PRDX6 Modulates Immune Checkpoint Inhibitor Response by Antagonizing Ferroptosis Induced By HDAC Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Therapeutic resistance to histone deacetylase (HDAC) inhibitors and immune checkpoint therapies poses a significant challenge in cancer treatment.
• While HDAC inhibitors can induce ferroptosis, cancer cells frequently develop resistance through antioxidant defense mechanisms.

Purpose of the Study:

• To identify key modulators of resistance to HDAC inhibitors and explore novel therapeutic strategies.
• To investigate the role of peroxiredoxin 6 (PRDX6) in ferroptosis suppression and its impact on cancer immunotherapy.

Main Methods:

• Genome-wide CRISPR activation screening was employed to identify resistance factors.
• Biochemical assays and syngeneic tumor models were utilized to study PRDX6 function.
• PRDX6 depletion effects on lipid peroxidation, ferroptosis, and the tumor microenvironment were assessed.

Main Results:

• PRDX6 was identified as a critical suppressor of ferroptosis induced by the HDAC inhibitor largazole, acting via phospholipase A2 activity and GPX4 expression maintenance.
• PRDX6 depletion significantly enhanced largazole-induced lipid peroxidation and ferroptotic stress.
• PRDX6 knockdown promoted T-cell infiltration and inflammatory cytokine release within the tumor microenvironment.

Conclusions:

• PRDX6 acts as a redox gatekeeper, linking ferroptosis resistance to immune evasion in cancer.
• Combined targeting of PRDX6 and HDAC pathways potentiates anti-PD-L1 immunotherapy efficacy and prolongs survival.
• Co-targeting PRDX6 and HDAC pathways represents a promising strategy to improve cancer immunotherapy responses.