Targeting NQO1 induces ferroptosis and triggers anti-tumor immunity in immunotherapy-resistant KEAP1-deficient...

Area of Science:

• Oncology
• Cancer Immunology
• Molecular Biology

Background:

• Immunotherapy has transformed cancer treatment but faces limitations due to treatment resistance.
• Tumors with Kelch-like ECH-associated protein 1 (KEAP1) mutations often exhibit resistance to ferroptosis, contributing to poor therapeutic outcomes.
• The precise mechanisms underlying KEAP1-mutant tumor resistance to immunotherapy are not fully elucidated.

Purpose of the Study:

• To investigate the mechanisms of ferroptosis resistance in KEAP1-mutant tumors.
• To identify therapeutic strategies to overcome immunotherapy resistance in these specific cancer types.
• To explore the role of NAD(P)H Quinone Dehydrogenase 1 (NQO1) in KEAP1-mutant tumors and immunotherapy response.

Main Methods:

• Investigated the functional consequences of KEAP1 loss-of-function on ferroptosis.
• Identified NAD(P)H Quinone Dehydrogenase 1 (NQO1) as a downstream target of nuclear factor erythroid 2-related factor 2 (NRF2).
• Utilized preclinical tumor models to validate findings and assess therapeutic interventions.

Main Results:

• Loss of KEAP1 function confers resistance to ferroptosis.
• Induction of NQO1-mediated ferroptosis in KEAP1-deficient tumors initiated an antitumor immune cascade.
• NQO1 protein levels emerged as a potential biomarker for predicting immunotherapy sensitivity in cancer patients.

Conclusions:

• KEAP1 mutations create a distinct tumor phenotype characterized by ferroptosis resistance.
• Targeting the NQO1 pathway presents a promising therapeutic avenue for overcoming immunotherapy resistance in KEAP1-mutant cancers.
• NQO1 induction offers a novel strategy to enhance immunotherapy efficacy in resistant tumors.