Approximately 1–2% of cases of non-small cell lung cancer (NSCLC) contain ROS1 gene fusions, whereas patients with lung squamous cell carcinoma (LUSC) with these fusions are exceptionally rare. The article describes a case of advanced LUSC with a ROS1 fusion, where the patient achieved a prolonged survival of 42 months thanks to sequential treatment with an ALK tyrosine kinase inhibitor (ALK-TKI) and a ROS1-TKI. Treatment was guided by serial next-generation sequencing (NGS), which showed distinct patterns of genomic changes in the three clinical samples. Immunofluorescence analysis of biopsies revealed treatment-induced changes in the tumor immune microenvironment, including increased CD8+ T-cell infiltration and PD-L1 expression on tumor cells. Peripheral monocyte profiling after Repotrectinib and radiotherapy showed 75% CD8+/CD3+ T cells, 14.2% CD4+/CD3+ T cells, 3.95% regulatory T cells, and 38% PD-1+ CD3+ T cells. The article provides an overview of clinical advances in ALK/ROS1-TKIs for NSCLC and mechanisms of resistance. The case highlights the role of NGS-guided precision oncology at LUSC.