Scientists Uncover How Cancer Hides From Immune System and Methods to Switch Off Cancer Genes

An international team of researchers has identified a critical biological process that helps pancreatic cancer grow and avoid detection by the immune system. When they interfered with this process in animal studies, tumors shrank dramatically. The findings were published in the journal Cell.

The researchers focused on MYC, a protein long recognized as a major force in cancer biology. MYC is known as an oncoprotein because it pushes cells to divide and multiply. In many types of tumors, this protein is one of the central drivers of cell division and thus of uncontrolled tumor growth. Yet one important mystery remained: tumors with high MYC activity grow aggressively, but they often escape detection by the immune system.

The study reveals that MYC does more than activate genes that promote growth. Under stressful conditions inside rapidly expanding tumors, MYC changes its behavior. Instead of attaching to DNA, it begins binding to newly formed RNA molecules. This shift sets off a chain reaction. Multiple MYC proteins gather into dense clusters known as multimers, forming structures that act like molecular condensates. These clusters draw in other proteins, especially the exosome complex, concentrating them in a single location within the cell.

The exosome complex then carries out a cleanup operation. It breaks down RNA-DNA hybrids, which are faulty byproducts of gene activity. Normally, these hybrids serve as strong internal warning signals, alerting the immune system that something abnormal is happening inside the cell. By organizing the removal of RNA-DNA hybrids, MYC effectively shuts off these warning signals before they can trigger an immune response. Without those signals, the immune system never receives the message that cancer is present.

The team demonstrated that this stealth function depends on a specific RNA-binding region within the MYC protein. Importantly, this region is not necessary for MYC's role in stimulating cell division, meaning the protein's growth-promoting activity and its immune evasion function are separate at a mechanistic level.

To test the importance of this RNA-binding region, researchers engineered MYC proteins that could no longer attach to RNA. The results in animal models were striking. 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. This showed that once the immune system was allowed to recognize the tumor, it played a decisive role in reducing its size.

The research was led by Leonie Uhl, Amel Aziba, and Sinah Löbbert, working with colleagues from the University of Würzburg (JMU), Massachusetts Institute of Technology (USA), and Würzburg University Hospital. The study was directed by Martin Eilers, Chair of Biochemistry and Molecular Biology at JMU, as part of the Cancer Grand Challenges KOODAC team. Funding support came from Cancer Research UK, the Children Cancer Free Foundation (Kika), and the French National Cancer Institute (INCa) through the Cancer Grand Challenges initiative. Additional support was provided by an Advanced Grant from the European Research Council awarded to Martin Eilers.

The findings suggest a new direction for drug development. Attempts to completely block MYC have been challenging because the protein is also essential for normal cells. Shutting it down entirely can cause harmful side effects. The newly identified mechanism offers a more selective option. 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 tumor's cloak of invisibility. In theory, this would allow the immune system to detect and attack cancer cells again.

In separate research, scientists at Monash University, working with Harvard University, report they have found a way to permanently switch off genes that help cancers survive. If the approach holds up in further testing, it could point to a new style of treatment that works with shorter courses and fewer of the harsh side effects that often come with long, continuous cancer therapy. The team described the work in Nature Cell Biology.

Their focus is epigenetic therapy, which aims to change how genes behave rather than rewriting the genes themselves. Epigenetics can be thought of as the cell's operating instructions for when to read a gene and when to keep it quiet. Cancer mutations can corrupt those instructions, locking dangerous growth programs in the "on" position. That problem is especially acute in some aggressive forms of acute leukemia. In these cases, a genetic error takes over the cell's usual gene control machinery, keeping cancer-promoting genes switched on around the clock.

Omer Gilan, Senior Research Fellow at Monash University's School of Translational Medicine and Australian Centre for Blood Diseases, led the team that traced a key part of the mechanism. They found that targeting the epigenetic proteins Menin or DOT1L can permanently switch off cancer-causing genes in leukemia cells. Menin and DOT1L are part of the molecular toolkit cells use to manage gene activity, including chemical signals that help sustain a gene program over time.

Daniel Neville, a Monash PhD candidate and lead author of the Nature Cell Biology study, explained that the advance builds on the concept of cellular "memory" linked to the epigenetic protein DOT1L in cancer cells. The drugs used to target Menin erase the memory provided by DOT1L, and continue killing the cancer cells, even after the treatment has stopped. By reducing the treatment period, patients may tolerate higher doses or be eligible for additional therapies to improve outcomes.

The discovery is set to be tested in a clinical trial run by Monash University and The Alfred, later this year. As clinical trials of Menin inhibitors continue, and particularly moving into combination studies, understanding better how these new therapies work may allow them to be utilized more effectively and with a greater degree of safety in the future.