Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with limited treatment options. Epidermal growth factor receptor (EGFR) is reported to be expressed in 50%–75% of TNBC patients, making it a promising target for cancer treatment. Here we show that EGFR-targeted chimeric antigen receptor (CAR) T cell therapy combined with radiotherapy provides enhanced antitumor efficacy in immunocompetent and immunodeficient orthotopic TNBC mice. Intriguingly, this combination therapy resulted in a substantial increase in the number of tumor-infiltrating CAR-T cells. The efficacy of this combination was independent of tumor radiosensitivity and lymphodepleting preconditioning. Cytokine profiling showed that this combination did not increase the risk of cytokine release syndrome (CRS). RNA sequencing (RNA-seq) analysis revealed that EGFR-targeting CAR-T therapy combined with radiotherapy increased the infiltration of CD8⁺ T and natural killer (NK) cells into tumors. Mechanistically, radiation significantly increased Icam1 expression on TNBC cells via activating nuclear factor κB (NF-κB) signaling, thereby promoting CAR-T cell infiltration and killing. These results suggest that CAR-T therapy combined with radiotherapy may be a promising strategy for TNBC treatment.

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，治疗选择有限。据报道，表皮生长因子受体 (EGFR) 在 50%–75% 的 TNBC 患者中表达，使其成为癌症治疗的有希望的靶点。在这里，我们表明，靶向 EGFR 的嵌合抗原受体 (CAR) T 细胞疗法与放射疗法相结合，可以增强免疫功能正常和免疫缺陷的原位 TNBC 小鼠的抗肿瘤功效。有趣的是，这种联合疗法导致肿瘤浸润 CAR-T 细胞的数量大幅增加。该组合的功效独立于肿瘤放射敏感性和淋巴细胞清除预处理。细胞因子分析表明，这种组合不会增加细胞因子释放综合征（CRS）的风险。^{RNA测序（RNA-seq）分析显示，靶向EGFR的CAR-T疗法联合放疗增加了CD8 +} T和自然杀伤（NK）细胞向肿瘤的浸润。从机制上讲，辐射通过激活核因子κB（NF-κB）信号显着增加TNBC细胞上Icam1的表达，从而促进CAR-T细胞浸润和杀伤。这些结果表明，CAR-T疗法联合放疗可能是TNBC治疗的一种有前景的策略。