{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNCR3LG1, also known as B7‐H6, is a member of the B7 family that is uniquely expressed on stressed and transformed cells, where it serves as a ligand for the activating receptor NKp30 on natural killer (NK) cells. Engagement of B7‐H6 with NKp30 triggers NK cell cytotoxicity and cytokine secretion, thereby promoting tumor cell recognition and elimination. This direct interaction has been substantiated at both functional and structural levels, emphasizing its role as an “induced self” signal in innate immune surveillance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in triggering NK cell activation, tumor‐derived B7‐H6 can be released into the microenvironment by proteolytic shedding, a mechanism that contributes to immune escape. Soluble forms of B7‐H6, generated through the action of metalloproteases, have been shown to attenuate NK cell responsiveness and modulate other immune cell subsets such as group 2 innate lymphoid cells (ILC2s), thereby facilitating tumor immune evasion. The dysregulated release of B7‐H6 has also been observed in hematological malignancies and even in non‐malignant contexts such as liver failure associated with hepatitis B, illustrating its versatile role in modulating immune responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nB7‐H6 expression is not exclusively restricted to tumor cells; in fact, its up‐regulation can also be induced in nontransformed cells such as proinflammatory monocytes and neutrophils upon stimulation with toll‐like receptor ligands and cytokines. This inducible expression under inflammatory conditions, as demonstrated in sepsis, suggests that B7‐H6 may also participate in the regulation of immune responses beyond tumor surveillance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its immunomodulatory functions, B7‐H6 has been implicated in tumor cell–intrinsic processes that influence cancer progression. In several cancer types—including ovarian, glioma, esophageal squamous cell, cervical, medulloblastoma, and melanoma—B7‐H6 expression often correlates with enhanced proliferation, migration, invasion, and even stem‐like features, which in many instances are associated with poor clinical outcomes. Evidence from these studies also points to its dual role: while in some tumors elevated B7‐H6 levels are linked to aggressive behavior and worse prognosis, in others (such as hepatocellular carcinoma) its presence may indicate a more favorable response. This dichotomy underscores the complexity of B7‐H6’s involvement in tumor biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe emerging understanding of B7‐H6’s molecular function has further stimulated the development of novel therapeutic approaches. Preclinical studies in nonhuman primate models have confirmed that NK cell recognition via NKp30 is conserved across species, strengthening the rationale for targeting the B7‐H6/NKp30 axis in cancer. Moreover, innovative strategies—such as the engineering of fusion proteins and the design of immunostimulatory peptides that mimic B7‐H6’s binding interface—have shown promise in enhancing NK cell–mediated anti‐tumor responses, thereby offering new avenues for immunotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, the multifaceted roles of NCR3LG1/B7‐H6—as both an activator of NK cell cytotoxicity and a modulator of tumor and inflammatory cell behavior—underscore its significance in tumor immunosurveillance, immune evasion, and cancer progression. Its variable expression and the context‐dependent outcomes associated with its engagement mark B7‐H6 as a valuable biomarker and a potential therapeutic target across a broad spectrum of malignancies, warranting further investigation into its precise regulatory mechanisms and clinical applications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "24"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "25"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "23"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_fs", "start_ref": "13", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cameron S Brandt, Myriam Baratin, Eugene C Yi, et al. 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