Researchers at Tel Aviv University’s Gray Faculty of Medical and Health Sciences have uncovered how a natural and essential immune system process can be hijacked to promote cancer progression. In a new study, the research team developed an advanced technology that enabled them to track macrophages, immune system cells, in real time and reveal how they alter their behavior within a cancerous tumor after consuming dead cancer cells. Their findings may pave the way for the development of new treatments targeting the specific macrophages identified in the study, restoring the immune system’s ability to fight the tumor instead of helping it.

The study was led by Dr. Merav Cohen and doctoral students Roi Balaban and Ori Moskowitz of the Gray Faculty of Medical and Health Sciences at Tel Aviv University. It was published in the prestigious journal Science Immunology.

When the Immune System Changes Sides

At the heart of the study are macrophages, immune cells whose role is to clear the body of damaged and dead cells. This process is essential for maintaining tissue health and preventing inflammation. However, the researchers discovered that within the environment of a cancerous tumor, this same mechanism can take an unexpected turn: instead of helping the body, it causes immune cells to adopt characteristics that actively support tumor growth.

To understand how this occurs, the researchers developed an innovative method called Effero-seq, which enables the tracking of changes that occur in immune cells after they engulf dead cells. Using this technology, the team found that as the process progresses, the immune cells undergo "reprogramming" and begin activating genes that promote tumor development.

Tracking Tumor-Supporting Immune Cells

Using a melanoma model, the researchers found that macrophages that had consumed dead cancer cells stimulated the formation of new blood vessels within the tumor. These blood vessels supply the tumor with oxygen and nutrients, enabling it to grow more rapidly. At the same time, these macrophages lost some of their ability to respond to signals that trigger anti-cancer immune activity.

The researchers also analyzed data from patients with uveal melanoma, a form of eye cancer. They found that patients whose tumors contained higher expression of immune cells bearing the genetic signature identified in the study tended to have lower survival rates.

According to Dr. Cohen, the findings provide a new perspective on how cancerous tumors manipulate their surroundings and harness the immune system for their own needs. “The better we understand these mechanisms, the better equipped we will be to develop treatments that block them and restore the immune system’s ability to fight cancer,” she says. “This research points to a new and promising therapeutic target, one that focuses not only on the cancer cells themselves, but also on the processes that enable them to thrive.”

A groundbreaking study by a team of researchers from the Gray Faculty of Medical and Health Sciences at Tel Aviv University offers new hope to millions of people suffering from irreversible hearing loss. The researchers have identified a unique biological mechanism that could, in the future, enable the regeneration of sensory hair cells in the inner ear - a process previously thought to be impossible in humans.

The study was conducted under the leadership of Prof. Karen Avraham, Dean of the Gray Faculty of Medical and Health Sciences Drs Sarah and Felix Dumont Chair for Research of Hearing Disorders incumbent. It was spearheaded by Lama Khalaily, a Tel Aviv University doctoral student, in collaboration with Prof. David Sprinzak of TAU’s Wise Faculty of Life Sciences, Shahar Kasirer from Prof. Sprinzak’s laboratory, Dr. Litao Tao of Creighton University in Omaha, and additional researchers. The findings were published in the journal Science Advances. 

Why Hearing Loss Is Permanent

Hearing loss is often caused by damage to hair cells in the cochlea - cells responsible for detecting sound and converting it into electrical signals transmitted to the brain. Unlike many other species, mammals, including humans, are unable to regenerate these cells once they are damaged, making the loss permanent.

Discovering Cells That Can Regenerate

Using live tissue imaging and single-cell multi-omics methods, the researchers focused on supporting cells - cells adjacent to the hair cells that, under normal conditions, cannot regenerate or transform into hair cells. To explore whether and how this limitation could be overcome, the research team inhibited the Notch signaling pathway, a key communication mechanism between cells that is responsible for hair cell differentiation during embryonic development. The team uncovered a rare subset of supporting cells with an unexpected regenerative potential. Rather than responding uniformly, only a distinct group of cells entered a transitional state and began converting into hair cells.

These cells, termed transdifferentiating Deiters’ cells (tDCs), are capable of making the transition from supporting cells to hair cells - a step that is essential for hair cell regeneration. The researchers found that these cells exhibit unique genetic and epigenetic characteristics, enabling them to respond to stimulation and initiate the regeneration process.

Live imaging of the cochlear sensory epithelium: Supporting cells are shown in green and hair cells in red.

The researchers note that a deeper understanding of the mechanisms that allow certain cells to regenerate may pave the way for the development of innovative treatments that activate this regenerative ability in additional cells. Future approaches may involve a combination of genetic and epigenetic interventions designed to bypass existing biological barriers. According to the research team, this represents a significant step toward the development of regenerative treatments for hearing loss - a field in which no restorative medical solutions currently exist, only assistive measures such as hearing aids and cochlear implants and limited gene therapy.

"A First but Significant Step"

Prof. Karen Avraham concludes: “Our study shows that even in tissues long considered incapable of regeneration, such as the cochlea of the inner ear, there is in fact a hidden regenerative capacity, though it is very limited and appears only in a rare subpopulation of cells. The major challenge now is to understand how this ability can be expanded and activated in additional cells. If we succeed in doing this, we may lay the foundation for the development of innovative biological treatments that restore hearing, rather than merely compensate for its loss. This is a first but significant step toward a deeper understanding of regeneration in the auditory system and in neural systems in general.”

The study was supported by a Breakthrough Research grant from the Israel Science Foundation, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, and the Sagol Center for Regenerative Medicine at Tel Aviv University.