How targeted therapies and immunotherapies shape tumors, and thereby influence subsequent therapeutic responses, is poorly understood. In the present study, we show, in melanoma patients and mouse models, that when tumors relapse after targeted therapy with MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite the different modes of action of these therapies. We find that cross-resistance is mediated by a cancer cell–instructed, immunosuppressive tumor microenvironment that lacks functional CD103⁺ dendritic cells, precluding an effective T cell response. Restoring the numbers and functionality of CD103⁺ dendritic cells can re-sensitize cross-resistant tumors to immunotherapy. Cross-resistance does not arise from selective pressure of an immune response during evolution of resistance, but from the MAPK pathway, which not only is reactivated, but also exhibits an increased transcriptional output that drives immune evasion. Our work provides mechanistic evidence for cross-resistance between two unrelated therapies, and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.

靶向治疗和免疫疗法如何塑造肿瘤，从而影响随后的治疗反应，人们知之甚少。在本研究中，我们在黑色素瘤患者和小鼠模型中表明，当肿瘤在 MAPK 通路抑制剂靶向治疗后复发时，它们对免疫疗法具有交叉耐药性，尽管这些疗法的作用方式不同。我们发现交叉耐药是由癌细胞指导的免疫抑制肿瘤微环境介导的，该微环境缺乏功能性 CD103 ⁺树突状细胞，从而阻碍了有效的 T 细胞反应。恢复 CD103 ⁺树突状细胞的数量和功能可以使交叉耐药肿瘤对免疫治疗重新敏感。交叉耐药性并非由耐药性进化过程中免疫反应的选择性压力引起，而是由 MAPK 通路产生，该通路不仅被重新激活，而且表现出转录输出增加，从而驱动免疫逃避。我们的工作为两种不相关疗法之间的交叉耐药性提供了机制证据，并为在患者对靶向治疗产生耐药性之前使用免疫疗法进行治疗提供了科学依据。