Abstract
In 2021, the fifth edition of the World Health Organization (WHO) classification of thoracic tumors introduced a new category, "Thoracic SMARCA4-deficient undifferentiated tumor", highlighting SMARCA4 deficiency as a key molecular marker for classifying as "other pulmonary epithelial tumors". SMARCA4 is a gene encoding a protein involved in chromatin remodeling, and approximately 8% of non-small cell lung cancer (NSCLC) patients exhibit SMARCA4 deletions. These patients are more prone to drug resistance, early recurrence, and unfavorable clinical outcomes. Moreover, NSCLC patients with concomitant SMARCA4 mutations may not benefit from currently available treatments, underscoring the distinctiveness of this subgroup. Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent distinct entities from SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC). This distinction is supported by their divergent pathological characteristics, demographic profiles, and survival outcomes. NSCLC cases deficient in SMARCA4 exhibit high malignancy, yet the precise biological mechanisms underlying this phenomenon remain under intensive investigation. Pathological examination and immunohistochemistry can effectively differentiate SMARCA4-UT from SMARCA4-dNSCLC. SMARCA4-UT typically manifests as adenocarcinoma or, more rarely, as squamous cell carcinoma with undifferentiated rhabdomyoblastic morphology. Therefore, elucidating the mechanisms underlying SMARCA4 alterations in NSCLC and their regulatory roles in tumorigenesis and the microenvironment is crucial. This article aims to discuss the structure, biological functions, significance in NSCLC development, and emerging potential therapeutic strategies related to SMARCA4 while providing clinical practice guidance for NSCLC patients with SMARCA4 deletions.