64 Quick summary: University of Calgary researchers have discovered that removing a single gene from treatment resistant colon cancer cells strips away their protective invisibility cloak, allowing the immune system to successfully recognize and target the disease. Preclinical trials yielded a 100% eradication of tumours when this gene knockout technique was paired with standard immunotherapy, offering a radical new therapeutic approach for advanced or young onset solid tumours. For clinical healthcare practice and public policy, translating these fundamental findings into human trials is vital towards transforming colorectal oncology, improving survival rates for late stage patients, and enhancing long-term survival well-being. A University of Calgary study has revealed that removing a single gene can make colon cancer cells visible to the immune system, offering new hope for effective immunotherapy treatment of a disease that often evades current approaches. The study, published recently in Cell Reports Medicine, was led by Dr Arshad Ayyaz, an assistant professor in the Department of Biological Sciences and a member of the Arnie Charbonneau Cancer Institute. “We’ve been able to remove the invisibility cloak that colon cancers use to hide from treatment,” says Ayyaz, who has dedicated 20 years to researching the gut. Immunotherapy trains a patient’s own immune system to recognise and attack tumours, reducing or removing the need for radiation and chemotherapy. It has yielded great results for several other types of cancer, but not colon cancer. “Only about 15% of colon cancers respond to immunotherapy. We performed a genetic analysis of them against those that don’t,” Ayyaz says. What the research uncovered was a new type of cancer cell. “The treatment-resistant tumours secrete a protein that confuses your immune system into thinking everything’s fine. It’s like an invisibility cloak,” he says. “So, we thought, what happens if we prevent the tumours from making this protein?” The experiment involved making gene-edited versions of those cancer cells. When the gene that coded the particular protein was knocked out, it made those cells visible to the immune system. The result was 100% eradication of tumours when paired with immunotherapy treatment in mouse models. “I couldn’t believe it at first,” Ayyaz notes. By just knocking out one gene, the results are black and white. “Even without the immunotherapy treatments, the tumours shrank, meaning they can’t hide from the body’s natural immune response anymore.” Colorectal cancer remains a significant health challenge in the UK and globally. According to Cancer Research UK, it is one of the most common cancers, with around 42,000 new cases diagnosed each year. It is the fourth most common cancer in the UK, and survival rates drop substantially when the disease is diagnosed at a later stage. The Canadian Cancer Society lists colorectal cancer as the fourth most diagnosed cancer in Canada, and the third leading cause of death from cancer in both men and women. It is also estimated that 25,300 Canadians will be diagnosed with it, representing 10% of all new cancer cases in a recent year. In people below the age of 50, the incidence of new colorectal cases is on the rise. “Lots of screening programmes are targeted towards catching early stage tumours in older populations, making it hard to find solutions for young patients who are typically diagnosed with an advanced disease,” says Dr Ayyaz. “We still don’t know why more and more people in younger demographics are getting colon cancer, but, in many of their cases, the disease is only detected after it has spread to other tissues and organs. At these stages, the disease is harder to treat, and patient survival is much lower.” Ayyaz says it is very fundamental research that is still quite some distance away from clinical settings. However, the findings might be applicable to other types of cancer. “Immunotherapy is generally ineffective against solid tumours, like those in pancreatic or lung cancer. It’s possible that a similar cloaking mechanism plays a role there. I’m hoping this discovery will go a long way to help us understand these cases better,” says Ayyaz. “There’s a lot of ongoing cancer research and everyone takes a slightly different approach to it. For example, most efforts are focused on making the immune system more effective against cancers, while others, like us, are attempting to find out how cancers can hide themselves from a perfectly functional immune system. Of course, we’re all working towards the same outcome in the end.” Experts note that microsatellite stable colorectal cancers, which form the majority of cases, are particularly resistant to current immunotherapies. This new insight into tumour-intrinsic mechanisms could inform future strategies not only for colon cancer but for other solid tumours where immunotherapy response rates remain low. The study highlights the potential of targeting cancer cell evasion tactics directly. While translation to human trials will require further rigorous testing for safety and efficacy, the complete tumour eradication observed in preclinical models with combined gene knockout and immunotherapy represents a striking contrast to standard outcomes. Researchers emphasise that this approach does not replace existing treatments but could complement them, potentially broadening the number of patients who benefit from immune-based therapies. Continued investment in such fundamental discoveries is seen as vital for advancing precision oncology.