Table 3.

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

Challenges	Possible solutions	References
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]

^aTAA tumor associated antigens, TME tumor microenvironment