Neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via c-Myc/NRF1 activation.

ABSTRACT: Adoptive transfer of chimeric antigen receptor (CAR)-modified natural killer (NK) cells represents a transformative approach that has significantly advanced clinical outcomes in patients with malignant hematological conditions. However, the efficacy of CAR-NK cells in treating solid tumors is limited by their exhaustion, impaired infiltration and poor persistence in the immunosuppressive tumor microenvironment (TME). As NK cell functional states are associated with IL-2 cascade, we engineered mesothelin-specific CAR-NK cells that secrete neoleukin-2/15 (Neo-2/15), an IL-2Rβγ agonist, to resist immunosuppressive polarization within TME. The adoptively transferred Neo-2/15-armored CAR-NK cells exhibited enhanced cytotoxicity, less exhaustion and longer persistence within TME, thereby having

SUBMITTER: Luo J 

PROVIDER: S-EPMC11873268 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature