黑色素瘤靶向分子疗法和免疫疗法的实施极大地改善了手术干预效果有限的患者的治疗结果。然而，很大一部分黑色素瘤患者仍然对这些新的治疗形式难以治疗或产生耐药性，这表明需要改进。在这里，我们报道了临床相关的丝裂原激活蛋白（MAP）激酶通路抑制剂达拉非尼和曲美替尼的组合与 RIG-I 激动剂诱导的免疫疗法协同作用，杀死 BRAF 突变的人和小鼠黑色素瘤细胞。激酶抑制不会损害宿主免疫细胞中 RIG-I 途径激动剂诱导的先天免疫反应。在黑色素瘤移植小鼠模型中，三联疗法优于单独疗法。我们的研究表明，激动剂诱导的 RIG-I 及其合成配体 3pRNA 的激活可以极大地改善大部分接受 MAP 激酶抑制剂的黑色素瘤患者的肿瘤控制。© 2024 作者。

The implementation of targeted molecular therapies and immunotherapy in melanoma vastly improved the therapeutic outcome in patients with limited efficacy of surgical intervention. Nevertheless, a large fraction of patients with melanoma still remain refractory or acquire resistance to these new forms of treatment, illustrating a need for improvement. Here, we report that the clinically relevant combination of mitogen-activated protein (MAP) kinase pathway inhibitors dabrafenib and trametinib synergize with RIG-I agonist-induced immunotherapy to kill BRAF-mutated human and mouse melanoma cells. Kinase inhibition did not compromise the agonist-induced innate immune response of the RIG-I pathway in host immune cells. In a melanoma transplantation mouse model, the triple therapy outperformed individual therapies. Our study suggests that agonist-induced activation of RIG-I with its synthetic ligand 3pRNA could vastly improve tumor control in a substantial fraction of patients with melanoma receiving MAP kinase inhibitors.© 2024 The Authors.