Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks.

Spatially confined IL-12 enhances CAR-NK cell activity by sustaining mTORC1, leading to durable tumor control in ovarian and pancreatic cancers.

• Why it matters: Overcoming immunosuppressive tumor microenvironments is crucial for effective immunotherapy, but systemic IL-12 toxicity limits its clinical use.
• What they did: Engineered CAR NK cells with tethered IL-12 that activates within the tumor matrix, promoting mTORC1 activity through Ras-ERK and PI3K pathways, and enabling autonomous expansion.
• The result: This approach improves immune cell persistence and function, remodels the tumor microenvironment, and achieves sustained tumor control without systemic toxicity.