Background: SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) is a rare and highly aggressive disease that lack clear treatment guidelines. This research reports the clinicopathological features of SD-TSTs and the promising efficacy of immune-checkpoint inhibitor with chemotherapy in SD-TSTs. Methods: A total of 16 patients were diagnosed and treated with SD-TSTs in Fudan University Shanghai Cancer Center (FUSCC) from January, 2017 to December, 2021. Clinicopathologic, genomic characteristics and treatment information were obtained and analyzed. Results: SD-TSTs were diagnosed at median age of 64.5 years old, and predominantly affected male (100%) with heavier smoking history (≥20 pack-year). Many patients were diagnosed at advanced stages (Stage I 18.8%, Stage II 25%, Stage III 25% and Stage IV 43.8%). The most often metastatic sites were adrenal gland, lymph nodes, bone and liver, while brain metastasis was not found. For patients underwent radical therapy, median disease-free survival is 4.8 months, indicating a rapid relapse pattern even for early-stage patients. 8 patients with Stage IV SD-TSTs were treated in FUSCC. As for first-line therapy, 3 patients received chemotherapy, whose regimen included gemcitabine plus cisplatin, doxorubicin plus ifosfamide, and vincristine, doxorubicin plus cyclophosphamide alternating with ifosfamine and etoposide. 5 patients received immune-checkpoint inhibitor plus chemotherapy as first-line therapy, including 3 patients treated with pembrolizumab plus nab-paclitaxel and carboplatin, 1 patient treated with tislelizumab plus nab-paclitaxel and carboplatin and 1 patient treated with sintilimab plus paclitaxel and carboplatin. Median progression-free survival (PFS) of first line was 6.53 months for all patients. First-line median PFS was significantly higher for patients with immune-checkpoint inhibitor plus chemotherapy than those treated with only chemotherapy (not reach vs. 2.73 months, p = 0.07). This result suggested that SD-TSTs were irresponsive to chemotherapy, including those used for sarcomas, and better responded to immune-checkpoint inhibitor included regimen. Conclusions: SD-TSTs is a highly aggressive disease. Immune-checkpoint inhibitor combined with chemotherapy showed promising efficacy in metastatic SD-TSTs than traditional chemotherapy. Considering the low incidence of SD-TSTs, our research contains the largest sample size by far to report the efficacy of immune-checkpoint inhibitor plus chemotherapy in this deadly disease.