A Dual PI3K/HDAC Inhibitor Induces Immunogenic Ferroptosis to Potentiate Cancer Immune Checkpoint Therapy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Targeted anticancer agents can modulate the immune system, suggesting potential for combination therapies with immunotherapy.
• Developing novel agents that synergize with immunotherapy is crucial for improving clinical outcomes in cancer treatment.

Purpose of the Study:

• To develop and evaluate a novel dual-targeting inhibitor, BEBT-908, targeting PI3K and HDAC.
• To investigate the efficacy of BEBT-908 in potentiating anti-PD1 therapy through the induction of immunogenic ferroptosis.

Main Methods:

• Development of a dual PI3K and HDAC inhibitor, BEBT-908.
• Assessment of BEBT-908's effect on tumor cell growth and ferroptosis induction in vitro and in vivo.
• Evaluation of BEBT-908's impact on the tumor microenvironment and host antitumor immune responses in combination with anti-PD1 therapy in mice.

Main Results:

• BEBT-908 potently inhibits tumor cell growth and induces ferroptosis by hyperacetylating p53 and facilitating ferroptotic signaling.
• Treatment with BEBT-908 promotes a proinflammatory tumor microenvironment, activating host antitumor immunity.
• BEBT-908-induced ferroptosis upregulates MHC class I and activates IFNγ signaling via STAT1, enhancing anti-PD1 therapy efficacy in mice.

Conclusions:

• The dual PI3K/HDAC inhibitor BEBT-908 is a promising targeted therapeutic agent for various cancer types.
• BEBT-908 effectively induces immunogenic ferroptosis in tumor cells, enhancing the efficacy of cancer immunotherapy.