In groundbreaking studies, researchers at Memorial Sloan Kettering Cancer Center (MSK) have uncovered a surprising link between the body’s innate immune system and cancer development, particularly in breast tissue. Dr. John Petrini and his team at MSK’s Sloan Kettering Institute found that while the innate immune system protects the genome from instability, chronic activation of this system may inadvertently fuel cancer growth.

The studies, recently published in Genes & Development and led by Dr. Hexiao Wang and former senior scientist Dr. Christopher Wardlaw, indicate that the innate immune system plays a critical role in genome stability during DNA replication. This discovery, says Dr. Petrini, sheds light on "how the body’s innate defenses work to sense, signal, and repair DNA damage" and how these processes can sometimes drive cancer.

The MSK team focused on a protein complex known as Mre11, crucial for genome stability by repairing double-strand DNA breaks. In experiments, researchers altered Mre11 in lab-grown mammary tissue organoids before implanting them in mice. They found that in mice where the Mre11 complex was compromised, tumors developed in 40% of cases when cancer-promoting genes, or oncogenes, were introduced, compared to only 5% in normal mice. The tumors in these Mre11-deficient mice were also notably aggressive.

This research highlights how chronic immune responses might contribute to cancer. The team observed elevated activity of interferon-stimulated genes (ISGs) in mice with altered Mre11. Interferons are molecules that cells release in response to infections or cellular stress. When Mre11 is disrupted, the normally secure packaging of DNA becomes loosely accessible, potentially leading to abnormal gene expression. “We saw differences in the expression of more than 5,600 genes,” Dr. Petrini explained, illustrating the profound genetic impact of Mre11 malfunction.

A key player in this process, the team discovered, is the immune sensor IFI205. This sensor activates when the immune system detects DNA instability, triggering interferon pathways that may unintentionally create conditions favorable for cancer growth. When IFI205 was removed, the researchers observed that the disordered DNA structure largely normalized, and cancer rates returned to those of typical mice. “The real lynchpin of this cascade is this innate immune sensor, IFI205,” said Dr. Petrini, which, when active, sends alarm signals that can support cancer development.

The second study by Dr. Wardlaw published in Nature Communications also examined Mre11’s role in maintaining genomic stability. The research found that inactive Mre11 results in the buildup of DNA in the cytoplasm, triggering immune responses that elevate cancer risk. This study highlighted ISG15, a protein associated with the interferon response, as a factor in defending against DNA replication stress.

Taken together, these findings point to a complex relationship between the immune system and cancer. The innate immune system, designed to protect, may contribute to cancer when chronically activated. “These studies shed new light on how the Mre11 complex works to protect the genome,” Dr. Petrini said, “and how, when it’s not working properly, it can trigger the immune system in ways that promote cancer.”

The MSK team hopes these insights will pave the way for targeted cancer treatments. By understanding how immune signaling influences genome stability, researchers may be able to develop therapies to prevent the dangerous consequences of chronic immune activation. As Dr. Petrini notes, this work is part of a broader effort to "identify new strategies to prevent or treat cancer" by interrupting this immune-driven process.