Natural Killer Cell Immunotherapy in Solid Tumors: Microenvironmental Obstacles and Translational 3D Models

Area of Science:

• Immunology
• Cancer Biology
• Biotechnology

Background:

• Natural killer (NK) cells are crucial for cancer immunotherapy.
• Solid tumors present a hostile tumor microenvironment (TME) that limits NK cell efficacy.
• Understanding TME barriers is vital for improving NK cell-based cancer treatments.

Purpose of the Study:

• To review the physical, molecular, and metabolic barriers in the TME that impair NK cell function.
• To evaluate advanced 3D preclinical models for studying TME-NK cell interactions.
• To highlight strategies for overcoming TME-induced NK cell dysfunction.

Main Methods:

• Comprehensive literature review of NK cell dysfunction in the TME.
• Analysis of physical barriers like extracellular matrix (ECM) density.
• Examination of molecular factors (e.g., TGF-β, immune checkpoints) and metabolic stressors (hypoxia, acidosis, adenosine).
• Evaluation of 3D preclinical platforms (spheroids, Organ-on-Chip).

Main Results:

• The TME imposes physical, molecular, and metabolic challenges that inhibit NK cell infiltration, activation, and cytotoxicity.
• Factors like high ECM density, immunosuppressive cytokines, and metabolic stress impair NK cell antitumor activity.
• 3D preclinical models offer distinct advantages for dissecting specific TME components and their impact on NK cells.

Conclusions:

• Deciphering TME barriers is essential for unlocking the therapeutic potential of NK cells in solid tumors.
• Advanced 3D platforms are critical tools for investigating these complex interactions.
• Targeting TME-mediated NK cell dysfunction can enhance cancer immunotherapy outcomes.