HA15 inhibits binding immunoglobulin protein and enhances the efficacy of radiation therapy in esophageal squamous cell carcinoma

Proteomic profiling is a promising approach to identify novel predictors of radiation response. The present study aimed to identify potential biomarkers of radiation response by serum proteomics in esophageal squamous cell carcinoma (ESCC) patients and find efficacious therapeutic drugs to enhance the efficacy of radiation therapy (RT). Serum binding immunoglobulin protein (BIP) was identified and validated as a treatment response predictor in ESCC patients treated with RT. Novel BIP inhibitor HA15 showed antitumor activity in ESCC cells by viability assay. Tumor cell colony formation and apoptosis assay revealed targeting BIP was associated with significant improvements of radiation sensitivity. Further analyses revealed that HA15 enhanced radiation-induced endoplasmic reticulum (ER) stress and immunogenic cell death (ICD) in ESCC. Clinical data indicated that high expression of BIP was associated with poor survival in patients of ESCC. In conclusion, proteomics analysis suggested BIP was a promising predictor of radiation response in locally advanced ESCC. The BIP inhibitor HA15 acted as an ER stress inducer and ICD stimulator; RT combined with HA15 was effective in suppressing the growth of ESCC in vitro and in vivo. Pretreatment BIP was an essential prognostic biomarker in locally advanced ESCC patients treated with RT.