DRP1 depletion protects NK cells from hypoxia-induced dysfunction

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• Cellular therapies show limited efficacy in solid tumors, largely due to the immunosuppressive tumor microenvironment.
• Tumor hypoxia significantly impairs natural killer (NK) cell function, a critical component of innate immunity against cancer.

Purpose of the Study:

• To investigate the impact of hypoxia on NK cell function.
• To evaluate strategies for restoring NK cell activity under hypoxic conditions.

Main Methods:

• NK cells (unarmed or CAR-engineered) were cultured in normoxia or hypoxia.
• Mitochondrial function, ROS production, and gene expression were analyzed.
• Cytotoxicity assays were performed against cancer cell lines and patient-derived organoids.
• DRP1 function was modulated via pharmacological inhibition or CRISPR-Cas9 knockout.

Main Results:

• Hypoxia reduced NK cell mitochondrial content and membrane potential, increased ROS, and altered gene expression.
• Cytotoxic activity was significantly impaired, even with CAR engineering.
• DRP1 inhibition or knockout restored mitochondrial function and preserved NK cell cytotoxicity under hypoxia.
• DRP1 knockout CAR NK cells maintained efficacy against cancer cell lines in hypoxic conditions.

Conclusions:

• DRP1 inactivation is a viable strategy to enhance NK cell function in the hypoxic tumor microenvironment.
• Metabolic engineering approaches targeting DRP1 may improve CAR-NK cell therapy for solid tumors.