Inside a mouse's tumor, one of cancer's sneakiest tricks is being undone by a delivery system no bigger than a virus. At the University of Adelaide, scientists have designed tiny "smart" particles that find the very immune cells helping tumors hide—and reprogram them into cancer fighters instead.
The secret behind these particles is the same technology that delivered COVID-19 vaccines: mRNA wrapped in fatty little bubbles called lipid nanoparticles. But instead of teaching the body to recognize a virus, these particles work deep inside a tumor's environment, where the immune system often gets switched off.
A tumor is like a fortress. It fills its surroundings with cells that tell the body's soldiers, "Stand down, nothing to fight here." One of the most important of these peacekeeping cells is the tumor-associated macrophage, or TAM for short—a large white blood cell that usually helps clean up debris but, inside a tumor, ends up protecting the cancer.
The Adelaide team, led by Professor Chunxia Zhao from the School of Chemical Engineering, didn't destroy these cells. They reprogrammed them. Each nanoparticle was coated with an antibody that latched onto a protein called TREM2, which sits thick on the surface of tumor macrophages. That antibody acts like a key, guiding the particle straight into the right cell.
Once inside, the particle released two tools. The first was a piece of mRNA carrying instructions to make a chemical called CXCL9—a sort of beacon that calls cancer-fighting CD8+ T cells to the tumor. The second was a compound named Resiquimod, which flips the macrophages away from their immune-suppressing behavior.
The results, published in Science Advances, were striking. In mice, the treatment cut the number of immune-suppressing macrophages by more than 60%. CXCL9 levels inside tumors rose fourfold. The researchers also saw more cancer-fighting T cells gathering in the tumor, more active, and a moderate slowing of tumor growth.
"One of the biggest challenges in cancer immunotherapy is that the immune system may be capable of attacking a tumor, but the tumor environment can stop those immune cells from doing their job," Zhao said. "Our approach is designed to change that environment from within the tumor."
When the team paired the treatment with existing drugs that block checkpoints PD-L1 and CTLA-4, they saw even more cancer-fighting T cells and the appearance of central memory T cells—cells that could help the immune system remember and fight cancer in the future. Interestingly, this combination didn't shrink tumors further in this particular mouse model, so there's still much to learn.
Zhao is careful not to overpromise. "There is still significant work to do before this approach could be considered for patients," she said. "But these results provide an encouraging foundation for developing more targeted cancer immunotherapies."
For solid cancers—the hardest tumors to treat, because their environments crowd out the immune system—this is a hopeful proof of concept. The research involved engineers, oncologists and immunologists, with help from SA Pathology and the Royal Adelaide Hospital. The next step is figuring out how these clever particles can be tuned for human tumors. If they work as well outside the lab as they do in mice, this could be a powerful new way to help the body's own defenses win a fight they were built to finish.