B7-H6/NKp30 Axis in Melanoma: Immune Surveillance, Tumor Escape, and Therapeutic Targeting

Melanoma treatment has been transformed by immune checkpoint blockade, yet many patients still experience primary resistance, limited durability of response, or acquired resistance. These limitations underscore the need for additional targets that reflect melanoma biology while enabling new therapeutic strategies. The B7-H6/NKp30 axis has gained attention as a link between tumor cell stress, immune recognition, and therapy-related adaptation. B7-H6 (NCR3LG1), an inducible ligand for NKp30, has been detected in melanoma cell lines and tumor specimens, and soluble B7-H6 has been identified in a subset of patients. Membrane-bound B7-H6 may support NK-cell activation, whereas ligand shedding and accumulation of soluble B7-H6 may reduce effective antitumor recognition and promote immune evasion. Emerging evidence further suggests that B7-H6 expression may be linked to tumor-intrinsic programs relevant to melanoma cell survival, migration, and adaptation to therapeutic stress. In this review, we examine the role of the B7-H6/NKp30 axis in immune surveillance, tumor escape, biomarker development, and therapeutic targeting, and discuss its translational potential in melanoma.