Using viral mimicry to help the immune system see — and fight — cancer

Cancer cells are masters of disguise.

Like villains in bad movies, they evade detection by masquerading as healthy cells, turning off the body’s built-in alarm systems and covering their tracks.

Their ability to hide from the immune system has long complicated cancer treatment. In recent years, however, scientists have found a way to turn this strength into a vulnerability.

This novel approach leverages a phenomenon called viral mimicry. Rather than relying on the immune system’s innate cancer detection capabilities, scientists use medications to “trick” the immune system into seeing cancer cells as a viral infection that needs to be eliminated.

“Cancer cells can be hard for the immune system to find because cancer cells start in our own bodies. They aren’t external threats like bacteria and viruses,” explains Dr. Stephen Baylin, a Van Andel Institute Director’s Scholar and the Virginia and D.K. Ludwig Professor of Oncology and Medicine at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center. “Viral mimicry helps the immune system see cancer cells as hazards, which in turn helps the body fight the disease.”

Making mimics

Viral mimicry has a few different meanings in biology.

For example, some viruses can emulate proteins found in the body, masking themselves from the immune system.

But when it comes to cancer, harnessing viral mimicry relies on activating dormant relics of ancient viruses found in our DNA called endogenous retroviruses, or ERVs. ERVs are bits of old viruses that long ago wove themselves into our genetic code.

Most ERVs are kept inactive thanks to an epigenetic process called DNA methylation, which uses chemical tags to silence or activate certain parts of our DNA. Epigenetics govern how and when the instructions in DNA are used without changing the DNA sequence itself.

Research suggests that epigenetic medications that remove methylation can reactivate ERVs. This enables the immune system to detect these now active bits of virus, destroying cancer cells in the process.

“Once these ERVs are switched on, it’s like a Bat Signal for the immune system,” Baylin said. “This approach makes it much harder for cancer cells to hide.”

In 2015, teams that included Baylin and VAI President and Chief Scientific Officer Dr. Peter A. Jones discovered that an epigenetic medication called decitabine works by inducing viral mimicry.¹ Since then, Jones, Baylin and collaborators on the Van Andel Institute–Stand Up To Cancer® Epigenetics Dream Team have launched several clinical trials exploring decitabine and other similar drugs in combination with immunotherapy medications. (In April, Dr. Daniel De Carvalho, the corresponding author of the 2015 study, was awarded the Peter Gilgan Canada Gairdner Momentum Award for his work on viral mimicry. Read more here).

Research into viral mimicry as an anti-cancer strategy also is underway in other VAI labs. In March 2024, Dr. Scott Rothbart and colleagues discovered that combining a pair of epigenetic medications triggered viral mimicry and better combated cancer cells than either drug on its own. The findings are the foundation for a planned phase 1 clinical trial to evaluate this combination as a possible treatment for colorectal cancer and other solid tumors.²   

Reversing resistance

Hiding from the immune system isn’t cancer’s only defense. Cancer cells also can become resistant to treatment, meaning medications that used to work no longer are effective.

Resistance is a particular problem in immunotherapy, which are treatments that harness the cancer-fighting power of the immune system.

Based on data from lab studies and clinical trials, Baylin, Jones and their collaborators believe combining epigenetic medications with immunotherapies can activate viral mimicry and reverse resistance. They also have identified specific molecular signatures that indicate if a person will be resistant to immunotherapy, which one day could open the door to more personalized treatments.  

“Cancer is a wily foe. Studying the many different ways it avoids the immune system helps us develop more effective and more targeted treatments,” Jones said. “Combining medications that switch on viral mimicry with those that boost the immune system may be a powerful way to treat cancer, especially those that resist other therapies.”  

Funding Acknowledgements

Research reported in this publication was supported by:

¹ The Cancer Research Society under award nos. CRS190902 and CRS 19091 (De Carvalho); the Canadian Cancer Society under award no. CCSRI703279, CCSRI703716 and NSERC489073 (De Carvalho); the Ontario Institute for Cancer Research with funds from the province of Ontario, the Princess Margaret Cancer Foundation and University of Toronto McLaughlin Centre under award no. MC-2015-02; the Princess Margaret Cancer Foundation (Pugh); and the National Cancer Institute of the National Institutes of Health under award no. R01CA082422 (Jones); and Stand Up To Cancer®.

² The National Cancer Institute of the National Institutes of Health under award nos. P50CA254897 (Issa, Baylin and Jones; sub-project 7830, Rothbart) and F32CA225043 (Chomiak); and the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM124736 (Rothbart). Scott Rothbart, Ph.D., was supported by a Research Scholar Grant (RSG-21-031-01-DMC) from the American Cancer Society. Rochelle L. Tiedemann, Ph.D., was supported by the American Cancer Society–Michigan Cancer Research Fund Postdoctoral Fellowship (PF-16-245-01-DMC).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding organizations.