HHLA2: a potential biomarker and therapeutic target in endocrine-related cancer.

[PURPOSE] Human endogenous retrovirus-H long terminal repeat-associating 2 (HHLA2), a member of the B7 family, is widely expressed across human cancers and is emerging as a promising immune checkpoint target for therapeutic development. This study aims to consolidate existing data on HHLA2 expression in endocrine-related cancers and evaluate its potential as a prognostic biomarker.

[METHODS] Original studies published in English up to December 2024 were searched using PubMed, Web of Science and Embase databases. Search strategies combined MeSH terms and keywords related to 'HHLA2', 'B7-H7', 'B7y', 'B7-H5' and 'cancer', with a specific focus on endocrine-related cancers.

[RESULTS] From a total of 117 studies reviewed, twelve met the inclusion criteria. Seven studies on pancreatic cancer indicated varied HHLA2 expression patterns, with high expression levels associated with better prognosis and improved overall survival. In ovarian cancer, one study suggested that high HHLA2 expression in tumor cells could predict improved survival. In contrast, another study linked HHLA2 to lymph node metastasis and poor overall survival, observing high expression only in stromal cells. On the other hand, studies on thyroid cancer and neuroendocrine tumors highlighted HHLA2's significance in disease progression, indicating poor prognosis and its association with metastasis.

[CONCLUSION] HHLA2 plays dual roles, exhibiting both immunosuppressive and tumor-suppressive functions in endocrine-related tumors, with its expression possibly influenced by the tumor microenvironment. This highlights its promise as an immune checkpoint biomarker and therapeutic target. The collective data from this review provide insights for future research endeavors in HHLA2-associated oncology.