EGFR Signaling in Cancer: From Tumor Cell Proliferation to Immune Modulation

EGFR is a member of the ErbB/HER family, and its ligands include EGF, amphiregulin (AREG), epiregulin (EREG), transforming growth factor-α (TGF-α), and others. Upon ligand binding, EGFR activates intracellular pathways such as PI3K/AKT, MAPK, Ras/Raf/Mek/Erk, JAK/STAT, and PLCγ/PKC, directly influencing tumor cell proliferation and apoptosis.

EGFR also plays a crucial role in shaping the tumor immune microenvironment (TIME). For instance, in response to IL-1 stimulation, macrophages upregulate IL-6 expression via EGFR, which in turn promotes hepatocellular carcinoma (HCC) proliferation. Furthermore, EGFR can regulate cellular glucose metabolism, impacting the activation of CD4+ T cells.

In CD8+ T cells, EGFR activation enhances their cytotoxic capabilities by promoting the secretion of IFN-γ and TNF-α. Conversely, AREG, another EGFR ligand, acts on FOXP3+ regulatory T cells (Tregs), maintaining their suppressive function through the EGFR/Foxp3 axis.

Understanding the multifaceted roles of EGFR signaling in both tumor cells and immune cells is crucial for developing effective cancer therapies targeting this pathway.