Fig. 4.

The challenges of CAR-NK existing in the process from lab production to tumor infiltration. The unsatisfactory CAR transduction efficiency and limited proliferation ability add barriers to CAR-NK production. Multiple approaches including virus-mediated and non-viral-mediated transduction have been utilized to boost CAR expression and stability. The ex-vivo expansion are mainly stimulated by cytokines or feeder cell system with limited potential. Upon infusion into the body, the trafficking and infiltration abilities are impeded by the disruptive chemokines/chemokine receptors axis in the dysregulated tumor vasculature. In tumor bed, suppressive cells (Treg cells, Breg cells and MDSCs) and soluble inhibitory cytokines (TGF-β, IL-10 and IL-6) can disrupt NK cell effector functions. The harsh TME owing to the nutrient deficiency, hypoxia, and acidic conditions can further suppress and dampen NK activities