Engineered Mesenchymal Stem Cell–NK Cell Complexes for Spatially Targeted and Functionally Revitalized Cancer Immunotherapy

Abstract Natural killer (NK) cells represent a powerful immunotherapeutic strategy due to their intrinsic cytotoxicity and ability to target tumor cells independently of antigen presentation. However, their clinical efficacy against solid tumors is limited by poor tumor infiltration and impaired functionality within the immunosuppressive microenvironment. Here, a genetically engineered cell‐cell complex delivery system comprising NK cells conjugated to IL‐15 expressing adipose‐derived mesenchymal stem cells (SCs) is developed. By exploiting SCs’ intrinsic tumor‐tropic properties and engineering them to consistently express interleukin‐15 (IL‐15) via lipid nanoparticle‐mediated mRNA transfection, the SC‐NK cell complexes exhibit markedly improved tumor localization and sustained cytokine‐mediated functional enhancement. Utilizing bioorthogonal click chemistry for precise conjugation, the approach effectively enhances NK cell infiltration and revitalizes their cytotoxic activity in both orthotopic murine lung cancer and patient‐derived xenograft ovarian cancer models. Furthermore, increased responsiveness of the cell‐cell complexes to Galectin‐9 blockade therapy is identified, leading to the reversal of NK cell dysfunction and significantly augmented antitumor efficacy. Collectively, the engineered SC‐assisted delivery system holds potential for overcoming the limitations of NK cell therapies and improving their therapeutic outcomes in solid tumor.