Inhibition of α-1,3-mannosyltransferase sensitizes head and neck squamous cell carcinomas to cetuximab via endoplasmic reticulum stress.

Developing effective therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) remains a considerable clinical challenge. Cetuximab, a first-line targeted therapy for HNSCC, exhibits limited efficacy. The aim of this study was to explore the potential of α-1,3-mannosyltransferase (ALG3) inhibition in augmenting the therapeutic efficacy of cetuximab. We first analyzed the Cancer Genome Atlas (TCGA) data and found that ALG3 was significantly overexpressed in HNSCC tissues, correlating with worse pathological features and lower overall and disease-specific survival. Functional studies using ALG3-knockdown cells and a subcutaneous tumor model demonstrated that ALG3 inhibition markedly suppressed HNSCC proliferation both in vitro and in vivo. Furthermore, combining ALG3 inhibition with cetuximab elicited potent anti-cancer effects in vitro and in vivo. Mechanistic investigations via quantitative polymerase chain reaction, western blotting, and transmission electron microscopy revealed that ALG3 knockdown induced endoplasmic reticulum (ER) stress in HNSCC cells through the Bip/IRE1α axis. Finally, blocking N‑linked glycosylation synergistically enhanced cetuximab-mediated growth inhibition of HNSCC cells. In conclusion, ALG3 is a promising target to enhance the therapeutic efficacy of cetuximab in HNSCC.