RNA m5C methylation orchestrates BLCA progression via macrophage reprogramming

Area of Science:

• Epigenetics
• Cancer Biology
• Immunology

Background:

• Epigenetic modifications, including RNA 5-methylcytosine (m5C), are increasingly recognized for their roles in the tumor microenvironment (TME) and response to immunotherapy.
• The specific functions of m5C modifications within the TME, particularly in bladder urothelial carcinoma (BLCA), remain largely unexplored.

Purpose of the Study:

• To investigate the role of m5C regulators in the BLCA tumor microenvironment.
• To identify m5C-based methylation patterns and their association with patient prognosis and immune cell infiltration.
• To elucidate the functional mechanism of specific m5C regulators, such as NSUN6, in modulating macrophage recruitment.

Main Methods:

• Analysis of 13 m5C regulators in 412 BLCA patients from The Cancer Genome Atlas (TCGA) database.
• Construction of an m5C score using unsupervised clustering and principal component analysis (PCA).
• Gene Set Variation Analysis (GSVA), ESTIMATE algorithm, immunohistochemical (IHC) staining, and macrophage chemotaxis assays were employed.

Main Results:

• Two distinct m5C methylation patterns were identified, correlating with different TME cellular infiltration profiles and patient survival.
• The C1 alteration pattern was associated with improved patient survival.
• NSUN6 was found to be highly correlated with macrophage recruitment, promoting HDAC10 expression via m5C mediation, thereby inhibiting macrophage-associated chemokine transcription and M2 macrophage infiltration.
• A high m5C score predicted a better prognosis in BLCA patients.

Conclusions:

• m5C modifications significantly influence the tumor microenvironment and patient outcomes in BLCA.
• NSUN6 acts as a suppressor of M2 macrophage recruitment through m5C-mediated inhibition of chemokine transcription.
• These findings provide novel insights into the epigenetic regulation of the TME and suggest potential clinical strategies for enhancing immunotherapy.