Anti-SIA-cIgG enhances chemotherapy effectiveness through PTPN13-regulated tumor stemness in head and neck squamous cell carcinoma

Abstract Background and Objectives The chemotherapy response rate in head and neck squamous cell carcinoma (HNSCC) remains low due to a lack of effective therapeutic targets, and treatment efficacy is further limited by chemoresistance and heterogeneity in drug response. Sialylated cancer IgG (SIA-cIgG) is a tumor-derived immunoglobulin implicated in tumor stemness. However, the relationship between SIA-cIgG and chemoresistance, and its potential as a therapeutic target, remain to be determined. Methods We evaluated the antitumor eficacy of SIA-cIgG inhibition combined with four chemotherapeutic agents using two HNSCC cell lines with high or low SIA-cIgG expression, along with in vivo xenograft models. Furthermore, we investigated the functional roles of SIA-cIgG and its downstream effector PTPN13 in regulating HNSCC stemness. Patient-derived organoids (PDOs) from 25 HNSCC patients were used to compare the antitumor eficacy of anti-SIA-cIgG-based combinations against conventional clinical chemotherapy regimens. Results Elevated SIA-cIgG protein levels correlated positively with an increased IC50 for cisplatin and poorer chemotherapy response. SIA-cIgG/PTPN13 axis was critical for tumor stemness and chemoresistance. Anti-SIA-cIgG treatment enhanced PTPN13 protein stability and upregulated PTPN13 mRNA expression via SP1. Anti-SIA-cIgG-based drug combinations demonstrated significantly higher anticancer efficacy than conventional clinical chemotherapy regimens and overcame tumor heterogeneity in drug response. Conclusions SIA-cIgG/PTPN13 axis regulates tumor stemness and contributes to chemoresistance, anti-SIA-cIgG-based drug combinations exhibit significant potential for clinical application.