TAM receptors and STAT–SOCS signaling shape the immune landscape of thymic epithelial tumors

Thymic epithelial tumors, rare cancers arising from the epithelial cells of the thymus, have long resisted molecular classification. A new study published in Medical Oncology has now mapped how two signaling systems long implicated in immune evasion—the TAM receptor tyrosine kinase family and the STAT–SOCS signaling axis—behave across these tumors, using genomic, transcriptomic, and clinical data from The Cancer Genome Atlas thymoma cohort integrated with normal thymus expression profiles from GTEx.

The TAM family comprises three receptors—AXL, MERTK, and TYRO3—that are activated by the ligands GAS6 and PROS1. The study examined these three receptors and their ligands as components of the TAM pathway in relation to the immune microenvironment of thymic epithelial tumors. The study also assessed the STAT1–SOCS1/SOCS3 axis alongside the TAM receptors in the same tumors. How these two systems interact in the distinctive immune microenvironment of thymic epithelial tumors had remained poorly characterized.

The research team, led by Deniz Aslar Oner, examined genomic alterations, gene expression patterns, survival associations, and immune infiltration using GEPIA2, patient-level TCGA-THYM data, and the TIMER2.0 platform. Single-cell RNA sequencing data from thymic epithelial tumors were used to determine which cell types express TAM pathway genes, and protein–protein interactions were assessed through the STRING database.

Genomic alterations affecting the TAM–STAT–SOCS axis turned out to be infrequent, limited to missense variants and copy-number amplifications. The infrequency of these genomic alterations contrasts with the higher expression of several TAM–STAT–SOCS components observed in tumor tissues. Indeed, expression analysis revealed that AXL, MERTK, PROS1, GAS6, STAT1, and SOCS1 were all expressed at higher levels in tumor tissues than in normal thymus, pointing to coordinated upregulation of both receptor and ligand components within the tumor microenvironment.

Survival analysis produced a nuanced picture. Higher MERTK expression was associated with poorer overall survival in the GEPIA2 analysis, though this association did not remain significant when the data were stratified by World Health Organization tumor subtype or adjusted in multivariable models. The authors therefore characterize MERTK as showing an initial association with overall survival rather than an independent prognostic marker, since the association was not significant in WHO-stratified and multivariable analyses.

The immune infiltration findings were among the most striking. AXL, MERTK, and TYRO3 expression were inversely correlated with the infiltration of both CD4-positive and CD8-positive T cells, the principal cytotoxic and helper populations that anti-tumor immunity depends upon. In contrast, GAS6, PROS1, STAT1, and SOCS3 were positively associated with neutrophil infiltration. This divergent pattern indicates that TAM receptor expression was inversely correlated with CD4-positive and CD8-positive T-cell infiltration, whereas GAS6, PROS1, STAT1, and SOCS3 were positively associated with neutrophil infiltration.

MERTK emerged as a particularly interesting node. Its expression was positively correlated with CD274, the gene encoding PD-L1, the immune checkpoint ligand targeted by widely used immunotherapy agents. Single-cell analysis further showed that MERTK was most frequently detected in macrophage and monocyte populations within the tumor, consistent with the receptor’s established role in immune regulatory myeloid cells. Together, these findings show that MERTK expression was positively correlated with CD274 and that single-cell analysis detected MERTK most frequently in macrophage/monocyte populations.

The study's integrative approach linked TAM–STAT–SOCS expression to genomic alterations, gene expression, survival, and immune infiltration in thymic epithelial tumors. Because the analysis was correlational, the reported associations between TAM receptor expression and immune infiltration do not establish a causal mechanism in thymic epithelial tumors.

Several limitations warrant emphasis. The analysis relied on bulk transcriptomic data from a rare tumor cohort, and the survival signal for MERTK did not survive WHO-stratified or multivariable testing. The single-cell findings, while informative about cell-type expression of TAM pathway genes, were based on TET single-cell RNA-seq data, and the study does not report the number of samples analyzed. The authors frame their conclusions carefully: TAM–STAT–SOCS expression was associated with the TET immune landscape, and MERTK showed an initial association with overall survival and further associations with T-cell infiltration, CD274 expression, and cell-type-specific expression patterns.

What the study reports is an integrative molecular profiling of the TAM–STAT–SOCS axis in thymic epithelial tumors. By showing that AXL, MERTK, PROS1, GAS6, STAT1, and SOCS1 were expressed at higher levels in tumor tissues than in normal thymus, and that their expression correlated with distinct immune infiltration patterns, the work provides a basis for future studies of this pathway in thymic epithelial tumors. The study did not test pharmacological TAM inhibition; the reported correlation patterns describe associations in existing TCGA-THYM and single-cell data rather than effects of any intervention.

Subject of Research: Molecular profiling of TAM receptors and STAT–SOCS signaling in thymic epithelial tumors

Article Title: Integrative molecular profiling of TAM receptors and STAT–SOCS signaling in thymic epithelial tumors

Article References: Oner, D. A. (2026). Integrative molecular profiling of TAM receptors and STAT–SOCS signaling in thymic epithelial tumors. Medical Oncology, 43(12), Article 366. https://doi.org/10.1007/s12032-026-03491-4

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03491-4

Keywords: thymic epithelial tumors, TAM receptors, MERTK, AXL, TYRO3, STAT–SOCS signaling, immune infiltration, TCGA-THYM, PD-L1, tumor microenvironment, single-cell RNA sequencing, immunotherapy