The advent of immune checkpoint inhibitors (ICIs) has transformed the management of certain metastatic cancers previously regarded as uniformly lethal, significantly improving survival in a subset of patients. However, response rates remain low, and the number of patients achieving durable clinical responses is still limited. This situation reflects an incomplete understanding of the mechanisms governing antitumor immunity and tumor immune resistance. There is therefore a pressing need for novel strategies to enhance ICI efficacy, as well as for predictive tools capable of identifying responders based on the composition of their tumor microenvironment.
This literature review focuses on the receptor tyrosine kinase AXL, whose expression has been associated with poor prognosis across numerous malignancies and with the emergence of treatment resistance. AXL belongs to the TAM receptor family, which comprises TYRO3, AXL, and MERTK. These receptors, characterized by an intracellular kinase domain and distinctive extracellular immunoglobulin-like and fibronectin type III domains, perform essential physiological functions in innate immunity, central nervous system development, angiogenesis, and platelet aggregation. AXL was the first member of this family to be cloned, having initially been identified as a transforming gene in chronic myeloid leukemia cells. Its dysregulation has since been linked to the pathogenesis of numerous human diseases, including cancer.
By binding to its ligand GAS6, AXL activates signaling cascades and modulates the communication between the various components of the tumor microenvironment: cancer cells, endothelial cells, and immune cells. The authors detail the multifaceted role of AXL in promoting immunosuppression and resistance to antitumor immunity. To evade the latter, cancer cells exploit intrinsic pathways that render them less susceptible to attack by immune cells and enable them to escape recognition. The convergent body of evidence designates AXL as an attractive molecular target for overcoming therapeutic resistance and immunosuppression, all the more so since AXL inhibitors hold potential for improving ICI efficacy.
By synthesizing the current literature, the authors place into perspective the prominent role of AXL in cancer progression, with particular attention to its effects on the antitumor immune response and on resistance to ICIs. Finally, they discuss future directions, with the aim of better delineating the complex role of AXL and TAM receptors in cancer and of assessing the value of their targeted inhibition for the benefit of patients.