Krüppel-like factor 4 downregulation during esophageal cancer formation facilitates immune evasion and impairs immunotherapy.

Impaired antigen processing and presentation are critical for cancer immune evasion, but the underlying mechanism is not fully known. Here, we show that downregulation of Krüppel-like factor 4 (KLF4) expression during the development of cancer is essential in this immuno-decisive process. We find that suppressed KLF4 expression causes diminished MHC class I production in esophageal cancer, forming immunosuppressive niches that limit CD8⁺ T cell infiltration. Mechanistically, KLF4 loss reduces chromatin accessibility at the MHC class I loci and the enhanceosome complex formation, suppressing MHC class I expression. In mouse allografts, KLF4 loss promotes tumor progression and immunotherapy resistance. Extending beyond esophageal cancer, we reveal that low KLF4 levels are significantly correlated with high immunotherapy failure rates across multiple human cancer types. We demonstrate that pharmacological induction of KLF4 results in enhanced antigen presentation, increases activity of CD8⁺ T cells and improves therapeutic efficacy to PD-1 blockade in mouse models. These findings extend our knowledge of cancer immunology and provide a novel insight for improving cancer immunotherapy.