Unveiling SMAD family member 6 as a novel biomarker for prognosis and immunotherapy response in testicular germ cell tumors

Despite its rarity, testicular germ cell tumor (TGCT) is commonly diagnosed in young males aged 20-40. In recent years, the global prevalence of TGCT has gradually increased, with 12-30% of patients experiencing relapse and metastasis. However, there are currently no reliable biomarkers for accurately predicting the prognosis of TGCT patients. Therefore, identifying novel biomarkers for risk stratification in TGCT is an immediate priority. Using TGCT samples from multiple centers, we identified a novel prognostic biomarker (SMAD family member 6 [SMAD6]) through differential expression analysis, Cox regression, and survival analysis. Immunohistochemistry (IHC) was then employed to evaluate SMAD6 expression levels in normal testicular tissues and TGCT samples. Finally, we examined the relationship between SMAD6 and its biological characteristics, mutation landscape, immune cell infiltration, and response to immunotherapy. Our study identified SMAD6 as a risk factor for TGCT prognosis. IHC revealed significant expression of SMAD6 in TGCT tissues. Functional enrichment analysis indicated that SMAD6 may contribute to the activation of tumor progression-related pathways and suppression of immune-related pathways. Additionally, high SMAD6 expression was correlated with reduced CD8+ T cell infiltration, while patients with low SMAD6 expression benefited more from immunotherapy. This study highlights the potential of SMAD6 may be useful for TGCT prognosis and immunotherapy response prediction, offering a promising target for personalized medicine strategies.