FK228 reshapes tumor microenvironment to enhance anti-PD-L1 efficacy.

The lack of a favorable tumor immune microenvironment (TIME) results in limited response rates to immune checkpoint blockade (ICB) across human solid tumors, necessitating the development of novel combination strategies. In this study, we repurposed FK228, an US FDA-approved histone deacetylase inhibitor that is used clinically in non-solid tumor treatment, as a novel ICB sensitizer in solid tumors and revealed the diverse regulatory functions of FK228 in the TIME. FK228 serves as a novel necroptosis inducer in cancer cells by triggering endoplasmic reticulum stress. This in turn enhances the immunogenicity of cancer cells and increases the infiltration of tumor-killing immunocytes, including CD8 T and natural killer cells, particularly activating tumor-infiltrated CD8 T cells. Meanwhile, FK228 treatment shifts macrophages toward the pro-inflammatory phenotype. Moreover, the combined use of FK228 and a PD-L1 inhibitor significantly delay tumor growth and extend the survival of tumor bearing mice. Overall, our findings reveal new possibilities for the clinical application of FK228 in solid tumors and underscore the critical role of histone deacetylases in maintaining the immune-unfavorable TIME.