Table 1.

Resistance to natural killer (NK) cell-based therapy.

Mechanisms	Therapy	Main Resistance Mechanisms	Overcoming Resistance
ADCC	MAbs	- Low NK cell numbers or activity - FCGR3A polymorphisms - Shedding or low expression of CD16 - Loss or modulation of expression of the target antigen - Expression of anti-apoptotic proteins by cancer cells - Tumor microenvironment interactions - Immunosuppressive cytokines and microenvironment - Expression of checkpoint proteins and inhibitory receptors	- Improving mAbs with increased affinity - Combination with immunomodulatory drugs and cytokines - Using multitarget BiKEs and TRiKEs - Metalloproteinase inhibitors to avoid CD16 shedding - Using pro-apoptotic drugs - Targeting inhibitory and immunosuppressive proteins
Missing-self recognition	HSTC allogenic NK cell transfer	- KIR/HLA repertoire - Presence of specific inhibitory KIR genes - Increased expression of non-classical MHC class I molecules - Short lifespan (adoptive transfer) - Poor persistence and trafficking (adoptive transfer)	- Activation and expansion of NK cells - Using allogenic HSTC - Using anti-KIR antibodies
Activating receptors	NK cell transfer Immuno-modulatory drugs and cytokines	- Downregulation of activating receptors or ligands - Increased expression of checkpoint proteins and inhibitory proteins - Expression of anti-apoptotic proteins by cancer cells - Tumor microenvironment interactions - Immunosuppressive cytokines and microenvironment - Short lifespan (adoptive transfer) - Poor persistence and trafficking (adoptive transfer)	- Activation and expansion of NK cells - Induction of NKG2D ligand expression - Using pro-apoptotic drugs - Targeting inhibitory and immunosuppressive proteins - Using NK cell lines (i.e., NK-92) - Therapy with NKG2D CAR-NK cells
Chimeric antigenic receptors	CAR-NK cells	- Short lifespan - Poor activation, persistence and trafficking	- IL-15-expressing CAR-NK cells - Using NK-92 cells as carriers - Combination with mAbs