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

Radiotherapy (RT) resistance remains a major barrier to effective treatment of triple-negative breast cancer (TNBC), highlighting the need to identify mechanisms driving resistance. In this study, we identified syndecan-1 (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 enolase 1 (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 RT 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. SIGNIFICANCE: SDC1-mediated ENO1 stabilization in cancer-associated fibroblasts promotes breast cancer radioresistance by reprograming metabolism to enhance lactate production that fuels tumor stemness and immunosuppression, highlighting the potential of targeting SDC1 to restore radiosensitivity.