EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape

TLDR

Oncogenic signaling, especially EGF in triple‑negative breast cancer, reprograms metabolism toward glycolysis, potentially promoting tumor growth and immune evasion. The study found that EGF signaling in TNBC cells activates early glycolysis while blocking the final step, causing accumulation of intermediates such as F1,6BP that bind EGFR to boost lactate secretion and suppress cytotoxic T‑cell activity, and that dual inhibition with 2‑deoxy‑glucose and gefitinib markedly reduces tumor growth, highlighting the EGFR/F1,6BP axis as a promising therapeutic target.

Abstract

Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC.