Abstract: Objective At present, there are controversies regarding the frequency and optimum treatment regimen of oncogenic driver mutations in squamous cell lung carcinoma （SqCLC） patients. This study aimed to analyze the mutation status and the efficacy of different treatment regimens in this population. Methods Patients with locally advanced and advanced SqCLC diagnosed at the Guangdong Lung Cancer Institute from September 1, 2019, to September 25, 2021, were selected. A retrospective analysis of mutation status and efficacy was performed on all patients who underwent gene detection. To verify and explore the basis for the efficacy of different therapies, drug susceptibility tests using patient-derived organoids and multi-immunohistochemistry （mIHC） were conducted. Results The mutational frequencies of EGFR, ALK, MET, HER2 and RET were 7.8%, 1.1%, 1.2%, 0.6% and 0.6%, respectively. Among the 21 patients with oncogenic driver mutations, a total of 14 patients received first-line tyrosine kinase inhibitors （TKIs）, with an objective response rate （ORR） of 42.9%. The ORR of 3rd-generation TKIs in patients with EGFR mutations was 80.0%. Drug susceptibility tests provided evidence for the potential benefit of targeted therapy. Additionally, the mIHC results indicated the different infiltrating characteristics of macrophages and NK cells in SqCLC patients with oncogenic driver mutations. Conclusions Targeted therapy does have certain benefits in locally advanced and advanced SqCLC patients with oncogenic driver mutations. At the same time, the correlation between the tumor immune microenvironment and the efficacy of both targeted therapy and immunotherapy among this population is worth exploring.