N ⁶ ‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis

May 15, 2025Cancer communications (London, England)

How m6A-modified RNA controls tiny particle release to create an immune-suppressing environment before stomach cancer spreads to the abdomen

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Abstract

Overexpression of METTL3 in gastric cancer cells is associated with enhanced RAB27A translation and increased exosome biogenesis.

METTL3 modifies the mRNA of RAB27A, facilitating its translation and promoting exosome production.
Exosomes derived from METTL3-overexpressed cells contain the miRNA-17-92 cluster, which targets SRCIN1 to activate SRC signaling in peritoneal macrophages.
Activated macrophages produce a shift in cytokine profiles, elevating IL-10 and TNF while reducing IL-1 and IL-6.
This cytokine shift is linked to inhibited T cell proliferation and cytotoxic activities, contributing to an immunosuppressive environment.
The relationship between METTL3, macrophage activation, and peritoneal metastasis is supported by clinical sample analysis.

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BACKGROUND: Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the (PMN), and its relationship with N-methyladenosine (mA) modification remain unclear. 6 6

METHODS: We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase-like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of mA, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA-immunoprecipitation, dual-luciferase assays, and point mutations in the ras-related protein Rab-27A (RAB27A) in cells. Macrophage and T-cell functions were assessed using enzyme-linked immunosorbent assay, flow cytometry, and cytotoxicity assays. 6

RESULTS: METTL3 overexpression in gastric cancer cells enhanced RAB27A translation by methylating its mRNA A502 base, facilitated by its mA "reader" YTH N-methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA-17-92 cluster was enriched in METTL3-overexpressed cell-derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto-oncogene, non-receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)-10 and tumor necrosis factor (TNF) and reducing the levels of IL-1 and IL-6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples. 6 6

CONCLUSIONS: Our study identified an intricate mA-regulated mechanism of peritoneal PMN development that is mediated by exosome-promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research. 6

Key numbers

5.146

Increased Risk of Peritoneal Metastasis

Odds ratio comparing METTL3-high to METTL3-low gastric cancer patients.

2.4×

Cytokine Elevation

Fold increase in IL-10 levels compared to control exosomes.

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N ⁶ ‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis

Abstract

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