Our immune systems are remarkably adept at sounding the alarm when something goes wrong—sometimes even to the point of overreacting. But what happens when a notorious oncoprotein like MYC learns to silence those alarms altogether? A new study reveals how MYC‑driven tumors cloak themselves from immune detection, exposing a previously hidden vulnerability in one of cancer biology’s most challenging targets.
The work, published in Cell under the title “MYC binding to nascent RNA suppresses innate immune signaling by R‑loop‑derived RNA‑DNA hybrids,” was led by researchers at the University of Würzburg (JMU), Massachusetts Institute of Technology (MIT), and Würzburg University Hospital. The study was spearheaded by Leonie Uhl, Amel Aziba, and Sinah Löbbert, with senior leadership from Martin Eilers, PhD, chair of biochemistry and molecular biology at JMU.
“In many types of tumors, this protein is one of the central drivers of cell division and thus of uncontrolled tumor growth,” Eilers explained. Yet despite MYC’s well‑established role in fueling proliferation, one mystery has persisted: Why do MYC‑high tumors often remain invisible to the immune system?
The new study uncovers a surprising answer. Under the chaotic, stressed conditions of rapidly dividing tumor cells, MYC undergoes a dramatic functional shift. As the authors wrote, “In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition,” leaving its usual DNA‑binding sites and relocating to nascent RNA.
Once bound to RNA, MYC forms higher‑order multimers that behave like molecular condensates. These structures concentrate the nuclear exosome, an RNA‑degrading complex, together with its targeting factors at sites rich in double‑stranded RNA and R‑loops. MYC contains four RNA‑binding regions, and one of them—RBRIII—is essential for recruiting the exosome to R‑loops and preventing the buildup of RNA–DNA hybrids.
These hybrids are not harmless byproducts. When allowed to accumulate, they activate the innate immune kinase TBK1 through the TLR3 pattern‑recognition receptor, triggering an antiviral‑like alarm response. By suppressing their accumulation, MYC effectively silences the innate immune alarm system, allowing tumors to grow undetected.
One of the study’s most striking findings is that MYC’s RNA‑binding function is mechanistically distinct from its classical role in transcriptional activation. RBRIII is dispensable for MYC‑driven proliferation in cultured pancreatic cancer cells, but indispensable for sustaining tumor growth in vivo, noted the authors.
This distinction proved critical in preclinical experiments. In mouse models of pancreatic cancer, tumors expressing normal MYC grew 24‑fold over 28 days. But tumors expressing MYC with a defective RNA‑binding region collapsed, shrinking by 94%—an effect that occurred only when the animals’ immune systems were intact, noted Eilers.
Because MYC is essential in healthy cells, attempts to inhibit it broadly have long been considered challenging. But this newly uncovered RNA‑binding function offers a more precise target. “Instead of completely switching off MYC, future drugs could specifically inhibit only its ability to bind RNA,” Eilers explains. “This would potentially leave its growth‑promoting function untouched but lift the tumor’s cloak of invisibility.”
David Scott, PhD, director of Cancer Grand Challenges, added that the work exemplifies how international collaboration can “open up new possibilities, not only for adult cancers but also for childhood cancers.”
The findings mark a conceptual shift: MYC is not just a driver of proliferation—it is also an architect of immune evasion. And that duality may finally offer a way to strike at one of cancer’s most formidable proteins.
