EphA4 Mediates Pro- and Anti- Tumoral Effects Through Upstream Negative Regulation of AKT in Head and Neck Squamous Cell Carcinoma- The effect of EphA4 knockout on RNA expression in HNSCC cell line.

We examined the immune-modulatory role of EphA4 in HNSCC using spatial analysis, multi-compartment RNA-sequencing from Oral Cavity Squamous Cell Carcinoma (OCSCC), and three genetically engineered mouse models. Within the HNSCC TME, EphA4 is primarily expressed in Tregs, macrophages, CD8+ T cells, and HNSCC cancer cells.

EphA4 in Tregs promotes tumor growth, whereas EphA4 in myeloid cells, CD8+ T cells, and cancer cells limits it. EphA4 mediates these differential effects through shared negative regulation of AKT signaling where its knockout increases AKT activation, leading to reduced Treg immunosuppression, increased M2 macrophage polarization, impaired CD8+ T cell memory differentiation, and enhanced cancer cell proliferation. APY-d3-PEG4, EphA4 inhibitor, reduced tumor growth primarily by targeting Tregs.