Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency, which is characterized by abnormal immune system functions caused by the lack of expression of WAS protein (WASp). A higher tumor susceptibility is observed in WAS patients; whether this is a direct consequence of impaired immunosurveillance due to WAS deficiency in immune cells is, however, an open question. In this issue of theWiskott-Aldrich syndrome (WAS) or its less severe forms, such as X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN), are caused by the lack of expression of WAS protein (WASp) or its expressed but nonfunctional form, respectively. Both clinical forms are primarily a result of the mutations in the WAS gene. WASp is a 502-amino acid intracellular protein that is exclusively expressed in cells of the hematopoietic system [1]. Together with ubiquitously expressed neural (N)-WASp and SCAR (suppressor of cAMP receptor)/WAVE (WASp-family verprolin homology protein), WASp forms a distinct family of proteins, which are involved in cell signaling and cytoskeletal reorganization. In a steady state, WASp exists in an autoinhibited form, and its activation is dependent on the activity of WIP (WASp interacting protein), Cdc42 (Cell division control protein 42) and PIP2 (phosphatidylinositol biphosphate), upon which the C-terminus of Correspondence: Dr. Chiara Romagnani e-mail: romagnani@drfz.de WASp binds to and activates the Arp2/3 (actin-related proteins) complex [2]. The Arp2/3 complex stimulates actin polymerization by creating a new nucleation core, which is an initial step in the formation of actin filaments [3] and important for processes, such as cell motility, phagocytosis, and the formation of the immunological synapse (IS . The mechanisms underlying this phenomenon could be multiple. In Fig. 1, we try to envisage at which steps Was deficiency could impact on NK-cell-mediated tumor immunosurveillance. These effects might at least partially depend on the inability of NK cells derived from Was −/− mice to form a lytic IS with the tumor cells (Fig. 1). Moreover, WASp has also been implied in regulating the stop signal resulting after the interaction between the NK-cell activating receptor NKG2D and its ligands on the target cells [21]. However, this may only be part of the story since it was shown that the control of B16 cell-derived melanoma depends on IFN-γ produced by NK cells rather than on perforin expression [22]. Although NK cells can produce IFN-γ directly after the interaction with a tumor cell and although T-cell cytokine secretion depends on WASp, the requirements for NK-cell IFN-γ release at the synapse are not well understood [16]. It should be remembered that NK-cell IFN-γ production is also induced by IL-12 and IL-18 derived from mature DCs. Furthermore, mature DCs secrete type I IFN, which enhances the cytotoxic function of NK cells and also mediates NK-cell survival and proliferation through IL-15 transpresentation [23]. Thus, crosstalk with DCs is crucial for NK-cell priming and activation and has also ...