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BZW1 Drives Immune Evasion in Lung Adenocarcinoma via Ferroptosis Suppression
Linyao Zhao1, Yue Peng2, Qing Liang1
1Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Despite multiple therapeutic strategies have provided clinical benefit for certain subsets of non-small cell lung cancer (NSCLC) patients, achieving durable treatment responses remains a significant challenge. Immunotherapy has shown clinical benefits in lung cancer patients, while the efficacy is not quite satisfactory, especially in patients with lung adenocarcinoma (LUAD). Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has recently emerged as a critical regulator of metabolic circuitry and anti-tumor immunity. Here, we identify BZW1 (Basic Leucine Zipper and W2 Domains 1) as a central regulator that promotes immune evasion through ferroptosis suppression in LUAD. Mechanistically, BZW1 attenuates ferroptosis via suppression of FTH1 degradation via autophagic degradation of NCOA4, the selective cargo receptor. Moreover, BZW1 competitively binds with NCOA4 and disrupts the binding of FTH1 and NCOA4, thus inhibiting ferritinophagy-mediated ferritin degradation. BZW1 attenuates ferroptosis and creates an immunosuppressive microenvironment by reducing immunogenic cell death and impairing T cell activation. Our findings establish BZW1 as a ferroptosis suppressor whose inhibition may synergize with immunotherapy in LUAD, highlighting the therapeutic potential of targeting the BZW1-ferroptosis axis for lung cancer treatment.
Insights
Basic Leucine Zipper and W2 Domains 1 (BZW1) suppresses ferroptosis in lung adenocarcinoma, promoting immune evasion. Inhibiting BZW1 may enhance immunotherapy efficacy in LUAD patients.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD), presents challenges in achieving durable treatment responses.
- Immunotherapy offers benefits but has limitations in LUAD efficacy.
- Ferroptosis, an iron-dependent cell death, is increasingly recognized for its role in anti-tumor immunity.
Purpose of the Study:
- To identify key regulators of immune evasion in LUAD.
- To investigate the role of BZW1 (Basic Leucine Zipper and W2 Domains 1) in ferroptosis and anti-tumor immunity.
- To explore the therapeutic potential of targeting the BZW1-ferroptosis axis in LUAD.
Main Methods:
- Investigated the role of BZW1 in LUAD using molecular and cellular assays.
- Examined the mechanism by which BZW1 regulates ferroptosis, focusing on NCOA4 and FTH1.
- Assessed the impact of BZW1 on the tumor microenvironment and T cell activation.
Main Results:
- BZW1 was identified as a central regulator promoting immune evasion by suppressing ferroptosis in LUAD.
- BZW1 attenuates ferroptosis by inhibiting the autophagic degradation of FTH1 via NCOA4.
- BZW1 disrupts the NCOA4-FTH1 interaction, preventing ferritin degradation and promoting an immunosuppressive microenvironment.
Conclusions:
- BZW1 acts as a ferroptosis suppressor in LUAD, contributing to immune evasion.
- Targeting the BZW1-ferroptosis pathway may enhance immunotherapeutic responses in LUAD.
- Inhibition of BZW1 presents a potential therapeutic strategy for lung cancer treatment.
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