Table 2.

Strategies for potential targets and cytokines to enhance NK cells and ADCC.

Target	Drug/ClinicalExperimental stage	Disease	Main mechanism	Ref.
Potential targets
NKp30/NKp80	B7-H6: HER2-scFv and AICL: HER2-scFv	Breast cancer	Enhances ADCC by the therapeutic antibodies trastuzumab and cetuximab synergistically	(58)
NKG2D/4-1BB/IL-27	NKG2D agonist	Prostate cancer	Improves activator receptor expression in NK cells and promotes the secretion of IFN-γ and TNF-α	(61)
ULBP2	ULBP2:HER2-scFv	Breast cancer	Promotes NK cell cytotoxicity against tumors and enhances ADCC in combination with cetuximab	(59)
CD137	Urelumab	Breast cancer	Overcomes TGF-β-mediated inhibition of human NK-cell proliferation and preserves the expressions of NKG2D, Granzyme B, and IFN-γ	(60)
NKG2A	Monalizumab/UPSTREAM trial	Recurrent/metastatic SCCHN	Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval: 2.7-NE).	(100)
NKG2A	Monalizumab/Phase II Study	Unresectable, Stage III NSCLC	Patients in the durvalumab plus monalizumab group had high objective remission rates and long PFS.	(101)
NKG2A	Monalizumab/Dose-Ranging and Cohort-Expansion Study	Recurrent gynecological malignancies	Intravenous monalizumab (10 mg/kg) treatment every 2 weeks was well tolerated in pretreated gynecological cancer patients. Short-term disease stabilization was observed.	(102)
NKG2A	Monalizumab+cetuximab/Phase II Study	SCCHN	The objective remission rate was 31%. The most common adverse events were fatigue (17%), fever (13%), and headache (10%).	(66)
KIR2D	Lirilumab/Phase II Study	Locally recurrent SCCHN	Adjuvant ivolumab and lirilumab were well tolerated, with a 43% pathologic response rate.	(69 )
KIR2D	IPH2101/Phase II Study	Multiple myeloma	The study was terminated due to the lack of patients meeting the defined primary objective (50% decline in M-protein).	(70)
Cytokines
IL2	FAP-IL-2v conjugates	High-risk neuroblastoma	Reduced tumor growth and improved survival, with increased numbers of NK and cytotoxic T cells	(99 )
IL2	Membrane-bound IL-2	Leukemia	Improved persistence of NK-92 cells and enhanced their anti-tumor activity	(86)
STING/IL2/PD-1	STING agonist	Breast cancer and lung metastasis	Synergized to stimulate sustained granzyme and cytokine expression by lung-infiltrating NK cells	(89)
IL-15	IL-15SA/IL-15RA complex	Breast, prostate, and lung cancers	Blocked the inhibitory effects of TGF-β1 on NK cell activation markers CD226, NKG2D, NKp30 and granzyme B and perforin	(87)
IL15	N-803	Pediatric recurrent and/or metastatic osteosarcoma, neuroblastoma, and GBM multiforme	Increased the proliferative capacity of NK cells and was associated with increased phosphorylation of STAT3, STAT5, AKT, and p38 MAPK	(103)
IL-12/TGF-β	/	Breast cancer	Increased maturation of tumor-associated NK cells	(84)
CISH	/	Breast cancer	CISH deletion also favored NCR signaling and antitumor functions.	(90)
IL-12, IL-27 and GM-CSF	LNPs encapsulated	Melanoma	Induced potent infiltration of immune effector cells and increased secretion of IFN-γ and TNF-α	(93)
IgG4 Fc fragment and IL-15/IL-15Rα	F4RLI (homodimer IL-15 super agonist)	Colorectal cancer	Stimulated the proliferation of human CD3+CD8+ T cells NK cells in vitro, with improved half-life and strong anti-tumor activity	(92)
IL6R/STAT-3	IL6R/STAT-3 inhibitors	Prostate cancer	Decreased STAT-3 phosphorylation level and increased NKP46 expression, thus increasing cytotoxicity of NK-92 cells by increasing FasL, granzyme A, and granzyme B	(97)
VIII Factors	VIII-FcFVIII complex	Hemophilia A	Efficient active NK cells in a CD16-dependent manner, leading to IFN-γ secretion and release of cytolytic perforin and granzyme B	(104)
TNF	Recombinant Mouse IgG2a Antibody TA99	Melanoma	Promoted infiltration of NK cells and macrophages into B16 melanoma	(105)