Researchers at the Medical University of Vienna have identified a new role played by epidermal growth factor receptor (EGFR) signaling in metastatic colorectal cancer (mCRC), finding that its activity in myeloid immune cells helps shape the tumor microenvironment and influences tumor growth. The study, published in Cell Death & Differentiation, indicates that EGFR signaling does not affect only cancer cells but contributes to how immune cells regulate anti-tumor responses.
“Our results show that EGFR in myeloid cells is a key regulator of the tumor-promoting immune landscape,” said senior author Maria Sibilia, PhD, a professor of tumor biology and director of the Center for Cancer Research at Medical University of Vienna.
Metastatic colorectal is a leading cause of cancer-related deaths worldwide. EGFR-blocking antibody treatments are already part of standard first-line therapy for patients with wild-type KRAS/BRAF tumors, but not all patients respond to this form of treatment, and even among those that do respond, resistance frequently develops. The new findings help clarify why EGFR expression in tumor cells alone does not fully predict therapeutic outcomes and suggest that immune-cell signaling is an important factor in treatment response.
While, EGFR has been broadly studied as a tumor cell receptor, earlier research has suggested that EGFR-positive myeloid cells are associated with worse prognosis in CRC and hepatocellular carcinoma. Studies in mice had also shown that deleting EGFR in myeloid cells reduced tumor burden, while deleting it in tumor epithelial cells had limited effect. However, the contribution of immune-cell EGFR signaling on the response to anti-EGFR therapy has not been broadly studied or understood.
To address this, the Sibilia lab used genetically engineered mouse models of colorectal cancer with single-cell RNA sequencing, proteomic profiling, and combined it with analysis of patient-derived datasets. The team focused on tumor-associated myeloid cells, including macrophage subsets known to shape immune suppression within the tumor microenvironment. To allow direct comparison of outcomes, EGFR was selectively deleted in either myeloid cells or tumor epithelial cells in preclinical models.
Single-cell analyses showed that loss of EGFR in myeloid cells reduced populations of tumor-promoting macrophages, including Spp1+ and C1qc+ subsets, and altered signaling pathways linked to inflammation and immune regulation. Reduced activity in TGFβ, IFNγ, and JAK/STAT pathways was associated with decreased expression of immune checkpoint molecules and changes in myeloid–T cell communication. CD8+ T cells in EGFR-deficient tumors showed lower expression of exhaustion markers such as Pdcd1 and Havcr2, suggesting a shift in T cell functional state.
A key finding was the identification of thrombospondin-1 (THBS1) as a myeloid-derived ligand regulated by EGFR signaling. Further analysis confirmed that EGFR activity influences THBS1 expression in macrophages and patient data also showed that high expression of both EGFR and THBS1 correlated with poorer outcomes, and combined gene signatures were associated with reduced survival.
The researchers also noted that tumor-associated macrophages and other myeloid populations can shift between anti-tumor and tumor-promoting states, and that their role in EGFR-targeted therapy response had not been fully defined.
One conclusion drawn by the researchers based on their work is that myeloid EGFR signaling contributes to immunosuppression in mCRC and may affect treatment response to both targeted therapy and immunotherapy approaches. “These findings strongly suggest that targeting EGFR specifically in myeloid cells may be of great therapeutic benefit for patients with CRC,” the researchers wrote.
The data also indicate that therapeutic strategies that only address tumor cell EGFR likely don’t address the full landscape of its effects and may not indicate the extent of treatment response. Instead, the investigators suggested, modulation of EGFR signaling in immune cells, particularly macrophage populations, could improve the effectiveness of existing EGFR inhibitors and may enhance response to immune checkpoint blockade by reducing T cell exhaustion and checkpoint expression.
Building on this, the team will now investigate myeloid-specific EGFR inhibition strategies and explore targeted delivery methods, such as nanoparticles directed toward EGFR-positive macrophage populations. Additional work will also seek to validate THBS1 as a biomarker for patient stratification and to determine how targeting this pathway might be integrated with immunotherapy regimens.
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