The findings were recently reported in Science Advances.

How Necroptosis Strengthens Immune Responses

Immunotherapy represents a major shift in cancer treatment, as it relies on the body's natural defenses to identify and eliminate tumor cells. Immune cells act like vigilant sentries, moving through tissues and detecting remaining cancer cells that could lead to relapse. Among the new approaches being explored is a form of programmed cell death called necroptosis. Unlike apoptosis, which quietly removes cells, necroptosis produces signals that draw immune cells to the area. These signals help prompt the immune system to attack and clear any surviving tumor cells.

Scientists in the Dynamics of Immune Responses Unit (a joint Inserm/Institut Pasteur unit) investigated whether necroptosis could help treat blood cancers. Their initial work showed that malignant B cells do not readily undergo necroptosis because they lack the MLKL protein, which is essential for this process.

Triple Therapy Overcomes a Key Barrier

To address this limitation, the team used a combination of three drugs already approved for clinical use. This combination successfully triggered necroptosis in malignant B cells and produced a powerful immune response that completely eliminated leukemia in a preclinical model. "The triple therapy we used forces cancer cells to die in a way that activates the immune system," says Philippe Bousso, Inserm Research Director and Head of the Institut Pasteur's Dynamics of Immune Responses Unit.

Real-Time Imaging Reveals Immune Activation

The researchers relied on an advanced intravital imaging method to watch immune cells interact with cancer cells in real time. This allowed them to directly observe how different forms of cell death influenced immune behavior.

"This novel immunotherapy strategy, successfully tested in preclinical models, turns tumor cells into triggers for the immune system, pointing to a potential therapeutic avenue for certain cancers, such as lymphomas or leukemias affecting B cells," explains Philippe Bousso.

"By changing the way cancer cells die, we can harness the support of our immune system to fight against the tumor," he adds.

The research received support from the institutions noted above, along with the European Research Council (ERC) and the ARC Foundation for Cancer Research.

The biodegradable patch contains extremely small needles filled with microscopic particles carrying interleukin-4 (IL-4), a molecule recognized for its role in immune regulation. When placed on the heart's surface, the microneedles dissolve and release IL-4 straight into the injured region, helping create conditions that support recovery.

Huang and his colleagues reported their results in Cell Biomaterials, with funding from the National Institutes of Health and the American Heart Association.

"This patch acts like a bridge," said Huang, assistant professor in the Department of Pharmaceutical Sciences. "The microneedles penetrate the outer layer of the heart and allow the drug to reach the damaged muscle underneath, which is normally very hard to access."

How Heart Damage Progresses After a Heart Attack

A heart attack deprives heart muscle cells of oxygen and nutrients, causing many of them to die. As a protective response, the body forms scar tissue in the damaged area. Although this scarring helps maintain structural stability, it does not contract like healthy heart muscle. As a result, the remaining muscle must work harder over time, which can contribute to heart failure.

Huang's team hopes their patch can interrupt this progression. By bringing IL-4 directly to the site of injury, the patch encourages immune cells known as macrophages to shift from a pro-inflammatory mode to one that supports healing. This change can limit scar development and improve long-term outcomes.

"Macrophages are the key," Huang explained. "They can either make inflammation worse or help the heart heal. IL-4 helps turn them into helpers."

Why Localized Delivery Matters

Earlier attempts to use IL-4 for repairing heart tissue involved injecting the molecule into the bloodstream, but circulating it throughout the body caused unwanted effects in other organs. The new patch addresses this issue by focusing the treatment precisely where it is needed.

"Systemic delivery affects the whole body," he said. "We wanted to target just the heart."

Unexpected Cellular Responses Linked to Healing

One of the most notable discoveries from the study was a shift in the behavior of heart muscle cells after receiving treatment. According to Huang, these cells became more responsive to signals from surrounding tissues, particularly endothelial cells that line blood vessels. This improved communication may play an important role in longer-term recovery. "The cardiomyocytes weren't just surviving, they were interacting with other cells in ways that support recovery," he said.

The team also found that the patch reduced inflammatory signals coming from endothelial cells, which can contribute to further heart damage. In addition, they detected increased activity in a pathway known as NPR1, which supports blood vessel health and overall heart function.

Future Versions Aim for Minimally Invasive Use

At the moment, placing the patch requires open-chest surgery, but Huang hopes to create a less invasive method. He imagines a design that could be delivered through a small tube, making the treatment easier and more practical in clinical settings.

"This is just the beginning," he said. "We've proven the concept. Now we want to optimize the design and delivery."

Huang is now partnering with Xiaoqing (Jade) Wang, assistant professor of statistics in the College of Arts and Sciences. Together they are developing an AI model that maps immune responses and helps guide future immunomodulatory therapeutic delivery.