PRDX6 Modulates Immune Checkpoint Inhibitor Response by Antagonizing Ferroptosis Induced By HDAC Inhibitors
Abstract:
Therapeutic resistance limits the efficacy of histone deacetylase (HDAC) inhibitors and immune checkpoint therapies in cancer. While HDAC inhibitors can induce ferroptosis, tumor cells often evade this cell death via antioxidant defenses. Here we identify peroxiredoxin 6 (PRDX6) as a critical modulator of resistance to HDAC inhibitor largazole by suppressing ferroptosis through its phospholipase A2 activity and maintaining GPX4 expression. Using genome-wide CRISPR activation screening, biochemical assays, and syngeneic tumor models, we show that PRDX6 depletion enhances largazole-induced lipid peroxidation, ferroptotic stress, and reshapes the tumor microenvironment to promote T-cell infiltration and inflammatory cytokine release. Importantly, combining PRDX6 knockdown with HDAC inhibition potentiates anti-PD-L1 immunotherapy efficacy and prolongs survival in vivo . These findings reveal PRDX6 as a redox gatekeeper linking ferroptosis resistance to immune evasion and suggest that co-targeting PRDX6 and HDAC pathways may improve responses to cancer immunotherapy.
Insights
Peroxiredoxin 6 (PRDX6) drives resistance to cancer therapies like HDAC inhibitors by suppressing ferroptosis. Targeting PRDX6 enhances cancer cell death and boosts immunotherapy effectiveness.
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.
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