“Smart” Nanoparticles Help Reprogram Tumor-Blocking Immune Cells

The immune system does more than fight bacteria and viruses. It also suppresses abnormal cells and removes cancer cells before they can grow. However, once a tumor forms, it can weaken cancer-fighting immune cells and, in some cases, reprogram them to suppress other parts of the immune system.

How tumors interfere with cancer immunotherapy

Overcoming this immunosuppressive tumor environment remains a major barrier to some of the most promising cancer treatments. “One of the biggest challenges in cancer immunotherapy is that while the immune system may be able to attack tumors, the tumor environment can prevent immune cells from working,” explains University of Adelaide Professor Chunxia Zhao in a press release.

Targeted mRNA therapy reprograms tumor-associated macrophages

In a study published this week in Science Advances, Zhao’s team developed a system that precisely delivers mRNA therapy to reprogram immune cells and help them attack tumors. The researchers focused on tumor-associated macrophages. When altered by signals from cancer, these cells can block the arrival and activity of T cells, one of the body’s main defenses against cancer.

The mRNA carries instructions for producing CXCL9, a chemical signal that recruits T cells to the tumor. While mRNA technology has advanced rapidly, particularly since its introduction to the public through coronavirus vaccines, immune-activating signals must be carefully targeted. If they spread throughout the body, they could overstimulate the immune system and cause dangerous, potentially fatal side effects.

How the “smart” nanoparticles work

To deliver the mRNA directly to tumors, the researchers developed what they call “smart” nanoparticles. In mRNA therapies, including standard COVID-19 vaccines, the mRNA is enclosed in a nanoparticle, usually a lipid envelope. This fatty structure helps the molecules enter cells.

The researchers added a targeting mechanism to the nanoparticles. They covered them with antibodies that bind to TREM2, a protein found on the surface of immunosuppressive tumor-associated macrophages. Because tumors contain many different types of cells, this approach is designed to deliver the treatment not only to the tumor site but also to the specific macrophages that need to be reprogrammed.

Promising results in laboratory tests

Along with mRNA, the nanoparticles contain resiquimod, a drug that stimulates specific immune pathways. Initial tests showed that previously inactive macrophages began producing CXCL9 and other markers of an active immune state. Expression of NOS2, one of these markers, increased 89.5-fold, while signals associated with more immunosuppressed states were significantly reduced.

The researchers then administered the smart nanoparticles to mice with advanced breast cancer. After three doses, tumor growth slowed. CXCL9 concentrations were approximately four times higher than in the control group, and the researchers detected T-cell activity. The treatment also reduced the proportion of macrophages with immunosuppressive properties by 63%.

Combining nanoparticles with checkpoint inhibitors

Cancer treatments are often combined to attack tumors from multiple directions. The researchers tested the nanoparticle treatment alongside two types of immunotherapies already in use, known as immune checkpoint inhibitors.

Although the combination did not further reduce tumor size, it produced important changes in the immune system. More types of T cells appeared inside the tumor and in nearby lymph nodes, a finding associated with the potential for a more sustained immune response.