Somatic activating mutations in the epidermal growth factor receptor (EGFR) are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer (NSCLC), metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy, but patients inevitably experience acquired resistance. Although immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types, their efficacy is limited in cancers harboring activating gene alterations of EGFR. Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3, B7x and HHLA2, is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment (TME). In this review, we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways. Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies. We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers, as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.

表皮生长因子受体 (EGFR) 的体细胞激活突变是癌症中最常见的致癌驱动因素之一，例如非小细胞肺癌 (NSCLC)、转移性结直肠癌、胶质母细胞瘤、头颈癌、胰腺癌和乳腺癌。针对 EGFR 信号通路的分子靶向药物已显示出强大的临床疗效，但患者不可避免地会出现获得性耐药。尽管针对 PD-1/PD-L1 的免疫检查点抑制剂 (ICI) 在多种癌症类型的一部分患者中表现出持久的抗肿瘤反应，但它们在具有 EGFR 激活基因改变的癌症中的功效有限。越来越多的研究表明，新的 B7/CD28 家族成员如 B7-H3、B7x 和 HHLA2 的上调，与 EGFR 信号传导相关，并可能通过创建免疫抑制性肿瘤微环境 (TME) 导致对 EGFR 靶向治疗的耐药性。在这篇综述中，我们讨论了 EGFR 信号对 PD-1/PD-L1 通路和新的 B7/CD28 家族成员通路的调节作用。了解这些相互作用可能会为联合治疗策略提供信息，并可能克服当前对 EGFR 靶向治疗的耐药性挑战。我们还总结了 EGFR 突变癌症中抗 PD-1/PD-L1 疗法的临床数据，以及正在进行的 EGFR 靶向疗法和抗 PD-1/PD-L1 免疫疗法组合的临床试验。我们讨论了 EGFR 信号对 PD-1/PD-L1 通路和新的 B7/CD28 家族成员通路的调节作用。了解这些相互作用可能会为联合治疗策略提供信息，并可能克服当前对 EGFR 靶向治疗的耐药性挑战。我们还总结了 EGFR 突变癌症中抗 PD-1/PD-L1 疗法的临床数据，以及正在进行的 EGFR 靶向疗法和抗 PD-1/PD-L1 免疫疗法组合的临床试验。我们讨论了 EGFR 信号对 PD-1/PD-L1 通路和新的 B7/CD28 家族成员通路的调节作用。了解这些相互作用可能会为联合治疗策略提供信息，并可能克服当前对 EGFR 靶向治疗的耐药性挑战。我们还总结了 EGFR 突变癌症中抗 PD-1/PD-L1 疗法的临床数据，以及正在进行的 EGFR 靶向疗法和抗 PD-1/PD-L1 免疫疗法组合的临床试验。