5mC plays an important regulatory role in tumorigenesis and development, and the discovery of 5mC regulators further indicate that DNA methylation plays an important role in maintaining genomic stability, mediating tumor cell differentiation, and shaping the tumor microenvironment (TME) [5]. Hu et al. [6] report a novel 5mC regulator-mediated molecular subtype system to predict the classical molecular subtypes, immunophenotypes, and clinical outcomes of BLCA. This study established a 5mC score system according to mRNA expression level, and BLCA patients were characterized into two subgroups according to the score. To note, because the mRNA expression and a high copy number amplification rates of genes (including MDM2, MDM4, DNMT3A, CCND1, FGF3, FGF4, and FGF19) were positively associated with immune-checkpoint blockade (ICB) response and were significantly higher expressed in the high 5mC score group, the incidence of ICB-related hyperprogression may be higher in the high 5mC group. This finding appears to be relevant for clinical treatment response. First, the 5mC score was negatively correlated with the anti-cancer immunity, and a high 5mC score is negatively related to the response to ICB and a higher incidence of ICB-associated hyperprogression. Second, the 5mC score was significantly related to the cancer stemness and could reflect TME heterogeneity. Usually, a higher cancer stemness indicates a decrease in anti-cancer immunity and lower ICB response. Thus, the 5mC score could effectively stratify the immune phenotypes of BLCA. In addition, the 5mC score was able to predict the clinical response to other treatments, including EGFR targeted therapy, radiotherapy, and several therapies targeting immune inhibited oncogenic pathways.
BLCA is one of the most common urinary malignancies. Despite great advances in ICB, neoadjuvant chemotherapy, and targeted therapies, many patients with advanced BLCA are not sensitive to these therapies, and there are no reliable and effective biomarkers or tools to accurately predict the clinical response to these therapies. This study demonstrates that the 5mC regulators-based subtype system could reflect many aspects of bladder cancer biology and provide new insights into bladder cancer therapy.