Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by Braf^V600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by Kras^G12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γ^hi, and CD8⁺ cytotoxic and proliferative (versus CD4⁺ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

合理排序和结合 PD-1/L1 和 MAPK 靶向治疗可以克服先天性和获得性耐药性。由于 MAPK 抑制剂 (MAPKi) 增加的临床益处与先前的免疫检查点治疗相关，我们比较了连续和/或组合方案在由Braf ^V600、Nras或Nf1突变以及结肠直肠和Kras ^G12C驱动的胰腺癌。MAPKi 组合之前的抗 PD-1/L1 导入通过促进巨噬细胞的促炎极化和干扰素-γ ^hi和 CD8 ^{+的克隆扩增来优化反应持久性}高度表达激活基因的细胞毒性和增殖性（相对于 CD4 ^{+调节性）T 细胞。}由于黑色素瘤脑转移 (MBM) 的治疗耐药性限制了患者的生存，我们证明在 MAPKi 组合之前对抗 PD-1/L1 治疗进行测序可抑制 MBM，并通过颅内和颅外转移部位的强大 T 细胞克隆扩增提高小鼠生存率。我们建议在 MAPKi 联合治疗之前临床测试短暂的抗 PD-1/L1（± 抗 CTLA-4）剂量以抑制治疗抵抗。