IFNγ-CIITA-MHC II 轴调节黑色素瘤细胞对 NK 细胞介导细胞毒作用的敏感性

Melanoma, the deadliest form of skin cancer, poses a significant challenge due to its genetic heterogeneity and high metastatic potential. While cytotoxic T cell (CTL)-based immunotherapies have made remarkable progress in recent years, the therapeutic potential of natural killer-(NK) cells is increasingly recognized.

However, resistance mechanisms to both CTL- and NK-cell-mediated immunotherapies hinder effective treatment. To evaluate the exclusive role of NK-cells in anti-melanoma immunity, we performed 2D and 3D co-culture-based cytotoxicity assays under varying conditions.

Our findings revealed a protective phenotype in melanoma cells following prolonged exposure to primary NK-cells. By combining experimental data with bioinformatic analyses, we identified key genes and pathways involved in melanoma cell adaptation to NK-cell-mediated killing (NKmK).

We found that cytokines such as IFN play a major role in suppressing NKmK with MHC II surface expression being a critical factor. Targeting the master regulator CIITA, which governs MHC II expression and is affected by IFN , significantly reduced melanoma cell resistance to NKmK.

This study provides potential strategies to overcome resistance to NK-cell-based immunotherapies and offers novel insights into melanoma immune escape mechanisms.