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M6A Methylation Suppresses anti-tumour immune responses in Colorectal Cancers by Inhibiting Double-stranded RNA accumulation from Alu Repeats [RNA-Seq1]

ABSTRACT: How cancer cells evade immune detection despite expressing immunostimulatory retroelement (RE) transcripts remains an open question in tumour immunology. In cancer cells, endogenous REs that escape histone and DNA silencing are transcribed into RNA and can form double-stranded RNA (dsRNA), triggering innate immune responses through a process known as viral mimicry. However, RNA-level checkpoints can limit this effect. Here, we identify the m6A RNA methyltransferase METTL3 as a key regulator of this suppression in colorectal cancer (CRC). Targeting METTL3 enhances the accumulation of dsRNA derived from both pre-existing and newly transcribed REs, thereby amplifying immunostimulatory signalling and activating cell-intrinsic anti-tumour immunity. Notably, CRCs exhibit differential sensitivity to METTL3 inhibition: tumours with high basal dsRNA levels and RNA methylation respond robustly to METTL3 blockade alone, whereas those with low endogenous dsRNA require combination therapy to achieve comparable immune activation. Co-treatment with DNA methyltransferase inhibitors (DNMTis) restores immune activation in these otherwise resistant tumours. Together, these findings uncover a novel mechanism by which METTL3 functions as an RNA-level immune checkpoint and suggest that combining METTL3 and DNMT inhibition may overcome resistance and serve as an effective therapeutic strategy in CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289971 | GEO | 2026/03/09

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer-related mortality. CRC can be classified into DNA mismatch repair proficient (MMRp) and deficient (MMRd) subtypes, with only ~50% of MMRd tumours responding to immunotherapy. Tumour architecture is spatially heterogeneous, ranging from the necrotic core to the invasive front, accompanied by diverse stromal and immune responses that influence tumour progression and treatment outcomes. To explore the spatial organisation of the tumour-immune microenvironment, we profiled the expression of ~1,000 genes in 846,469 cells from 23 tumour and normal tissue samples using the CosMx Spatial Molecular Imager (SMI). Using a custom bioinformatic pipeline, we performed quality control, cell type annotation, identified 9 spatial niches and provide an interactive web application to explore this data. Spatial niches included normal colonic crypts, tumour masses, neutrophil-rich regions, and lymphoid aggregates. Differential gene expression analysis revealed niche-specific changes to chemokine signalling, T cell infiltration and myeloid cell polarisation could either support or inhibit tumours depending on the niche. To expand the analysis, we integrated public single-cell RNA-Seq datasets, identifying increased tumour stemness in samples with higher neutrophil content that appeared to be driven by inflammation-mediated stromal reprogramming. Additionally, samples enriched in lymphoid aggregates, as defined by a spatial lymphoid aggregate signature, displayed heightened interferon signalling and an increased abundance of proliferating B cells. Finally, we identify gene expression patterns that distinguish tumour cells from normal epithelial cells within tumours. Our analysis reveals that many of the most pronounced changes in tumour gene expression originate from alterations in the tumour microenvironment, while also revealing tumour-intrinsic gene expression. By studying the spatial niches of CRC, we reveal niche-specific dynamics that drive tumours through innate stromal signalling and suggest both tumour-specific and stromally-mediated potential therapeutic targets.

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M6A Methylation Suppresses anti-tumour immune responses in Colorectal Cancers by Inhibiting Double-stranded RNA accumulation from Alu Repeats [RNA-Seq1]

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