Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non–small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand–1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.

表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）是通过阻断致癌受体信号传导来快速杀死肿瘤（例如与非小细胞肺癌相关的肿瘤）的一线疗法，但肿瘤经常复发。在这里，我们观察到大分割 EGFR TKI 治疗 (HypoTKI) 比标准超分割 EGFR TKI 治疗 (HyperTKI) 更有效，并且其与预防肿瘤复发相关的抗肿瘤作用取决于 T 细胞。 HypoTKI 通过 Myd88 信号通路触发对 I 型 IFN 和 CXCL10 产生的更强的先天感应，从而增强肿瘤特异性 T 细胞浸润和再激活。我们还证明，及时的程序性细胞死亡配体-1 (PD-L1) 阻断可以与 HypoTKI 协同控制晚期大肿瘤，并有效限制肿瘤复发，且不会产生严重副作用。我们的研究为探索 EGFR TKI 和免疫疗法的适当组合作为治疗 EGFR 驱动的肿瘤的一线治疗的潜力提供了证据。