Engineered Mesenchymal Stem Cell-NK Cell Complexes for Spatially Targeted and Functionally Revitalized Cancer...

Area of Science:

• Immunology
• Biotechnology
• Cancer Research

Background:

• Natural killer (NK) cells are potent immunotherapeutics but face challenges in solid tumors, including poor infiltration and immunosuppression.
• Existing NK cell therapies struggle with limited efficacy due to the tumor microenvironment's hostile nature.

Purpose of the Study:

• To develop an engineered cell-cell complex delivery system for enhanced NK cell therapy in solid tumors.
• To improve NK cell tumor localization, infiltration, and cytotoxic activity using IL-15 expressing mesenchymal stem cells.

Main Methods:

• Genetically engineered adipose-derived mesenchymal stem cells (SCs) to express interleukin-15 (IL-15) via lipid nanoparticle-mediated mRNA transfection.
• Utilized bioorthogonal click chemistry to conjugate NK cells with engineered SCs, forming SC-NK cell complexes.
• Evaluated the efficacy of SC-NK cell complexes in orthotopic murine lung cancer and patient-derived xenograft ovarian cancer models.

Main Results:

• SC-NK cell complexes demonstrated improved tumor localization and sustained IL-15-mediated functional enhancement.
• Enhanced NK cell infiltration and revitalized cytotoxic activity were observed in both cancer models.
• The complexes showed increased responsiveness to Galectin-9 blockade, reversing NK cell dysfunction and augmenting antitumor efficacy.

Conclusions:

• Engineered SC-assisted delivery systems can overcome NK cell therapy limitations in solid tumors.
• This approach offers a promising strategy for improving therapeutic outcomes in cancer immunotherapy.
• The combination of SCs, NK cells, and targeted blockade therapy presents a novel immunotherapeutic avenue.