TAM Receptor Tyrosine Kinase Signaling in Cancer Biology

The TAM family of receptor tyrosine kinases—TYRO3, AXL, and MERTK—play pivotal roles in cancer biology through modulation of cell proliferation, survival, immune evasion and metastasis. Ligands such as growth arrest-specific protein 6 (Gas6) and protein S engage these receptors, initiating downstream pathways that include PI3K–AKT, MAPK–ERK and NF-κB. These cascades support malignant behaviours: promotion of epithelial-mesenchymal transition, resistance to chemotherapy and maintenance of cancer stem cell phenotypes. In the tumour microenvironment, TAM signalling orchestrates immunosuppression by polarising macrophages towards a pro-tumour M2 phenotype and by inhibiting antigen presentation. Aberrant overexpression or activation of AXL, in particular, has been correlated with poor prognosis across diverse cancers, driving metastasis and therapeutic resistance. Recent advances have elucidated mechanisms by which ubiquitin-mediated receptor turnover, ligand availability and phospholipid interactions fine-tune TAM activity. Therapeutic strategies under investigation span small-molecule inhibitors, monoclonal antibodies, ligand traps and cellular therapies targeting the Gas6–TAM axis. The global significance of this research lies in its potential to enhance the efficacy of existing treatments, reverse drug resistance and engage the immune system to achieve durable responses.

Research from Nature Portfolio

Recent studies have highlighted the contribution of AXL to resistance in radiotherapy combined with immunotherapy. Experimental models have demonstrated that overexpression of AXL in breast tumours dampens antigen presentation and fosters a suppressive myeloid microenvironment. Genetic deletion of AXL enhanced T-cell infiltration and increased radiosensitivity, yielding durable tumour control when paired with immune checkpoint blockade. These findings suggest that inhibiting AXL may unlock the full potential of combined radiotherapy and immunotherapy by reprogramming the tumour immune milieu.

TAM Receptor Tyrosine Kinase Signaling in Cancer Biology publication trend

The graph below shows the total number of articles in tam receptor tyrosine kinase signaling in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

TAM receptors: Family of receptor tyrosine kinases comprising TYRO3, AXL and MERTK that regulate cell survival, immune responses and phagocytosis.

Gas6 and protein S: Vitamin K-dependent ligands that bind and activate TAM receptors, often in conjunction with phosphatidylserine on target cells.

Epithelial-mesenchymal transition (EMT): Cellular programme in which epithelial cells acquire mesenchymal traits, enhancing motility and invasiveness.

Efferocytosis: Clearance of apoptotic cells by phagocytes, mediated by TAM signalling to maintain tissue homeostasis but co-opted by tumours to suppress immunity.

CAR-T cells: Patient-derived T cells engineered to express chimeric antigen receptors, redirecting cytotoxicity towards cells expressing a chosen antigen or ligand.

Single-domain antibodies (sdAbs): Small antigen-binding fragments derived from heavy-chain only antibodies, offering improved tissue penetration and modular design.

References

1. GAS6-based CAR-T cells exhibit potent antitumor activity against pancreatic cancer. Journal of Hematology & Oncology (2023).
2. AXL-specific single domain antibodies show diagnostic potential and anti-tumor activity in Acute Myeloid Leukemia. Theranostics (2024).
3. STAMBPL1/TRIM21 Balances AXL Stability Impacting Mesenchymal Phenotype and Immune Response in KIRC. Advanced Science (2024).
4. Reprogramming the immunological microenvironment through radiation and targeting Axl. Nature Communications (2016).
5. Differential TAM receptor–ligand–phospholipid interactions delimit differential TAM bioactivities. eLife (2014).
6. Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment. Molecular Cancer (2019).
7. Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases*. Journal of Biological Chemistry (1996).