{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Human endogenous retrovirus‐H long terminal repeat–associating protein 2 (HHLA2) is an evolutionarily novel member of the B7 family that modulates T‐cell responses and tumor immunity. Although not expressed in murine tissues, HHLA2 is widely detected on human antigen‐presenting cells and a variety of tumor cells, where its aberrant expression is frequently linked to tumor progression, metastasis, and poor clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Early studies demonstrated that HHLA2 can inhibit CD4+ and CD8+ T‐cell proliferation and impair cytokine production when T‐cell receptor signaling is engaged"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", whereas subsequent work also identified costimulatory functions through engagement with the receptor TMIGD2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and, contrastingly, inhibitory signals via binding to KIR3DL3"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and in transcriptomic analyses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " These divergent functions may be context dependent and are likely determined by the relative expression of its two receptors—TMIGD2, which generally transduces costimulatory signals, and KIR3DL3, which mediates coinhibition—as well as by the tumor milieu."}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n HHLA2 is overexpressed in numerous malignancies including renal cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", non–small cell lung cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", hepatocellular carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and medullary thyroid carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", as well as in osteosarcoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and pancreatic cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In these settings, HHLA2 expression is frequently associated with either an immunosuppressive microenvironment—characterized by a reduced density of CD3+ and CD8+ tumor-infiltrating lymphocytes or enhanced M2 macrophage polarization"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "—or with adverse clinicopathological features such as lymph node metastasis and advanced tumor stage"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Notably, meta‐analyses have underscored that high HHLA2 expression portends a worse overall survival in many solid tumors, although exceptions exist (for instance, in pancreatic ductal adenocarcinoma or certain gliomas it may correlate with a favorable outcome)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Mechanistic studies further reveal that HHLA2 can modulate oncogenic signaling pathways (e.g., EGFR/MAPK/ERK and JAK/STAT) and influence the tumor immune microenvironment, thereby promoting immune escape."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In many tumor models, simultaneous blockade of HHLA2 along with other checkpoints (such as PD-1/PD-L1) is being investigated to overcome tumor-induced immunosuppression and improve antitumor efficacy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "21"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, HHLA2 plays a complex and multifaceted role in cancer immunobiology. Depending on the tumor type and microenvironmental conditions, it may exert coinhibitory and/or costimulatory effects on T cells that ultimately influence tumor progression and patient prognosis. This duality not only highlights its potential as a prognostic biomarker but also underscores its promise as a therapeutic target for next-generation cancer immunotherapy.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ruihua Zhao, Jordan M Chinai, Susan Buhl, et al. 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