Background <p>Stage III non-small cell lung cancer (NSCLC) is heterogeneous and poses significant treatment challenges. In recent years, neoadjuvant therapy has emerged as a promising treatment strategy for patients with stage III NSCLC.</p> Case presentation <p>We report the case of a 39-year-old woman with stage IIIB lung adenocarcinoma harboring a neuroplastin-neuregulin 1 (NPTN<b>-</b>NRG1) fusion who achieved a dramatic response to neoadjuvant afatinib. After three months of therapy, imaging showed a partial response; the patient subsequently underwent complete surgical resection with an uneventful recovery and has remained disease-free to date. To explore the mechanism underlying this response, we performed single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) sequencing of tumor tissues and lymph nodes. The analysis revealed a mutual interaction between CD8⁺ effector T cells, CD8⁺ memory T cells, and natural killer-like (NK-like) T cells via C-C chemokine ligand (CCL)5-C-C chemokine receptor (CCR)5, CCL5-CCR3, and CCL5-CCR1 ligand-receptor pairs. These findings indicate that the post-treatment microenvironment is characterized by active chemokine signaling and immune cell crosstalk, which may contribute to the anti-tumor response.</p> Conclusions <p>This case highlights the efficacy of afatinib in the perioperative treatment of NSCLC with NRG1 fusion, and supports its potential as a personalized therapeutic strategy.</p>