Table 3 Challenges in building more efficient CAR NK cells for treatment of solid tumors and possible solutions^a

Lack of available targets

 TAA expression not homogenous

Use of oncolytic viruses in combination therapy or bi-specific CARs

[116, 228]

  Clonal evolution

  On-target, off-tumor effects

Anatomical barriers

  Insufficient trafficking or infiltration

Intra-tumoral injection of CAR NK cells; focused ultrasound guided delivery of CAR NK cells into tumor; targeting tumor vasculature; CAR NK cells expressing a chemokine(s)

[149, 155]

Locoregional injection, use of stronger co-stimulatory domains, lymph depletion, in vivo administration of chemokine or cytokine-expressing CARs

[146, 169]

Insufficient NK cell proliferation and/or activation in vivo

  Immunosuppressive TME

TGF-β inhibition through neutralizing antibodies or dominant negative receptors

[229]

Use of cytokines such as IL-2, IL-15, IL-12, or IL-18 to simulate NK cell proliferation and activation

[68]

Inhibition of checkpoint blockades using anti-PD1, anti-TIGIT, etc

[165]

  Metabolic abnormalities

Metabolic stimulation through inhibition of CD73 or arginase

[162]

  NKG2D inhibition by TME

NKG2D activation through histone deacetylase inhibitors

[160, 230]