AXL at the nexus of therapeutic resistance, tumor vascularization, and immune evasion in cancer.

AXL, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinase family, has emerged as a high-priority therapeutic target in oncology. Unlike canonical oncogenic kinase drivers, AXL activation is rarely attributable to direct genetic alterations but instead arises through adaptive, non-genetic mechanisms including hypoxia, inflammation, epithelial-to-mesenchymal transition, and therapeutic selection pressure. In this review, we synthesize the current understanding of AXL biology and the translational opportunities for AXL inhibition across multiple malignancies, with a focus on glioblastoma. We explore the expanding landscape of AXL-directed therapeutics, discuss the rationale for combinatorial strategies, and highlight emerging areas of AXL regulation including the AXL-ferroptosis axis. The current understanding of AXL suggests it functions not as a bystander but as an active mediator of tumor adaptation. Successful targeting of AXL has the potential to simultaneously suppress cancer cell survival, angiogenesis, and epithelial-to-mesenchymal transition while reinvigorating antitumor immunity.