“This enables us to do one-step engineering of CAR-NK cells that can avoid rejection by host T cells and other immune cells. And, they kill cancer cells better and they’re safer,” says Jianzhu Chen, an MIT professor of biology, a member of the Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. 

In tests using mice with humanized immune systems, the newly engineered cells successfully destroyed most cancer cells while avoiding attack from the host’s own immune defenses.

Rizwan Romee, an associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, is also a senior author of the paper, which was published in Nature Communications. The study’s lead author is Fuguo Liu, a postdoctoral researcher at the Koch Institute and a research fellow at Dana-Farber.

Evading the immune system

Natural killer (NK) cells are a vital part of the body’s built-in immune defense, responsible for identifying and destroying cancerous and virus-infected cells. They eliminate these threats through a process called degranulation, which releases a protein known as perforin. This protein punctures the membrane of target cells, leading to their death.

To produce CAR-NK cells for treatment, doctors typically collect a blood sample from the patient. NK cells are then extracted and engineered to express a specialized protein called a chimeric antigen receptor (CAR), which is designed to target specific markers found on cancer cells.

Once modified, the cells must multiply in the lab for several weeks before there are enough to be infused back into the patient. The same general process is used for CAR-T cell therapies, some of which have already been approved to treat blood cancers like lymphoma and leukemia. CAR-NK therapies, however, are still being tested in clinical trials.

Because growing enough personalized CAR-NK cells takes time and the patient’s cells may not always be healthy enough for reliable use, scientists have been exploring an alternative: creating NK cells from healthy donors. These donor-derived cells could be mass-produced and stored for rapid use. The challenge, however, is that the recipient’s immune system often identifies donor cells as foreign and destroys them before they can attack the cancer.

In their latest research, the MIT team aimed to solve this problem by helping NK cells “hide” from immune detection. Their experiments showed that removing surface proteins known as HLA class 1 molecules allowed NK cells to avoid attack from T cells in the host’s immune system. These proteins normally act as identity markers that tell the immune system whether a cell belongs to the body.

To make use of this insight, the researchers added a sequence of siRNA (short interfering RNA) that silences the genes responsible for producing HLA class 1 proteins. Along with this genetic tweak, they introduced the CAR gene itself and another gene that encodes either PD-L1 or single-chain HLA-E (SCE), both of which help strengthen the NK cells’ cancer-fighting abilities.

All of these genetic components were combined into a single DNA construct, which allowed the team to efficiently convert donor NK cells into immune-evasive CAR-NK cells. Using this method, they engineered cells that target CD-19, a protein commonly found on malignant B cells in lymphoma patients.

NK cells unleashed

The researchers tested these CAR-NK cells in mice with a human-like immune system. These mice were also injected with lymphoma cells.

Mice that received CAR-NK cells with the new construct maintained the NK cell population for at least three weeks, and the NK cells were able to nearly eliminate cancer in those mice. In mice that received either NK cells with no genetic modifications or NK cells with only the CAR gene, the host immune cells attacked the donor NK cells. In these mice, the NK cells died out within two weeks, and the cancer spread unchecked.

The researchers also found that these engineered CAR-NK cells were much less likely to induce cytokine release syndrome — a common side effect of immunotherapy treatments, which can cause life-threatening complications.

Because of CAR-NK cells’ potentially better safety profile, Chen anticipates that they could eventually be used in place of CAR-T cells. For any CAR-NK cells that are now in development to target lymphoma or other types of cancer, it should be possible to adapt them by adding the construct developed in this study, he says.

The researchers now hope to run a clinical trial of this approach, working with colleagues at Dana-Farber. They are also working with a local biotech company to test CAR-NK cells to treat lupus, an autoimmune disorder that causes the immune system to attack healthy tissues and organs.

The research was funded, in part, by Skyline Therapeutics, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund and the Elisa Rah Memorial Fund, the Claudia Adams Barr Foundation, and the Koch Institute Support (core) Grant from the National Cancer Institute.

“These large engravings are not just rock art – they were probably statements of presence, access, and cultural identity,” said lead author, Dr. Maria Guagnin from Max Planck Institute of Geoanthropology.

Dr. Ceri Shipton, co-lead author from the Institute of Archaeology, University College London, said: “The rock art marks water sources and movement routes, possibly signifying territorial rights and intergenerational memory.”

Unlike previously known sites where engravings were hidden in crevices, the Jebel Mleiha and the Jebel Arnaan panels were etched onto towering cliff faces, some up to 39 meters high, in visually commanding locations.

One panel would have required ancient artists to climb and work precariously on narrow ledges, underscoring the sheer effort and significance of the imagery.

Artefacts including Levantine-style El Khiam and Helwan stone points, green pigment, and dentalium beads suggest long-distance connections to Pre-Pottery Neolithic (PPN) populations in the Levant region.

However, the scale, content, and placement of the Arabian engravings set them apart.

“This unique form of symbolic expression belongs to a distinct cultural identity adapted to life in a challenging, arid environment,” said Dr. Faisal Al-Jibreen, from the Heritage Commmission, Saudi Ministry of Culture.

“The project’s interdisciplinary approach has begun to fill a critical gap in the archaeological record of northern Arabia between the LGM and the Holocene, shedding light on the resilience and innovation of early desert communities,” said Michael Petraglia, lead of the Green Arabia project.

The study ‘Monumental rock art illustrates that humans thrived in the Arabian Desert during the Pleistocene-Holocene transition’ has been published in Nature Communications.

“This is the first time we’ve been able to identify what specific brain cell types are affected in depression by mapping gene activity together with mechanisms that regulate the DNA code,” said senior author Dr. Gustavo Turecki, a professor at McGill, clinician-scientist at the Douglas Institute and Canada Research Chair in Major Depressive Disorder and Suicide. “It gives us a much clearer picture of where disruptions are happening, and which cells are involved.”

Rare brain bank enables breakthrough

The team conducted their work using post-mortem brain tissue from the Douglas-Bell Canada Brain Bank, one of the few collections worldwide that includes donations from people with psychiatric conditions.

Through advanced single-cell genomic analysis, the researchers examined RNA and DNA from thousands of individual brain cells to determine which ones behaved differently in people with depression and which DNA sequences might explain these variations. The study analyzed tissue from 59 individuals who had depression and 41 who did not.

They discovered that gene activity was altered in two types of brain cells: a class of excitatory neurons responsible for mood and stress regulation, and a subtype of microglia, the immune cells that manage inflammation in the brain. In both cell types, many genes were expressed differently in people with depression, pointing to possible disruptions in vital neural systems.

By identifying the specific cells affected, the research deepens understanding of the biological foundation of depression and helps dispel outdated views of the condition.

“This research reinforces what neuroscience has been telling us for years,” Turecki said. “Depression isn’t just emotional, it reflects real, measurable changes in the brain.”

Looking ahead, the scientists intend to explore how these cellular changes influence brain function and whether targeting them could lead to more effective treatments.

About the study

“Single-nucleus chromatin accessibility profiling identifies cell types and functional variants contributing to major depression” by Anjali Chawla and Gustavo Turecki et al., was published in Nature Genetics.

The study was funded by Canadian Institutes of Health Research, Brain Canada Foundation, Fonds de recherche du Québec – Santé and Healthy Brains, Healthy Lives initiative at McGill University.