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

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Limited response to immune checkpoint blockade (ICB) in solid tumors is linked to an unfavorable tumor immune microenvironment (TIME).
• Novel strategies are needed to enhance ICB efficacy in solid tumors.

Purpose of the Study:

• To investigate the potential of FK228, a histone deacetylase inhibitor, as an ICB sensitizer in solid tumors.
• To elucidate the mechanisms by which FK228 modulates the TIME.

Main Methods:

• FK228 was evaluated for its ability to induce necroptosis and endoplasmic reticulum stress in cancer cells.
• Effects of FK228 on immune cell infiltration and phenotype (CD8+ T cells, NK cells, macrophages) within the TIME were assessed.
• Combination therapy with FK228 and a PD-L1 inhibitor was tested in a murine tumor model.

Main Results:

• FK228 acts as a necroptosis inducer by triggering endoplasmic reticulum stress, enhancing cancer cell immunogenicity.
• FK228 increased the infiltration and activation of tumor-killing immune cells, including CD8+ T cells and NK cells.
• FK228 treatment promoted a pro-inflammatory macrophage phenotype and, when combined with PD-L1 blockade, significantly delayed tumor growth and extended survival in mice.

Conclusions:

• FK228 demonstrates potential as a novel sensitizer for immune checkpoint blockade in solid tumors.
• Histone deacetylase inhibition plays a critical role in overcoming immune-suppressive TIME.
• Repurposing FK228 offers new therapeutic possibilities for solid tumor treatment.