HHLA2 (HERV-H LTR-associating protein 2), also known as B7-H7, is a B7 family immune checkpoint molecule that exhibits dual regulatory functions in immune responses through interactions with distinct receptors 1. The protein functions as a costimulatory molecule when binding to TMIGD2 (CD28H), enhancing T-cell proliferation and cytokine production via AKT-dependent signaling pathways, particularly on resting or naïve T cells 12. Conversely, HHLA2 acts as a coinhibitory molecule through its interaction with KIR3DL3, primarily expressed on activated CD8+ T cells and NK cells, leading to immune suppression via recruitment of SHP-1 and SHP-2 phosphatases that attenuate Vav1, ERK1/2, AKT, and NF-κB signaling 1. This dual mechanism positions HHLA2 as a critical regulator of immune homeostasis within the tumor microenvironment 3. HHLA2 is aberrantly overexpressed in various solid tumors including kidney, lung, gallbladder, stomach, and breast cancers, where it correlates with poor prognosis and tumor immune evasion 12. The KIR3DL3-HHLA2 pathway represents a promising therapeutic target for cancer immunotherapy, with KIR3DL3 blockade showing efficacy in humanized mouse models 12.