EGFR deletion in myeloid cells reprograms the immunosuppressive landscape of colorectal cancer.

Despite advances in the treatment of metastatic colorectal cancer (mCRC), it remains the second leading cause of cancer-related mortality, with limited effective therapeutic options. While EGFR inhibition is a standard first-line therapy for mCRC patients lacking KRAS mutations, resistance frequently develops, limiting its clinical benefit. Murine CRC models have shown that EGFR deletion in myeloid cells reduces tumor burden, and the presence of EGFR-positive myeloid cells is associated with poor prognosis in mCRC patients. However, the role of these cells in the therapeutic response to anti-EGFR therapies remains poorly understood. In this study, we integrated mouse models, single-cell RNA sequencing (scRNAseq), proteomics, and patient-derived mCRC datasets to investigate how EGFR signaling in myeloid cells shapes the tumor microenvironment (TME). In a preclinical therapeutic trial, we demonstrate that EGFR deletion in myeloid cells of tumor-bearing CRC mice reduced tumor growth, whereas EGFR loss in intestinal epithelial tumor cells alone had no therapeutic impact. EGFR deletion also decreased the abundance of F4/80