Targeting HDAC and PARP Enhances STING-Dependent Antitumor Immunity in STING-Deficient Tumor

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• The stimulator of interferon genes (STING) pathway is crucial for tumor immunosurveillance.
• STING deficiency in tumors impairs crucial interferon responses, with unclear mechanisms.
• Histone deacetylase (HDAC) suppresses STING expression via reduced H3K9 acetylation at the STING promoter.

Purpose of the Study:

• To elucidate the mechanism of STING suppression by HDAC.
• To investigate the therapeutic potential of combined HDAC and poly(ADP-ribose) polymerase (PARP) inhibition in STING-deficient tumors.
• To evaluate the efficacy of dual HDAC and PARP inhibition in enhancing antitumor immunity and response to immune checkpoint blockade.

Main Methods:

• Investigated HDAC's role in suppressing STING expression using H3K9 acetylation analysis.
• Utilized combined HDAC and PARP inhibition to reinduce STING expression and cytosolic DNA accumulation.
• Assessed the impact of dual inhibition on T cell and dendritic cell infiltration and activation in the tumor microenvironment.
• Studied the effect of dual inhibition on adaptive immune memory and response to immune checkpoint blockade.

Main Results:

• HDAC suppresses STING expression by reducing H3K9 acetylation at the STING promoter.
• Combined HDAC and PARP inhibition reinduced STING expression and activated the interferon response in STING-deficient tumors.
• The bifunctional HDAC and PARP inhibitor induced "BRCAness," restoring synthetic lethality and STING reactivation.
• Dual inhibition promoted T cell and dendritic cell infiltration and activation, significantly enhancing antitumor immunity and immune checkpoint blockade efficacy.
• STING depletion reversed the observed antitumor effects, confirming STING pathway's critical role.

Conclusions:

• HDAC suppresses STING expression, contributing to impaired interferon responses in tumors.
• Combined HDAC and PARP inhibition is a promising strategy to overcome STING pathway deficiency.
• Dual inhibition reinduces STING expression, enhances antitumor immunity, and augments responses to immune checkpoint blockade by inducing adaptive immune memory.