Indeed, NK cells have been shown to contribute to the efficacy of anti-PD-1/PD-L1 treatment through reinvigoration of NK cell effector functions [63]. human blood. These cells are characterized by a strong anti-tumor potential in terms of direct killing of cancer cells and immune regulation [1,2,3,4]. Intrinsic NK cell features make them particularly interesting for therapeutic intervention in cancer. Natural killer cells are engaged to kill target cells upon binding of ligands to activating receptors expressed on their cell surface [5,6,7,8,9,10,11,12]. In humans, one of the most efficient activating receptors expressed by NK cells is Cluster of Differentiation (CD) 16 or Fc Receptor (FcR) IIIa [13,14,15,16,17,18,19,20,21]. The Fc receptors bind the Fc portion of the antibody and transduce activating or inhibitory signals into the cells [20]. The FcRIIIa is the main Fc receptor expressed by human NK cells and induces activation signals and killing of target cells opsonized by the antibodies [21]. In some individuals, a fraction of NK cells can express FcRIIc (CD32c), an inhibitory Fc receptor [22]. The study of Fc receptors is difficult because there is a divergence in human and mouse Fc receptor expression and function. Mouse FcRIV seems to be the orthologue of FcRIIIa, and mouse FcRIII is the most closely related Fc receptor to human FcRIIIa [21]. Murine NK cells, in homeostatic conditions, not only express FcRIII but can also express FcRIV in other conditions [21,23,24,25]. Immune checkpoint inhibitors (ICIs) are among the most efficient immunotherapeutic approaches currently used to treat cancer, and are antibodies that bind inhibitory molecules on the surface of tumor-infiltrating lymphocytes allowing anti-tumor immune responses to be reactivated [26,27,28,29,30,31,32,33]. In addition to this blocking ability, ICIs carry an Fc portion that elicits a separate biological effect resulting in the activation of Fc receptors [23,34,35,36,37,38,39,40,41,42,43,44]. In the tumor microenvironment, myeloid cells, monocytes, macrophages, neutrophils, and NK cells comprise the two main subsets of Fc-receptor expressing cells [23,34,35,37,40]. Often myeloid cells are deleterious and tumor-promoting, for this reason their stimulation should be carefully evaluated [45,46,47]. On the other hand, NK cell stimulation may potentially result in both enhanced Fc-mediated functions and increased direct tumor killing [48,49,50]. For this reason, boosting NK cells could represent a better option for combination therapy regimens (Figure 1). Open in a separate window Figure 1 Multiple ways to trigger Fc-receptor function in NK cells. Schematic representation of the agents used to trigger Fc-receptor function in NK cells in the context of tumors. The figure includes the block of inhibitory receptors (mediated by anti-PD1 and anti-NKG2A or Natural Killer Group protein 2A) or the boosting of activating receptors (Interleukin (IL) 12 receptor, IL2/IL15 receptor, ADCC-enhanced antiPD-L1 or CTLA-4 and multifunctional receptor engagers). PD-1: Programmed cell death protein 1; ADCC: antibody-dependent cellular cytotoxicity; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; PD-L1: Programmed death-ligand 1. 2. Immune Checkpoint Inhibitors and NK TFR2 Cell Fc Receptors Antibodies targeting CTLA-4 and/or PD-1/PD-L1 are one of the most promising therapeutic approaches to treating cancer P300/CBP-IN-3 patients. PD-1 and CTLA-4 alone or in combination have been very successful and are approved for the treatment of metastatic melanoma and advanced PD-L1-positive non-small cell lung cancer (NSCLC) [51,52,53,54,55]. PD-1 is expressed by activated T cells and marks the so-called exhausted population of CD8 T cells and CD4. The signature of exhausted P300/CBP-IN-3 T cells represents a post-activation state of highly activated T-cells that undergo a state of anergy, becoming functionally inactive and, thus, unable to kill P300/CBP-IN-3 cancer cells or virus-infected cells [56]. PD-1 is expressed by NK cells, which is upregulated upon viral infection and tumor growth in both mice and human patients [57,58,59,60,61,62,63]. Antibodies targeting PD-1 release the break imposed on cytotoxic T cells and NK cells by the tumor microenvironment, thus allowing anti-tumor immune responses to be re-activated [63,64,65,66]. Anti-PD-1 antibodies in pre-clinical models showed poor Fc-mediated effects [67]. Human anti-PD-1 antibodies used in clinical practices include the human anti-PD-1 nivolumab and the humanized anti-PD-1 pembrolizumab. Both nivolumab and pembrolizumab are IgG4 and both are designed as blocking antibodies and, therefore, have poor Fc-mediated functions in order to avoid depletion of.