Background: As a rare tumor with poor prognosis, the first-line treatment strategy of advanced SMARCA4-deficient thoracic tumors is inconclusive. Although previous studies have shown immunotherapy to be effective, the efficacy and safety of different immune checkpoint inhibitors (ICIs) combination treatment strategies have not been explored in detail. This study aims to identify optimal immunotherapeutic combinations for this population. Methods: We collected the clinical and pathological information of 55 patients with SMARCA4-deficient non-small cell lung cancer (SMARCA4-deficient NSCLC) and SMARCA4-deficient undifferentiated tumor (SMARCA4-deficient UT), after which we evaluated and analyzed the survival status and clinicopathological characteristics of the patients. Results: Following statistical analysis, it was found that the patients were mainly male smokers with a mean age of 66 years (range, 46-81 years old). Histologically, NSCLC accounts for the majority (n=40, 72.7%). Survival analysis demonstrated that overall survival (OS) was significantly longer in patients who received first-line immunotherapy compared to those who did not receive immunotherapy for first line (21.67 vs. 8.80 months, P=0.003). A trend of prolonged OS was observed in patients who received immunotherapy in the first line compared with those who received immunotherapy in the latter line (21.67 vs. 15.30 months, P=0.14). Furthermore, the OS of patients who received anti-angiogenesis therapy plus immunotherapy was superior to that of patients who received three other first-line treatments [not reached vs. 21.67 months (chemotherapy plus immunotherapy) vs. 8.80 months (chemotherapy plus anti-angiogenesis therapy) vs. 7.83 months (chemotherapy), P=0.02]. Conclusions: The early use of ICI-based treatment may result in superior survival outcomes for these patients with SMARCA4-deficient thoracic tumors compared to other treatment modalities. Besides, ICIs combined with anti-angiogenesis therapy may be a potential first-line treatment.