For a long time, anti-cancer therapeutic strategies have mainly addressed the tumor, in the attempt to subvert the altered signaling pathways leading to oncogenesis (1, 2). It is however evident that the tumor microenvironment plays a major role in determining tumor survival and growth. In particular, the role of immunity in eliminating or promoting tumor growth has been now clearly recognized (3–5).

The complex nature of tumorigenesis requires the identification of different therapeutic targets and the implementation of different therapeutic approaches, including drugs/strategies that could overcome resistance after treatment. The immunotherapeutic approaches with immune checkpoint inhibitors are an example of treatment that does not induce resistance, as its target is not the tumor but the re-activation of specific tumoricidal immune cells (6, 7). Thus, the development of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors has opened the way to novel anti-tumor approaches that go beyond inhibiting oncogenic signals and address the tumor microenvironment as a whole. In this context, AXL is an attractive target for designing future treatment targets.

AXL is a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family (8–10). High AXL expression in tumor cells promotes aggressiveness, metastatic capacity and refractoriness to drug treatment (11, 12). In parallel, it was observed that the expression of AXL and other TAM receptors is higher in macrophages polarized towards the M2 anti-inflammatory pro-tumoral functional phenotype and that activation of AXL can induce M2 macrophages polarization (13–16). Since the M2 phenotype is typical of pro-tumoral tumor-associated macrophages, this points to AXL inhibition as a double target to reduce the aggressiveness of tumor cells and the tumor-promoting activity of the innate immune cells (macrophages). Importantly, AXL has been identified as a receptor used by several viruses (Zika, Dengue, RSV, JEV, SARS-CoV-2) for entry into host cells and spreading infections (17–20). Thus, inhibition of AXL in infectious diseases could have the double advantage of blocking virus entry and allowing protective macrophage activation (M1 polarization), by inhibiting M2 development. For these reasons, new drugs targeting AXL are being developed. An overview of AXL role in tumor and immune cells and the potential benefits of its inhibition are presented in Figure 1 .

New technologies to suppress AXL functions include inhibition of downstream signaling with antibodies or blockade of GAS6, the ligand of AXL, and the use of small molecules that can inhibit AXL phosphorylation. The state-of-the-art of the use of AXL inhibitors in cancer therapy is reported by Tanaka et al., who have extensively described the AXL signaling pathway and listed the most promising AXL inhibitors that have been developed clinically or preclinically (21). The review presents the anti-tumor mechanisms of AXL inhibitors, and the i privement of therapeutic efficacy and immunoactivity of chemotherapy currently use in clinical practice (21).

The contribution of AXL to immune evasion underlines the importance of its inhibition in anti-tumor therapies. GAS6/AXL signaling can participate to evasion from anti-tumor immune response within the tumor microenvironment in multiple ways (Son and Jeong). These include modulation of MHC-1 and PD-L1 expression, production of immunosuppressive cytokines, increased recruitment of myeloid derived suppressor cells and decreased infiltration of T cells, inhibition of apoptosis, promotion of CTLA4 and Foxp3 expression in Treg cells and of their immunosuppressive activity, and regulation of tumor associated innate immune cells. The use of AXL inhibitors, both in preclinical studies and in clinical trials, provides valuable information on the modulation of GAS6/AXL-mediated immune evasion (Son and Jeong). Not only AXL but also other receptors of the family, such as TYRO3, are strongly involve in the regulation of tumor cell apoptosis, as demonstrated in colon carcinoma in vitro and in vivo models by using a specific inhibitor (Kim et al.).

The potential application of AXL inhibitor as a single agent or in combination with immunotherapy in patients with lung cancer has been investigated based on clinical treatment results and treatment advantages (Sang et al.). AXL inhibitors have shown therapeutic benefits in combination with chemotherapy to increase survival rate through enhanced activation of immune cells (Lee et al.). However, detailed anti-tumor effects of AXL signaling pathway is yet to be understood.

While the current development of AXL inhibitors offers promising opportunities for effective therapeutic intervention against cancer, future research should aim at fully clarifying the effects of AXL and, more in general, TAM inhibitors. This should start from a complete understanding of the physiological role of these receptors and the assessment of their pathology-linked molecular and functional variations. On these grounds, AXL inhibition can be precisely targeted, to attain high therapeutic efficacy and limited side effects. The possibility of modulating AXL functions in macrophages and in virus-host interactions opens a large spectrum of therapeutic/preventive possibilities beyond cancer.