80% of colorectal cancers resist immunotherapy—this DNA treatment could help

A University of Alberta research team has identified a DNA structure that activates the immune system in cancer cells that are usually resistant to immunotherapy, offering hope of new, more effective treatments for colorectal and other cancers.

Principal investigator Kristi Baker, associate professor in the departments of oncology and medical microbiology and immunology, explains that 80% of colorectal cancers are resistant to currently available immunotherapies.

That's because they fail to activate a protein known as STING (stimulator of interferon genes) that is key to antitumor immune responses within cancer cells. In research recently published in Cell Reports, Baker's team identifies and sequences a DNA molecule shown to activate STING-resistant colorectal cancer cells.

"What we're thinking is that by combining immunotherapies with these DNA structures that can super-activate STING, maybe we can induce a much stronger immune response in the patients who normally don't respond," says Baker.

According to Colorectal Cancer Canada, 69 Canadians are diagnosed with colorectal cancer each day, and the Canadian Cancer Society says it is the second leading cause of cancer death in men and the third for women.

The team carried out its experiments in cell cultures, animal models and human "organoids," which are 3D models made from donated human tumor samples. DNA sequencing revealed the highly repetitive DNA structures that trigger STING. The team is now using atomic force microscopy to identify other structures that might also be beneficial.

"When we added the highly repetitive DNA to that really poorly immunogenic tumor type, we could see better STING activation and induce cytotoxic T cells that actually kill tumor cells," says first author Shayla Mosley, a Ph.D. candidate in oncology who led the work as part of her thesis.

"That tells us that this is a way we can improve the immune response against these poorly immunogenic cancers," says Mosley. "We'd like to combine that with immunotherapies and really see an improved response and a decrease in the growth of those tumors."

Mosley notes that radiation and some chemotherapy treatments also increase the presence of the STING-activating DNA structures. By combining treatments, the aim is to create enough of the structures to activate STING and prompt a sufficient immune response to kill the tumors.

"Tumors start to adapt whenever you hit them with a therapy, so if you have another therapy ready that you can then give to your patient, you stay one step ahead in treating the cancer and preventing it from growing," Baker says. "The better we understand what it is about these DNA structures that activates STING, the better we will be able to make a therapy based on this."

Baker gives credit to patients who have donated their expertise and their tissues to support her research through Applied Research & Patient Experience.

Mosley, who hopes to defend her thesis this summer, notes that STING has been implicated in other diseases beyond cancer, including viruses, rheumatoid arthritis and Alzheimer's.

"We're learning in our work how to make a structure that will turn the STING pathway on," she says. "Perhaps in the future we can flip that and make a structure that will turn it off in these autoimmune diseases."

More information: Shayla R. Mosley et al, Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity, Cell Reports (2025). DOI: 10.1016/j.celrep.2024.115177

This article was originally published on MedicalXpress Breaking News-and-Events.