TAM Receptors Promising Therapeutic Targets in Rheumatoid Arthritis

The TAM receptor family, which includes Tyro3, Axl, and MerTK receptors, has potential as a new therapeutic target for rheumatoid arthritis (RA) therapies, according to a new review published in Cell & Bioscience.¹

TAM receptors are broadly expressed throughout the body and seen as important regulators of immune homeostasis and inflammatory resolution, the authors explained. Previous research has shown that mice with a TAM deficiency experienced spontaneous chronic inflammation and autoimmune phenomena, which the authors said may be clinical precursors to RA.²

In humans, the investigators noted that TAM receptors serve as a key inhibitory feedback mechanism.¹

“Blocking TAM signaling results in severe defects in the clearance of ACs (apoptotic cells), exacerbates systemic inflammation, and induces overactivation of the immune system, thereby contributing to the onset and progression of RA,” the authors wrote.

Activation of TAM receptors, meanwhile, helps restore tissue integrity, in part by suppressing innate immune cell activation, enhancing AC clearance, and promoting tissue repair.

However, the authors said the different TAM receptors have different roles to play in RA. Axl and MerTK have been shown to have protective benefits in RA.³ Tyro3 appears to exacerbate inflammation and joint destruction, they said.

“This functional dichotomy suggests distinct therapeutic strategies: targeted activation of Axl/MerTK pathways may restore immune balance, whereas Tyro3 inhibition could mitigate synovitis and bone erosion,” the authors wrote, adding that a wave of research has been exploring ways to capitalize on our emerging understanding of TAM receptors.¹

One possible application is the use of soluble forms of TAM receptors (sTAM) as biomarkers for evaluating RA disease status, the authors said.

“These soluble variants are generated through metalloproteinase-mediated cleavage of the extracellular domains of their membrane-bound counterparts and are markedly elevated in the synovial fluid of RA patients, showing promise as indicators of disease activity, severity, and prognosis,” the authors said.

Studies have shown correlations between different sTAMs and clinical characteristics, including a link between serum sTyro3 levels and systemic inflammation. However, the authors said it will be important to come up with standardized detection methods for sTAMs, which they said require further investigation and validation.

A number of TAM-targeted therapies are currently in clinical development, the authors noted. The focus, they said, is largely on small molecules that can inhibit receptor-ligand binding and/or suppress kinase activity. The investigators said most of the development thus far has centered on oncology indications, but they said the therapies’ mechanisms of action suggest they can potentially be effective in autoimmune diseases.

Approximately 20 small-molecule TAM inhibitors have entered the clinical evaluation phase, of which 15 remain in active commercial development. They said oncological applications of the therapies have centered on using TAM inhibitors to mediate drug resistance as part of combination strategies.

Additionally, the authors said a diverse range of multiple small-molecule TAM inhibitors are also in the preclinical stage.

“These emerging compounds highlight the continuing diversification of TAM-targeting strategies in preclinical development,” they said.

Future therapeutic development in the RA context “should focus on receptor-specific modulators to overcome structural homology challenges and explore combination strategies with existing therapies,” the authors wrote.

The authors said understanding TAM signaling and its correlation with different diseases and stages will be necessary before drug developers can realize the full therapeutic potential of the TAM pathway.

References

1. Dai M, Yang X, Yao F, et al. From pathogenesis to therapeutic targeting: new insight into TAM receptors in rheumatoid arthritis. Cell Biosci. 2025;15(1):157. Published 2025 Nov 19. doi:10.1186/s13578-025-01503-w

2. Waterborg CEJ, Koenders MI, van Lent PLEM, van der Kraan PM, van de Loo FAJ. Tyro3/Axl/Mertk-deficient mice develop bone marrow edema which is an early pathological marker in rheumatoid arthritis. PLoS One. 2018;13(10):e0205902. Published 2018 Oct 18. doi:10.1371/journal.pone.0205902

3. Gao L, He C, Yang A, et al. Receptor tyrosine kinases Tyro3, Axl, and Mertk differentially contribute to antibody-induced arthritis. Cell Commun Signal. 2023;21(1):195. Published 2023 Aug 3. doi:10.1186/s12964-023-01133-0