TAM receptor protein tyrosine kinase TYRO3 is a ubiquitylation substrate for CBL-B and essential regulator of immune homeostasis. Deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. TAM receptors have also been associated with cancer development and progression. In a cancer setting, TYRO3 has a dual regulatory role, controlling the initiation and progression of tumor development as well as the associated anti-tumor responses of diverse immune cells. Thus, modulation of TYRO3 has emerged as a potential novel strategy for cancer treatment.

TYRO3 inhibition or degradation plays a significant role in NK cell activation. Treatment of NK cells with a small molecule, a TAM kinase inhibitor, conferred therapeutic potential by efficiently enhancing anti-metastatic NK cell activity in vivo. The TAM inhibitor markedly reduced NK-dependent mammary cancer and melanoma metastases. TAM/CBL-B inhibitory pathway shows a possibility to develop new therapies that awakens the innate immune system to kill cancer metastases.