Introduction Thoracic SMARCA4-deficient tumors, which are rare and aggressive malignancies found in the lung or thoracic cavity, present a challenge in treatment standardization. This challenge arises from their resistance to chemotherapy and the absence of targeted therapy options. Methods Thoracic SMARCA4-deficient tumors were identified retrospectively using pathology databases. The clinicopathological characteristics of these tumors are outlined, and the clinical outcomes of advanced patients treated with immune checkpoint inhibitors (ICIs) in combination with chemotherapy and chemotherapy alone are reviewed. Results Thirty-nine patients had thoracic SMARCA4-deficient tumors, with a median age of 62 years. The cohort consisted of 92.3% males, and 89.7% had a history of smoking. Within this group, 94.9% had stage III/IV disease at diagnosis. SMARCA4-deficient non-small cell lung cancer (SMARCA4-DNSCLC) and SMARCA4-deficient undifferentiated tumors (SMARCA4-DUT) display distinct histological and immunohistochemical features. Thirty-five patients underwent systemic therapy, achieving an ORR of 51.4%, a DCR of 82.9%, and a median OS of 20.9 months. Patients were categorized into chemotherapy (28.6%) and ICIs plus chemotherapy (71.4%) groups. The ICIs plus chemotherapy group exhibited an ORR of 64.0% and a DCR of 96.0%, while the chemotherapy group had an ORR of 20.0% and 50.0%, respectively ( P