with basement membrane 1), is a scaffold protein. It plays a crucial role in regulating immune cell functions, especially those related to natural killer (NK) cells, B cells, and macrophages. In NK cells, it is involved in memory cell differentiation and function, and in B cells, it affects activation thresholds. In macrophages, it selectively regulates Toll-like receptor signaling and cytokine production [1,4,6,8].

In NK cells, Themis2-deficient mice expressing Ly49H show enhanced differentiation into memory NK cells and better host protection against MCMV infection. Themis2 inhibits NK cell effector function after the stimulation of multiple activating NK receptors by suppressing Ly49H signaling through attenuating ZAP70/Syk phosphorylation and translocating to the nucleus to promote Zfp740-mediated repression [1]. In B cells, Themis2-deficient mice showed normal B cell development, activation, and antibody responses, indicating it is not required for these processes [4]. However, Themis2 was found to lower the threshold for B-cell activation by low-avidity antigens, increasing the positive selection of B1 cells and germinal center B cells [6].

In the context of cancer, Themis2 knockdown in primary human NK cells promoted effector functions, and Themis2-deficient mice showed low metastatic burden in an NK cell-dependent manner, suggesting its inhibitory role in the antitumor activity of NK cells [2]. In hepatocellular carcinoma, lncRNA THEMIS2-211 promotes cancer cell growth and metastasis by acting as a competing endogenous RNA [3]. In triple-negative breast cancer, THEMIS2 enhances cancer stemness and chemoresistance by releasing PTP1B from MET [5]. In ovarian cancer, THEMIS2 promotes metastasis via DOCK4-mediated activation of Rap1 signaling, and in thyroid cancer, it is a biomarker of immune infiltration and prognosis [7,9].

In conclusion, Themis2 is a key regulator in multiple biological processes, especially in immune cell function and cancer-related events. Studies using gene-knockout mouse models have revealed its diverse functions in NK cell-mediated immunity, B cell activation, and cancer progression. Understanding Themis2 provides insights into immunological memory, antitumor immunity, and cancer development mechanisms, which may offer potential therapeutic targets for related diseases.