A novel SLC3A2-targeting antibody-drug conjugate exerts potent antitumor efficacy in head and neck squamous cell cancer

•SLC3A2 was highly expressed in HNSCC cell lines and tissue, and higher expression of SLC3A2 in tumors correlated with worse overall survival.•A novel anti-SLC3A2 ADC (19G4-MMAE) against SLC3A2 were generated by our group.•SLC3A2-targeted treatment may be associate with intracellular autophagy in HNSCC.•Anti-SLC3A2 ADC (19G4-MMAE) induced amounts of ROS accumulation and induced apoptosis of SLC3A2-positive HNSCC cells and exhibited MMAE-derived antitumor activities against SLC3A2-expressing HNSCC in preclinical models. The development of innovative therapeutic strategies for head and neck squamous cell carcinoma (HNSCC) is a critical medical requirement. Antibody-drug conjugates (ADC) targeting tumor-specific surface antigens have demonstrated clinical effectiveness in treating hematologic and solid malignancies. Our investigation revealed high expression levels of SLC3A2 in HNSCC tissue and cell lines. This study aimed to develop a novel anti-SLC3A2 ADC and assess its antitumor effects on HNSCC both in vitro and in vivo. This study developed a potent anti-SLC3A2 ADC (19G4-MMAE) and systematically investigated its drug delivery potential and antitumor efficacy in preclinical models. This study revealed that 19G4-MMAE exhibited specific binding to SLC3A2 and effectively targeted lysosomes. Moreover, 19G4-MMAE induced a significant accumulation of reactive oxygen species (ROS) and apoptosis in SLC3A2-positive HNSCC cells. The compound demonstrated potent antitumor effects derived from MMAE against SLC3A2-expressing HNSCC in preclinical models, displaying a favorable safety profile. These findings suggest that targeting SLC3A2 with an anti-SLC3A2 ADC could be a promising therapeutic approach for treating HNSCC patients.