BLK suppresses melanoma progression and improves prognosis via pyroptosis regulation

Melanoma progression is characterized by complex molecular mechanisms and immune dysregulation. In this study, we investigated the role of pyroptosis, a caspase-dependent and pro-inflammatory form of programmed cell death, as a potential modulator of anti-tumor immunity. Analysis of datasets from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) revealed that B lymphocyte tyrosine kinase (BLK), a member of the Src family kinases, is significantly downregulated in melanoma samples. Notably, elevated BLK expression was positively associated with improved overall survival. Functional assays in human melanoma cell lines revealed that BLK overexpression significantly suppressed melanoma cell proliferation, migration, invasion, and was associated with pyroptosis, characterized by Caspase-3 activation and subsequent GSDME cleavage. Moreover, analysis of clinical cohort data (TCGA) revealed that high BLK expression correlated with enhanced infiltration of CD8⁺ T cells, NK cells, and M1 macrophages, suggesting an immunostimulatory role in the tumor microenvironment. Importantly, higher BLK expression level was associated with increased sensitivity to immune checkpoint blockade therapies. These findings position BLK as a key regulator of melanoma progression by promoting pyroptosis and strengthening anti-tumor immunity, thus offering a promising biomarker and a potential avenue for enhancing immunotherapeutic efficacy.