SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC) is a poorly differentiated tumor with dismal prognosis. Currently, there are few molecular features reported on this type of tumor, and exploring the clinico-pathological features of SMARCA4-dNSCLC is crucial for prognosis and investigating treatment options.Immunohistochemistry (IHC) was used to detect the expression of CK, Vimentin, CK7, TTF-1, Napsin-A, P40, CK5/6, Syn, CD34, SALL-4, SOX2, BRG-1, INI-1, PD-L1, and Ki-67 in 9 patients. DNA-based Next-generation sequencing (NGS) technology for tumor-related mutations was applied to detect the relevant molecular characteristics in 6 patients.Among the 9 patients, 8 were male and 1 was female; 6 had a long-term smoking history (10-60 years, 3-40 cigarettes/day); 6 presented with lymph node or bone metastases. For IHC, CK7 was strong positive in all cases. CD34 was negative in all. BRG-1 was consistently absent. INI-1 was not lost in any case. Napsin-A and P40 were positive in 1/9 cases. Vimentin, TTF-1, and Syn were positive in 2/9 cases. CK5/6, SALL-4, and SOX-2 were partially positive in 3/9 cases. PD-L1 expression demonstrated heterogeneous distribution: 33.3 % (3/9) of cases showed negative expression, 55.6 % (5/9) exhibited low expression, and 11.1 % (1/9) demonstrated high expression. and the Ki-67 proliferation index ranged from 20 % to 90 %. Among the 6 patients who underwent genetic testing, SMARCA4 gene mutations were detected in 4 cases (4/6), while TP53 gene mutations were present in all 6 cases (6/6). Genetic alterations in LRP1B were observed in 4 patients (4/6), and KEAP1 gene changes were identified in 3 cases (3/6). STK11 gene alterations were found in 2 patients (2/6), whereas EGFR gene mutation was only detected in 1 case (1/6). None of the 6 patients showed genetic changes in KRAS, ROS, or ALK genes. Regarding tumor mutational burden (TMB), 3 cases demonstrated low TMB frequency while the other 3 exhibited high TMB.This study analyzed the clinicopathological characteristics and immunohistochemical profiles of 9 cases of SMARCA4-dNSCLC, and performed next-generation sequencing on 6 of these cases to preliminarily investigate the molecular genetic alterations in this tumor type. The findings provide reference value for clinicopathological diagnosis and treatment strategy formulation. However, due to limitations including the small sample size and relatively short follow-up period, the conclusions of this study require validation through larger cohort studies. Future work will focus on expanding the sample size, extending follow-up duration, and initiating multicenter collaborations to further elucidate the clinicopathological and molecular characteristics of this disease.Copyright © 2025. Published by Elsevier GmbH.