An international team has identified an early 'Big Bang' moment in colorectal (bowel) cancer when tumor cells first evade immune surveillance, a finding that could refine who benefits from immunotherapy. The work, funded by Cancer Research UK and the Wellcome Trust, analyzed samples from 29 patients and was published in Nature Genetics on November 5, 2025.
Researchers from The Institute of Cancer Research in London, Fondazione Human Technopole in Milan, and Chalmers University of Technology in Sweden report that colorectal cancer undergoes a decisive early event—immune escape—that sets the tumor’s future course. Once this immune-evasive state is established, the tumor’s interaction with the immune system changes little as the cancer grows, the team found.
Professor Trevor A. Graham, Professor of Genomics and Evolution and Director of the Centre for Evolution and Cancer at The Institute of Cancer Research, said: "Some bowel cancers are 'born to be bad.' How they interact with the immune system is set early on. Immunotherapy and bowel cancer vaccines hold enormous promise for treating the disease. Our research suggests that a bowel cancer's relationship with the immune system doesn't change very much as it grows. If we can target that relationship early on, treatment should have a stronger chance of success."
The study examined tumor and immune cells from 29 patients, sequencing DNA and RNA and profiling chromatin accessibility. The authors conclude that epigenetic alterations—not just genetic mutations—reduce expression of antigen‑presenting machinery and silence neoantigens, making cancer cells harder for immune cells to detect. These changes appear early and are shared across the tumor, consistent with a "Big Bang" model of evolution.
Colorectal cancer is a major public health burden in the UK, where it is the fourth most common cancer with about 44,100 new cases each year—roughly 120 per day, according to Cancer Research UK.
The findings also help explain why only a subset of patients benefit from current immunotherapies. About 15% of colorectal cancers are mismatch repair–deficient (MMRd), a group that generally responds to immune checkpoint inhibitors, though not all do; checkpoint blockade is typically ineffective in mismatch repair–proficient tumors. The researchers suggest that combining immunotherapy with drugs that modify the epigenome could enhance antigen display and improve responses, a strategy that will require further testing.
Study lead author Eszter Lakatos, a mathematical biologist at Chalmers University of Technology and the University of Gothenburg, said: "Our research group has investigated and found answers to how cancer cells render themselves invisible to the immune system. Our hope is that these insights will eventually lead to more targeted, effective and early treatments, in addition to surgery."
Cancer Research UK’s Director of Research, Dr. Catherine Elliott, added: "To beat bowel cancer for everyone, we need to understand what happens at the very earliest stages of the disease. No matter how different bowel cancer tumors can look, one defining moment at the start makes a big difference to how the cancer grows."
The paper, "Epigenetically driven and early immune evasion in colorectal cancer evolution," appeared in Nature Genetics on November 5, 2025.
