IL-26-driven epigenetic remodeling promotes immune evasion in colorectal cancer.

Cancer cells acquire malignant traits through epigenetic remodeling driven by inflammatory secretomes in the tumor microenvironment. However, how immune-derived inflammatory factors regulate cancer cell epigenetics remains poorly understood. Here, we show that IL-26 produced by tumor-specific type 17 T cells acts as a key mediator of epigenetic reprogramming associated with cancer malignancy. We identify selective accumulation of IL-26-expressing T cells in colorectal tumors resistant to immune checkpoint blockade therapy. IL-26 functions as a noncanonical cytokine by translocating into the nucleus of tumor cells, where it directly binds STAT1 and forms transcriptional complexes with NF-κB and AP-1. Nuclear IL-26 induces a transcriptionally active chromatin state characterized by BRD4 and H3K27ac enrichment, resulting in upregulation of CXCL chemokines. This process promotes neutrophil infiltration and enhances immune evasion and tumor progression by suppressing CD8 + T cell responses. Together, these findings support a model in which tumor-specific type 17 T cells directly reprogram cancer cell epigenetics through IL-26, reshaping the tumor immune microenvironment to promote immune evasion.