A membrane-bound IL-2 promotes CAR-NK cell proliferation, anti-apoptosis and anti-tumor activity.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells hold promise for off-the-shelf cancer immunotherapy, yet their clinical application is hindered by poor persistence due to cytokine dependency and systemic toxicity from exogenous cytokine support. Here, we developed membrane-bound cytokine (mbCytokine) modules to enable autonomous survival signaling in CAR-NK cells. By fusing IL-2, IL-15, or the potent mimic Neo-2/15 to their cognate receptor α-chains (IL-2Rα or IL-15Rα), we generated self-sustaining CAR-NK92 cells that bypass reliance on external cytokines.

A novel MICA/B-targeted chimeric antigen receptor augments the cytotoxicity of NK cells against tumor cells.

Chimeric antigen receptor (CAR)-modified immune cells have emerged as a promising approach for cancer treatment, but single-target CAR therapy in solid tumors is limited by immune escape caused by tumor antigen heterogeneity and shedding. Natural killer group 2D (NKG2D) is an activating receptor expressed in human NK cells, and its ligands, such as MICA and MICB (MICA/B), are widely expressed in malignant cells and typically absent from healthy tissue. NKG2D plays an important role in anti-tumor immunity, recognizing tumor cells and initiating an anti-tumor response.

The SpyCatcher-SpyTag interaction mediates tunable anti-tumor cytotoxicity of NK cells.

Chimeric antigen receptor (CAR)-modified T and NK cell immunotherapy is a promising approach for cancer treatment. Due to the lack of tunability in anti-tumor activity, conventional CAR therapies have limited efficacy at low tumor antigen densities. To tune the CAR response to tumor cell surface antigens, we have developed a split CAR using the SpyCatcher-SpyTag system.