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IL-26-driven epigenetic remodelling promotes immune evasion in colorectal cancer

ABSTRACT: Cancer cells acquire malignant traits through epigenetic remodeling driven by exposure to inflammatory secretomes within 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 that induces epigenetic reprogramming associated with cancer malignancy. We identify a selective accumulation of IL-26–expressing T cells in tumors resistant to immune checkpoint blockade therapy in colorectal cancer. Notably, IL-26 functioned as a noncanonical cytokine by translocating into the nucleus of tumor cells, where it directly bound the transcription factor STAT1 and formed transcriptional complexes with NF-κB and AP-1. Nuclear IL-26 further induced a transcriptionally active chromatin state characterized by enrichment of BRD4 and H3K27ac, resulting in robust upregulation of CXCL chemokines. This process promoted excessive neutrophil infiltration and enhanced immune evasion and tumor progression through suppression of CD8+ T cell responses. Together, these findings support a conceptual model in which tumor-specific type 17 T cells directly reprogram cancer cell epigenetics through IL-26, thereby reshaping the tumor immune microenvironment to promote immune evasion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE334984 | GEO | 2026/06/19

REPOSITORIES: GEO

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Project description:Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer with limited effective therapeutic options. Although immune checkpoint inhibitors (ICIs) have shown little benefit in unselected ovarian cancer populations, clinical activity observed in a subset of OCCC patients suggests the presence of a histotype-specific immune vulnerability that remains poorly defined. To elucidate this biology, we integrated transcriptomic analyses from multiple independent human OCCC cohorts with immunohistochemical profiling and mechanistic studies using an immunocompetent syngeneic OCCC mouse model. Tumor cell–intrinsic and microenvironmental responses to IL-17 were investigated through in vitro stimulation assays, in vivo IL-17 administration, single-cell RNA sequencing of tumor-infiltrating T cells, and immune checkpoint blockade in a Th17-biased partial chimera model. OCCC was characterized as an IL-6–high tumor entity with a globally immune-sparse but CD4⁺ T-cell–skewed tumor immune microenvironment. Transcriptomic analyses identified a Th17-associated program marked by elevated RORC expression in a subset of tumors. Across large clinical cohorts, an IL17A^high subset demonstrated a T cell–inflamed gene expression profile independent of microsatellite instability and tumor mutational burden; however, this phenotype was not associated with survival in untreated disease. Mechanistically, IL-17 directly activated NF-κB–dependent inflammatory programs in OCCC tumor cells, inducing cytokines involved in T-cell recruitment and activation. In vivo, IL-17 remodeled the immune microenvironment, increasing infiltration and activation of both CD4⁺ and CD8⁺ T cells. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4⁺ T cells and cytotoxic, non-terminally exhausted CD8⁺ T cells. Consistent with these findings, anti–PD-L1 therapy significantly improved survival exclusively in Th17-biased partial chimera mice. Collectively, these results demonstrate that a Th17-biased, IL-17–responsive immune contexture in OCCC engages tumor cell–intrinsic NF-κB inflammatory signaling to prime antitumor T-cell states and enable checkpoint blockade efficacy. This immune biology is predictive rather than prognostic, supporting a biomarker-driven immunotherapy strategy for OCCC within otherwise ICI-refractory ovarian cancer.

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IL-26-driven epigenetic remodelling promotes immune evasion in colorectal cancer

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