M6A Modifier-Mediated Methylation Characterized by Diverse Prognosis, Tumor Microenvironment, and Immunotherapy Response in Hepatocellular Carcinoma

Objective. Emerging evidence highlights the clinical implications of N-6-methyladenosine (m(6)A) modification in HCC. Yet, the roles of m(6)A modification in modulating cancer immunity and shaping tumor microenvironment (TME) are undefined in hepatocellular carcinoma (HCC). Methods. Here, m(6)A modification classification was determined for HCC through 23 m(6)A modifier levels by employing consensus clustering approach. Prognosis analysis was presented for comparing the differences in survival outcomes. The ssGSEA and ESTIMATE approaches were adopted for evaluating the abundances of tumor-infiltrating immune cell populations. The m(6)A scoring system was computed for reflecting m(6)A modification classification via PCA algorithm. Results. Three m(6)A modifier-mediated modification patterns were established among HCC specimens, which were characterized by different prognosis, signaling pathways, and TME features. After extracting m(6)A phenotype-associated DEGs, we determined m(6)A scores in individual HCC and stratified patients into high- and low-score groups. Patients with low m6A score displayed the survival advantage and higher sensitivity to gemcitabine. Moreover, those with low m(6)A score possessed the better anti-PD-1/PD-L1 therapeutic response in the IMvigor210 immunotherapy cohort. Conclusion. Our findings highlighted that m(6)A modification exerted a nonnegligible role in remodeling diverse and complex TME. Quantification of the m(6)A modification patterns of individual HCC may enhance the comprehension of TME features and facilitate immunotherapeutic plans.