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

Qian Zhang1, Bo Yin1, Munaiwaier Sabier1

  • 1Department of Geriatric Respiratory and Critical Care, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|August 19, 2025
PubMed

Insights

Engineered stem cell-NK cell complexes improve solid tumor immunotherapy by enhancing infiltration and function. This novel delivery system overcomes natural killer (NK) cell limitations for better cancer treatment outcomes.

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.
Keywords:
Galectin‐9 blockadeNK cell therapybioorthogonal click chemistrymRNA transfectionmesenchymal stem cells

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