膜结合型 IL-2 促进 CAR-NK 细胞增殖、抗凋亡及抗肿瘤活性

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 -chains (IL-2R or IL-15R ), we generated self-sustaining CAR-NK92 cells that bypass reliance on external cytokines. Among these constructs, membrane-bound IL-2 (mbIL2) demonstrated superior efficacy, driving robust proliferation and resistance to apoptosis under serum-free conditions.

Notably, mbIL2-armored CAR-NK cells exhibited enhanced cytotoxicity against MICA/B-expressing tumor cells.

Mechanistically, mbIL2 mitigated activation-induced apoptosis and suppressed exhaustion during tumor engagement, thereby sustaining NK cell viability.

These findings establish mbIL2 as a critical enhancer of CAR-NK cell persistence and antitumor function, offering a clinically translatable strategy to overcome the limitations of cytokine-dependent therapies.