Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Activating innate immunity via viral mimicry converts "cold" tumors to "hot."
• Cytoplasmic nucleic acid sensing pathways are key to this immune activation.

Purpose of the Study:

• Identify factors repressing viral mimicry in small cell lung cancer (SCLC).
• Investigate DHX9 as a potential target for enhancing antitumor immunity.

Main Methods:

• CRISPR-based screen of RNA helicases.
• Depletion of DHX9 in SCLC models.
• Analysis of cytoplasmic dsRNA, R-loops, DNA damage, and replication stress.
• In vivo tumor growth and immunogenic microenvironment assessment.

Main Results:

• DHX9 was identified as a repressor of double-stranded RNA (dsRNA) and R-loops in SCLC.
• DHX9 depletion induced cytoplasmic dsRNA, R-loops, DNA damage, and replication stress.
• DHX9 deletion reduced tumor growth and increased tumor immunogenicity.
• DHX9 inhibition enhanced responsiveness to immune-checkpoint blockade.

Conclusions:

• DHX9 is a critical repressor of tumor-intrinsic innate immunity and replication stress.
• DHX9 is a promising therapeutic target for SCLC and other "cold" tumors.
• Targeting DHX9 can enhance antitumor immunity and immunotherapy efficacy.