The SDC1-ENO1 Axis in Cancer-Associated Fibroblasts Generates a Lactate-Rich Microenvironment that Drives Tumor Radioresistance.

Abstract

Radiotherapy resistance remains a major barrier to effective treatment of triple-negative breast cancer (TNBC), highlighting the need to identify mechanisms driving resistance. Here, we identified SDC1 as a pivotal mediator of cancer-associated fibroblast (CAF)-induced radioresistance in breast cancer. SDC1 bound the TIM barrel domain of the glycolytic enzyme ENO1, preventing FBXW7-mediated degradation and driving aerobic glycolysis and lactate accumulation. The resulting lactate-rich microenvironment not only promoted tumor stemness but also significantly impaired the cytotoxic functions of both NK cells and CD8⁺ T cells. Pharmacologic inhibition of ENO1 or lactate export restored radiosensitivity. Targeting SDC1⁺ CAFs with the antibody-drug conjugate indatuximab ravtansine (BT062) synergized with radiotherapy in vivo, markedly reducing tumor burden, depleting stem-like tumor cells, and remodeling the immune microenvironment. These findings define a CAF metabolic program that fuels tumor stemness and rewires the immune microenvironment to confer radioresistance, supporting the therapeutic targeting of SDC1⁺ CAFs in TNBC.