목적: Upper aerodigestive squamous cell carcinoma (UASCC), encompassing those arising from the head and neck (HNSCC) and esophagus (ESCC), presents significant challenges in clinical management due to its aggressive nature and unclear mechanisms underlying early malignant transformation. In this study, we elucidate the role of MLL3 mutations as early, clonal genomic events in UASCC tumorigenesis, highlighting their role as foundational drivers of cancer development. 방법: Utilizing CRISPR-edited, cross-species organoid modeling, we demonstrate that loss of MLL3 promotes early squamous neoplastic evolution. 결과:We identify an MLL3/GRHL2 protein complex that regulates the UASCC epigenome, particularly impacting immune response pathways. Notably, a novel MLL3/GRHL2-IRF1 axis promotes the expression of Th1 chemokines, including CXCL9 and CXCL10, enhancing anti-tumor immunity by facilitating T cell infiltration into the tumor microenvironment. In both subcutaneous and orthotopic syngeneic mouse models, we show that MLL3 regulates the in vivo efficacy of immune checkpoint blockade (ICB) therapy. These results are corroborated by the strong association between MLL3 expression and human patients’ clinical response to ICB therapy. 결론:Our work thus underscores the significance of MLL3 in UASCC pathogenesis and highlights the interplay between MLL3/GRHL2 and immune response pathways as potential therapeutic targets for UASCC treatment.