Themis2, also known as ICB1 (Induced on contact with basement membrane 1), is a scaffold protein that plays diverse roles in the immune system and cancer-related processes. In the immune system, it is involved in regulating the function and differentiation of natural killer (NK) cells and macrophages. In cancer, it has been associated with tumor growth, metastasis, and chemoresistance [1,2,3,4,5,6].

In NK cells, Themis2-deficient mice showed enhanced differentiation of Ly49H-expressing NK cells into memory NK cells, augmenting host protection against MCMV infection. Mechanistically, Themis2 suppresses Ly49H signalling by attenuating ZAP70/Syk phosphorylation and translocates to the nucleus to regulate memory NK cell persistence through the Themis2-Zfp740 pathway [1]. In the context of antitumor activity, knockdown of THEMIS2 in primary human NK cells promoted effector functions, and Themis2-deficient mice had a low metastatic burden in an NK cell-dependent manner, indicating its inhibitory role in NK-mediated antitumor activity [2]. In hepatocellular carcinoma, lncRNA THEMIS2-211, a transcript related to Themis2, promotes cancer cell proliferation, migration, invasion, and EMT by interacting with miR-940 and promoting SPOCK1 expressions [3]. In triple-negative breast cancer, THEMIS2 enhances cancer stemness and chemoresistance by suppressing the association of PTP1B with p-MET and MET [4]. In ovarian cancer, THEMIS2 promotes metastasis via DOCK4-mediated activation of Rap1 signalling, as knockdown of THEMIS2 impeded OC cell migration and invasion both in vitro and in vivo [5].

In conclusion, Themis2 is a crucial regulator in multiple biological processes. Gene-knockout mouse models have been instrumental in revealing its roles in NK cell-mediated immunity, cancer stemness, metastasis, and chemoresistance. Understanding Themis2 provides potential therapeutic targets for NK cell-mediated cancer immunotherapy and treatment of various cancers [1,2,4,5].