{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNCR3, which encodes the natural cytotoxicity receptor NKp30, plays a central role in mediating innate immune recognition and elimination of tumors, infected cells and even certain pathogens. Expressed primarily on natural killer (NK) cells and select innate lymphoid cell subsets, NKp30 initiates rapid cytolytic responses and cytokine secretion upon engagement with its tumor‐associated ligands, such as B7‐H6, BAT3 and other stress‐induced molecules. This receptor not only triggers direct tumor cell lysis but also modulates NK–dendritic cell cross talk—for example, promoting dendritic cell maturation via production of TNFα and IFNγ—thus orchestrating downstream immune responses. Furthermore, variations in NKp30 splice isoforms have been linked to differential NK cell functionality and clinical outcomes in cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic studies have revealed that NKp30 engages its ligands via unique binding interfaces that differ substantially from those employed by inhibitory receptors. This distinctive mode of binding underlies NKp30’s ability to associate with diverse ligands such as B7‐H6, which can be either membrane‐bound or released in soluble forms, as well as with other modulatory proteins like Galectin‑3. The interplay of ligand binding, receptor isoform expression, and receptor cross‑talk with other activating molecules (for instance, via co‑receptors such as CD59) is critical for fine‑tuning NK cell activation. In addition, innovative approaches have exploited the extracellular domain of NKp30 to engineer chimeric antigen receptors that redirect T cells to target B7‑H6+ tumors, underscoring the translational potential of understanding NCR3 ligand recognition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond tumor surveillance, NKp30-mediated recognition extends to controlling infectious and immunoregulatory processes. For instance, NKp30 engagement facilitates NK cell cytotoxicity against fungal pathogens and influences immune evasion mechanisms in solid tumors and hematologic malignancies by mediating interactions with myeloid-derived suppressor cells and by being modulated in autoimmune conditions. Moreover, fine-tuning of NK cell responses via NKp30 is evident in its role during early pregnancy in decidual NK cells and in the peripheral blood milieu, where cytokines such as IL-15 further regulate its surface expression. These collective findings highlight NCR3/NKp30’s multifaceted roles in innate immunity and its promise as a target for novel immunotherapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Raffaella Augugliaro, Silvia Parolini, Roberta Castriconi, et al. 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