DNA/RNA-binding protein KIN17 supports esophageal cancer progression via resolving noncanonical STING activation...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Targeting the DNA damage response (DDR) can enhance anti-tumor immunity and patient outcomes.
• However, compensatory mechanisms in some cancers limit DDR-targeting therapy efficacy.
• The role of activated DDR proteins in esophageal squamous cell carcinoma (ESCC) remains unclear.

Purpose of the Study:

• Investigate the function of DDR proteins in ESCC progression.
• Determine the impact of DDR protein KIN on the tumor immune microenvironment.
• Explore KIN's role in R-loop resolution and its therapeutic potential in ESCC.

Main Methods:

• Analysis of DDR gene expression in ESCC tissues.
• Depletion of KIN in ESCC cells and assessment of proliferation and DNA damage.
• Investigated KIN's interaction with DHX9 and R-loop resolution.
• Assessed STING pathway activation and immune response following KIN depletion.
• Evaluated KIN depletion effects on the immune microenvironment and immunotherapy in a mouse model.

Main Results:

• Increased DDR gene expression correlates with ESCC progression and a suppressed immune microenvironment.
• Abundant KIN in ESCC facilitates DNA damage repair and apoptosis evasion.
• KIN depletion inhibits ESCC cell proliferation, increases DNA damage, and activates the STING pathway via NFκB signaling.
• KIN acts as an R-loop binding protein, recruiting DHX9 to resolve DNA damage-associated R-loops.
• Depletion of KIN improves the immune microenvironment and enhances immunotherapy efficacy in a mouse model.

Conclusions:

• KIN is a novel R-loop binding protein that promotes ESCC progression by resolving R-loops and suppressing innate immunity.
• Targeting KIN may overcome resistance to DDR-targeting therapies by reactivating anti-tumor immune responses.
• KIN inhibition represents a potential therapeutic strategy to enhance immunotherapy in ESCC.