Single-cell N⁶-methyladenosine-related genes function within the tumor microenvironment to affect the prognosis and treatment sensitivity in patients with gastric cancer

Background: Gastric cancer (GC) ranks fifth for morbidity and third for mortality worldwide. The N⁶-methyladenosine (m⁶A) mRNA methylation is crucial in cancer biology and progression. However, the relationship between m⁶A methylation and gastric tumor microenvironment (TME) remains to be elucidated.

Methods: We combined single-cell and bulk transcriptome analyses to explore the roles of m⁶A-related genes (MRG) in gastric TME.

Results: Nine TME cell subtypes were identified from 23 samples. Fibroblasts were further grouped into four subclusters according to different cell markers. M⁶A-mediated fibroblasts may guide extensive intracellular communications in the gastric TME. The m⁶A-related genes score (MRGs) was output based on six differentially expressed single-cell m⁶A-related genes (SCMRDEGs), including GHRL, COL4A1, CAV1, GJA1, TIMP1, and IGFBP3. The protein expression level was assessed by immunohistochemistry. We identified the prognostic value of MRGs and constructed a nomogram model to predict GC patients' overall survival. MRGs may affect treatment sensitivity in GC patients.

Conclusion: Our study visualized the cellular heterogeneity of TME at the single-cell level, revealed the association between m⁶A mRNA modification and intracellular communication, clarified MRGs as an independent risk factor of prognosis, and provided a reference for follow-up treatment.