Supplementing sialic acid analogs overcomes radiotherapy resistance in triple-negative breast cancer by exacerbating ER stress

Radiotherapy is a cornerstone treatment for triple-negative breast cancer (TNBC), and its incorporation has significantly delayed tumor recurrence. However, the emergence of radiotherapy resistance remains a major clinical challenge, substantially compromising treatment efficacy. Sialylation play a pivotal role in tumor therapeutic resistance which refers to the covalent linkage of sialic acids at the terminal ends of glycoproteins, a process catalyzed by a family of sialyltransferases. However, the function and mechanisms of sialylation in radiotherapy resistance remain elusive. In this study, upregulation of Galbeta1-4 GlcNAc alpha 2,3 sialyltransferase (ST3GAL4) was observed in association with sialylation in TNBC patients with radiotherapy resistance and predicted poorer survival. ST3GAL4 catalyzed α2,3-sialylation of HSP90B1, then facilitates its retrograde trafficking from the Golgi to ER mediated by SURF4 cargo receptor. ER-localized HSP90B1 accelerates the clearance of radiotherapy-induced misfolded proteins and upregulates the PERK-EIF2α-ATF4 pathway, which further transcriptionally upregulates antioxidant factors, such as SLC1A5, GCLC, and CTNS, to inhibit radiotherapy-induced ROS accumulation, ultimately leading to radiotherapy resistance, and poor clinical outcomes. Most importantly, sialic acid analogs (SAA) 3Fax-NeuAc inhibited the sialylation of HSP90B1 and its transport to the ER, thereby effectively overcomed radiotherapy resistance in TNBC. This study suggests that ST3GAL4 confers radiotherapy resistance through the induction of adaptive ER stress by sialylated HSP90B1, while the application of SAA provides a novel therapeutic option against radioresistance of TNBC.