How cancer cells protect themselves from the immune system
Could this mark a shift in how we think about cancer therapy? At least in the laboratory, evidence suggests it may be. An international research team has succeeded in deciphering a key mechanism that controls the growth of pancreatic cancers. The scientists identified a potential central mechanism by which cancer cells protect themselves from attack by the body's own immune system. Blocking this mechanism resulted in a dramatic reduction in tumors in laboratory animals.
In their study, the researchers focused on a specific protein that has long been known in cancer research: the oncoprotein MYC. “In many types of tumors, this protein is one of the central drivers of cell division and thus of uncontrolled tumor growth,” explains the senior author. However, one crucial question remained unanswered: How do tumors with high MYC activity manage to evade the body's immune defences? Although MYC-driven tumors grow very rapidly, they often remain invisible to the immune system.
The answer to this question is provided by the recently published study in the journal Cell. The key discovery made by the international research team is that MYC has a dual function. In addition to its known role of binding to DNA and activating growth-promoting genes, it can change its function when the cell is under stress. Under the chaotic conditions that prevail in rapidly growing tumors, MYC takes on a new function: instead of binding to DNA, it binds to newly formed RNA molecules.
This binding to RNA has far-reaching consequences: several MYC proteins form dense clusters, known as multimers, which function like molecular condensates. These “droplets” act as collection points, specifically attracting other proteins — in particular the exosome complex —and concentrating them in one place.
The exosome complex then breaks down cellular waste products in a very targeted manner – primarily so-called RNA-DNA hybrids. These are defective products of gene activity and normally act like a loud alarm signal inside the cell, signalling to the immune system that something is wrong.
This is precisely where MYC's camouflage function comes into play. By organising the degradation of RNA-DNA hybrids with the help of exosome complexes, it eliminates the alarm signals before they can activate the immune defence. As a result, the downstream signalling chain does not even get started. The tumor remains invisible to the immune cells.
The researchers were able to demonstrate that an RNA-binding region within the MYC protein is responsible for this camouflage. Crucially, this region is not required for MYC's growth-promoting function, i.e. its ability to bind to DNA. The two functions – driving growth and deceiving the immune system – are mechanistically separate.
The next step was obvious: MYC proteins with a genetically modified RNA-binding region should no longer be able to call on the exosome for help and block the alarm pathway. Indeed, the consequences of this discovery were dramatic in the corresponding experiments in animal models: “While pancreatic tumors with normal MYC increased in size 24-fold within 28 days, tumors with a defective MYC protein collapsed during the same period and shrank by 94 per cent – but only if the animals' immune systems were intact,” says the senior author, describing the key finding of the study.
These results open up promising new avenues for cancer therapy. Previous attempts to completely block MYC have proven difficult because the protein is also important for healthy cells. The newly discovered mechanism now offers a much more specific target.
“Instead of completely switching off MYC, future drugs could specifically inhibit only its ability to bind RNA. This would potentially leave its growth-promoting function untouched, but lift the tumour's cloak of invisibility,” explains the author. The tumor would thus become visible and vulnerable to the immune system again.
However, the scientist warns that there is still a long way to go before a corresponding therapy is ready for the market. The next step is to clarify exactly how the immune-stimulating RNA-DNA hybrids are transported out of the cell nucleus and how MYC's RNA binding influences the immediate environment of the tumor.
https://www.cell.com/cell/fulltext/S0092-8674(25)01432-1
https://sciencemission.com/MYC-binding-to-nascent-RNA-suppresses-innate-immune-signaling
