Cornell engineers and physicians have discovered that ultrasmall silica nanoparticles can flip “cold” tumors “hot,” helping immunotherapy work better in tough-to-treat cancers. The finding could open a new path for treating melanoma and other solid tumors.
Tiny particles first designed to light up cancers on a scan are now showing they can help the immune system fight those tumors from the inside out.
A Cornell-led team has found that ultrasmall silica nanoparticles, called Cornell prime dots or C’dots, can reprogram the environment around melanoma tumors and dramatically boost the power of cancer immunotherapy in mouse models.
The research, led by Michelle Bradbury of Weill Cornell Medicine and engineer Ulrich Wiesner of Cornell Engineering, is published in the journal Nature Nanotechnology.
C’dots are fluorescent, core-shell silica nanoparticles that have already been tested in human clinical trials as imaging tools and drug carriers. The new study reveals something unexpected: the particles themselves act as potent cancer-fighting agents, even without carrying a drug.
“It’s a very surprising discovery,” Wiesner, the Spencer T. Olin Professor of Engineering in the Department of Materials Science and Engineering whose lab originally developed C’dots, said in a news release. “C’dots on their own – without any pharmaceutical entity on their surface – induce a whole range of antitumoral effects in the TME of melanoma models that, in part, are entirely unexpected.”
The tumor microenvironment, or TME, is the complex neighborhood of cancer cells, immune cells, blood vessels and support tissues that surrounds a tumor. In many aggressive solid cancers, this environment is hostile to the immune system and resists modern immunotherapies, which are drugs that unleash the body’s own defenses against cancer.
Melanoma, along with prostate, breast and colon cancers, often creates what researchers call “cold” tumors. These tumors do not trigger a strong immune response and frequently fail to respond to immunotherapy.
In the new study, the Cornell team used aggressive, immunotherapy-resistant melanoma models to test what happens when C’dots are introduced into this suppressive environment. They found that the nanoparticles activate several antitumor processes at once.
The particles stimulated innate immune responses by engaging pattern-recognition receptors, the cellular sensors that detect danger signals. They pushed cancer cells into cell-cycle arrest, slowing or stopping their ability to multiply. They reduced immune suppression in the tumor microenvironment and reprogrammed key immune cells, including T cells and macrophages, to attack cancer more effectively.
This changes how scientists think about the role of such nanoparticles, according to Bradbury, the Endowed Professor of Imaging Research in Radiology and a professor of radiology at Weill Cornell Medicine.
“This platform is not simply acting as a passive carrier or delivery vehicle; these nanoparticles are intrinsically active therapeutic agents,” she said in the news release. “Rather than targeting a single pathway, these particles engage multiple mechanisms simultaneously and in ways that conventional therapies cannot easily achieve.”
By shifting multiple levers at once, C’dots turned “cold” tumors “hot,” creating an inflamed, immune-active environment that made the cancers far more vulnerable to treatment.
To see how this might translate into better outcomes, the researchers combined C’dots with a dual immunotherapy strategy that targeted both an immune checkpoint and a cytokine, a signaling molecule that helps regulate immune responses. In mouse models, animals that received the combination lived significantly longer than those treated with immunotherapy alone.
The two approaches worked together: the nanoparticles reshaped the immune landscape inside the tumor, and the immunotherapies then delivered a much stronger blow.
“Many aggressive tumors are resistant to immunotherapies alone,” Bradbury added. “What these nanoparticles do is mitigate inhibitory activities within the TME, in turn suppressing tumor growth and limiting resistance.”
Although the study focused on melanoma, the team has seen similar immune-activating effects of C’dots in other solid tumor models, including prostate and ovarian cancers. That suggests the approach could have broad applications if it proves safe and effective in further testing.
The findings also raise intriguing questions about why silica, a common mineral, would have such wide-ranging effects on the immune system.
Wiesner pointed to the long evolutionary history of organisms interacting with tiny silica particles.
“From the early stages of evolution, biological organisms have been exposed to nanoparticulate silica on the inside, including through intake of foods like grasses and seaweed,” he said.
He and colleagues are exploring a hypothesis that links this long-term exposure to the body’s ability to maintain balance, or homeostasis, even in the face of diseases like cancer.
“The hypothesis is that cancer pushes your system out of equilibrium, away from homeostasis. But silica pushes back, and the reason it’s multifactorial is because over millions of years, organisms developed various mechanisms by which silica can basically maintain homeostasis,” added Wiesner.
That idea is still speculative, and much work remains before C’dots could become a standard part of cancer care. The current findings come from animal models, and researchers will need to better understand the mechanisms at play, refine dosing and delivery strategies, and test safety and effectiveness in people.
The team is now collaborating with Cornell nutritional sciences researchers to probe the evolutionary and dietary angles of silica exposure, while also exploring how C’dots might be used against a wider range of solid tumors.
If future studies are successful, the same type of nanoparticle that once helped doctors see tumors more clearly could one day help patients’ immune systems destroy them, offering a new way to tackle cancers that have long resisted treatment.
Source: Cornell University