NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Innate immune sensing within the tumor microenvironment (TME) is crucial for effective T cell-targeted immunotherapy.
• NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly expressed in many tumors and represents a potential therapeutic target.
• Current immunotherapies face challenges with resistance in established tumors.

Purpose of the Study:

• To investigate if targeting NQO1 can trigger innate immune sensing to enhance anti-tumor immunity.
• To evaluate the efficacy of NQO1-targeting prodrug β-lapachone in controlling tumor growth.
• To determine if this strategy can overcome resistance to existing immunotherapies.

Main Methods:

• Utilized NQO1-targeting prodrug β-lapachone in preclinical tumor models.
• Assessed β-lapachone bioactivation by NQO1, leading to reactive oxygen species (ROS) generation and oxidative stress.
• Measured release of damage signals, activation of the TLR4/MyD88/type I interferon pathway, and Batf3 dendritic cell cross-priming.
• Evaluated T cell responses and tumor control in established tumors, including combination with checkpoint blockade therapy.

Main Results:

• NQO1-bioactivation of β-lapachone induced tumor-selective innate sensing via ROS production.
• This process triggered the release of high mobility group box 1 (HMGB1), activating the TLR4 pathway and promoting dendritic cell cross-priming.
• Targeting NQO1 effectively reactivated T cells, leading to tumor control and overcoming resistance to checkpoint blockade therapy.

Conclusions:

• Targeting NQO1 with β-lapachone is a potent strategy to stimulate innate immune sensing within the TME.
• This approach bridges innate and adaptive immunity, enhancing T cell-mediated anti-tumor responses.
• NQO1-targeted therapy synergizes with immunotherapy to overcome adaptive resistance in established tumors.