Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• KRAS-driven lung cancers often inactivate TP53 and/or STK11/LKB1, creating distinct tumor subclasses.
• KRAS-LKB1 (KL)-mutant lung cancers are aggressive, PD-L1 negative, and poorly responsive to immune checkpoint blockade (ICB).
• The mechanism behind the impaired immunogenicity in KL-mutant lung cancers, despite high mutational load, is unclear.

Purpose of the Study:

• To investigate the mechanistic basis for impaired immunogenicity in LKB1-inactivated KRAS-mutant lung cancers.
• To explore the role of STING (stimulator of interferon genes) signaling in this tumor context.
• To identify potential therapeutic strategies targeting STING restoration.

Main Methods:

• Analysis of STING expression in KL-mutant lung cancer cells.
• Investigation of cytoplasmic double-strand DNA (dsDNA) sensing pathways.
• Assessment of DNMT1 and EZH2 activity and their role in STING regulation.
• Evaluation of the effects of ectopic STING expression on KL cells and downstream signaling (IRF3, STAT1, TBK1).

Main Results:

• LKB1 loss leads to significant silencing of STING expression and insensitivity to cytoplasmic dsDNA sensing.
• STING silencing is partly mediated by DNMT1 and EZH2 hyperactivation due to elevated S-adenylmethionine.
• Ectopic STING expression in KL cells activates IRF3/STAT1 signaling but impairs cellular fitness due to mitochondrial dsDNA accumulation.

Conclusions:

• LKB1 inactivation silences STING, contributing to immune escape and ICB resistance in KRAS-mutant lung cancer.
• Mitochondrial dysfunction and cytoplasmic dsDNA accumulation are consequences of STING activation in this context.
• Restoring STING expression represents a potential therapeutic strategy for treatment-refractory KL-mutant lung cancers.