Colorectal cancer is one of the most common cancers worldwide, and the fourth most common cancer in the UK. While new treatments have improved outcomes for patients, many tumours still find ways to avoid immune responses that might otherwise help control or eliminate them. A recent study led by Dr Parinaz Mehdipour at the Ludwig Institute for Cancer Research, Oxford, has identified an RNA-level mechanism that helps colorectal cancer cells suppress innate anti-tumour immunity, pointing towards a potential new treatment approach.
The study explores how colorectal cancer cells control the accumulation of double-stranded RNA (dsRNA), a molecule often associated with viral infection. Cells can generate viral-like dsRNA from retroelements – repetitive sequences embedded within our genome that are normally kept under tight control. When activated, these elements can form dsRNA, which in turn can trigger a built-in antiviral response known as “viral mimicry”, activating immune signalling against cancer cells. Cancer cells, however, can develop mechanisms to limit this response.
The research identifies a key player in this process: METTL3, an enzyme that adds a chemical modification called m⁶A to RNA molecules, including messenger RNA (mRNA). The m⁶A modification plays a critical role in regulating mRNA stability, splicing and translation into protein. Here, the researchers show that METTL3 suppresses viral mimicry through m⁶A-dependent regulation of retroelement-derived RNAs, thereby limiting dsRNA accumulation. When METTL3 is inhibited, more of these RNAs accumulate in double-stranded forms. This activates intracellular immune sensors, triggering antiviral signalling and ultimately leading to tumour cell death. Importantly, this effect is not uniform across all colorectal cancers. Some models, particularly those with higher levels of m⁶A RNA methylation and a greater capacity to form dsRNA, are sensitive to METTL3 inhibition, while others show little response.
The difference appears to lie not simply in how many retroelements are expressed, but in whether their RNA can form immunostimulatory double-stranded structures. In resistant models, this capacity is limited. However, the research shows that this resistance can be overcome by combining METTL3 inhibition with drugs known as DNA methyltransferase inhibitors, which can release retroelements from DNA-level silencing and increase their transcription. Together, these treatments increase dsRNA levels sufficiently to trigger an immune response.
These findings suggest that METTL3 acts as an “RNA-level immune checkpoint”, helping cancer cells remain hidden from innate immune detection. Targeting this pathway, especially in combination with other therapies, could point towards a new strategy for treating colorectal cancer.