Targeting immune checkpoint B7-H6 in cancer immunotherapy

Vollständiger Abstract

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Natural killer (NK) cells are central mediators of antitumor immunity and possess the unique ability to recognize and eliminate malignant cells independently of major histocompatibility complex (MHC) restriction. Compared with T-cell-based approaches, NK-cell immunotherapies generally exhibit a more favorable safety profile, highlighting their growing therapeutic potential in oncology. Among the ligands that regulate NK-cell activity, B7-H6 has emerged as a particularly attractive target because of its highly restricted expression in normal tissues and frequent upregulation across diverse malignancies. Initially identified as a ligand for the activating NK-cell receptor NKp30, B7-H6 is now recognized as a multifunctional molecule with roles extending beyond immune recognition. Accumulating preclinical evidence suggests that B7-H6 may contribute to tumor progression by regulating signaling pathways involved in proliferation, survival, migration, invasion, and immune evasion. Furthermore, the existence of soluble B7-H6 adds an additional layer of biological complexity and may influence both NK-cell function and therapeutic responsiveness. In this review, we summarize current knowledge regarding the regulation, expression patterns, and biological functions of B7-H6, with particular emphasis on its dual roles in tumor immunology and cancer cell biology. We discuss the emerging significance of soluble B7-H6, evaluate the current landscape of B7-H6-targeted therapeutic strategies, including bispecific engagers and cellular immunotherapies, and highlight key translational challenges that may influence clinical development. Collectively, current findings position B7-H6 as a promising immuno-oncologic target at the intersection of immune surveillance, immune escape, and malignant progression, warranting continued investigation as a next-generation therapeutic axis in cancer immunotherapy.