Esophageal cancer (ESCA) ranks as a leading cause of cancer-related morbidity globally, due to its persistently high incidence and mortality. Statistics reveal that ESCA is the ninth most prevalent cancer in terms of global incidence and the sixth leading cause of cancer-related mortality [1]. In China, esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal cancer cases, posing a significant public health burden [2]. Despite recent advancements in multimodal treatment approaches, the overall survival of ESCC patients has not seen a substantial improvement, especially for those with advanced disease, who face a poor prognosis. Therefore, it is crucial to explore more effective treatment strategies and elucidate the mechanisms of resistance.

Recently, immune checkpoint inhibitors (ICIs) have achieved significant breakthroughs in the realm of tumor therapy. Neoadjuvant chemoimmunotherapy (NACI), which combines PD-1/PD-L1 inhibitors with chemotherapeutic agents (such as nab-paclitaxel and cisplatin) [3], [4], has been shown to significantly increase the pCR rate and progression-free survival in ESCC patients [5], [6]. However, while some patients respond well to NACI, a considerable proportion fail to benefit, indicating the presence of mechanisms of resistance to immunotherapy [2]. Thus, identifying molecular markers of resistance and clarifying their regulatory mechanisms is of great significance for optimizing individualized treatment strategies.

Members of the keratin family have been closely associated with tumor progression and the regulation of the immune microenvironment in various cancers [7]. In ESCC, the overexpression of Keratin 15 (KRT15) has been linked to adverse prognostic factors, including higher T stage, increased lymph node metastasis, and shorter survival [8]. In this study, bioinformatics analysis revealed that KRT15 is predominantly expressed in malignant cells, with negligible expression in immune cells. Previous research has shown that KRT15 is associated with an immunosuppressive microenvironment in multiple cancers. In craniopharyngioma, high KRT15 expression is negatively correlated with the infiltration of regulatory T cells and natural killer T cells (NKT) [9]. In head and neck squamous cell carcinoma (HNSCC), elevated KRT15 expression is associated with reduced infiltration of CD8+ T cells mediated by p53 [10]. These findings suggest that KRT15 may influence the response to immunotherapy by modulating the composition of immune cells in the tumor microenvironment.

In the immune microenvironment regulation of ESCC, CD276 (B7-H3), as an important immune checkpoint molecule, is closely related to tumor immune evasion [11]. It has been reported that β-catenin can promote the transcription of CD276 [12], and GSK3β, as a key regulator of the β-catenin pathway, directly affects the stability of β-catenin [13]. Notably, keratin family members such as KRT19 have been proven to interact with GSK3β to regulate its phosphorylation status [14], providing important clues for studying the functional mechanisms of KRT15 in ESCC. Given the high sequence similarity (>70%) between KRT15 and KRT19, we hypothesize that KRT15 may play a role in modulating the ESCC immune microenvironment via an analogous molecular mechanism.

In summary, this study aims to investigate whether KRT15 modulates NK cell function through the GSK3β/β-catenin/CD276 signaling pathway, thereby influencing the sensitivity of ESCC to NACI treatment.