M⁶A Modifier-Mediated Methylation Characterized by Diverse Prognosis, Tumor Microenvironment, and Immunotherapy...

Emerging evidence highlights the clinical implications of N⁶-methyladenosine (m⁶A) modification in HCC. Yet, the roles of m⁶A modification in modulating cancer immunity and shaping tumor microenvironment (TME) are undefined in hepatocellular carcinoma (HCC).

Here, m⁶A modification classification was determined for HCC through 23 m⁶A 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 m⁶A scoring system was computed for reflecting m⁶A modification classification via PCA algorithm.

Three m⁶A modifier-mediated modification patterns were established among HCC specimens, which were characterized by different prognosis, signaling pathways, and TME features. After extracting m⁶A phenotype-associated DEGs, we determined m⁶A 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 m⁶A score possessed the better anti-PD-1/PD-L1 therapeutic response in the IMvigor210 immunotherapy cohort.

Our findings highlighted that m⁶A modification exerted a nonnegligible role in remodeling diverse and complex TME. Quantification of the m⁶A modification patterns of individual HCC may enhance the comprehension of TME features and facilitate immunotherapeutic plans.