KRT15 drives immunosuppression in esophageal squamous cell carcinoma through GSK3β/β-catenin/CD276 signaling

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive disease that carries a poor prognosis and limited therapeutic efficacy, particularly in advanced stages. While immune checkpoint inhibitors (ICIs) have improved outcomes in some patients, resistance mechanisms remain poorly understood. Keratin 15 (KRT15) has been implicated in tumor progression and immune regulation, yet its role in ESCC immunotherapy resistance is unclear.

Transcriptome data from 12 ESCC patients receiving neoadjuvant chemoimmunotherapy (NACI) were analyzed, categorizing them into pathologic complete response (pCR) and non-pCR groups. An independent tissue microarray (TMA) of 102 patients was used to assess KRT15 expression and prognosis. Bioinformatics, immunohistochemistry, and immunofluorescence were employed to validate findings, followed by functional validation.

KRT15 was significantly overexpressed in non-pCR patients and ESCC tissues, correlating with poor prognosis. Genetic silencing of KRT15 enhanced tumor sensitivity to immunotherapy, with increased intratumoral CD8⁺ T cells and NK cells, and reduced CD276 expression. Mechanistically, KRT15 interacted with GSK3β to stabilize β-catenin, promoting CD276 transcription and suppressing NK cell function. Rescue experiments confirmed that CD276 overexpression or GSK3β inhibition reversed these effects.

KRT15 regulated GSK3β phosphorylation to promote β-catenin stability and CD276 expression, thereby inhibiting NK cell function and contributing to immune resistance in ESCC.