INSR Armoring Protects CAR-NK and CAR-T Cells Against Tumor Stroma-Induced CAR Shedding by Maintaining Cholesterol Homeostasis.

INSR overexpression in CAR-NK and CAR-T cells stabilizes lipid rafts and maintains CAR expression, enhancing antitumor activity in gastrointestinal tumor models.

• Why it matters: Solid tumors pose a challenge for CAR therapies due to tumor stroma-induced CAR shedding, which impairs treatment efficacy. Understanding this stromal-mediated immune evasion could enable more effective therapies.
• What they did: The study identified a metabolic mechanism involving CYP27A1-derived 27HC that depletes membrane cholesterol and destabilizes lipid rafts, promoting CAR loss. Researchers engineered INSR-overexpressing CAR-NK92 and primary CAR-T cells to restore cholesterol biosynthesis and stabilize lipid rafts.
• The result: Metabolically armored INSR-overexpressing CAR cells preserved CAR expression and lipid raft integrity, leading to improved antitumor activity in patient-derived organoids, tumor slices, and xenograft models.