Identification and validation of poor prognosis immunoevasive subtype of esophageal cancer with tumor-infiltrating SAMD3 + NK cell abundance.

INTRODUCTION: Esophageal cancer (EC) remains highly lethal due to tumor microenvironment (TME)-mediated immune evasion. While natural killer (NK) cells are central to antitumor immunity, their functional states in EC are poorly characterized. METHODS: We integrated bulk RNA-seq (TCGA/GEO) and single-cell data to construct an NK cell-derived prognostic signature (NK score) via LASSO-Cox regression. Immunofluorescence was applied to assess the clinical relevance of SAMD3 + NK cells in EC. Using both xenograft mouse models and in vitro co-culture procedures, the impact of SAMD3 on NK cell function was confirmed. RESULTS: In EC patients, the prognostic NK score-which is generated from important NK cell markers including SAMD3-was substantially correlated with a worse chance of survival. NK cells within the TME had significant levels of SAMD3 expression, as seen by immunofluorescence labeling. Moreover, NK cells with SAMD3 knockdown exhibited enhanced antitumor activity, leading to decreased tumor development in the xenograft model. DISCUSSION: Our results demonstrate the predictive significance of NK cell markers in EC and pinpoint SAMD3 as a critical modulator of NK cell activity. We pioneer SAMD3 + NK cells as architects of TME immunosuppression in EC. Our findings nominate SAMD3 inhibition as a combinatorial strategy to overcome immune checkpoint blockade resistance.