In the ever-evolving war against cancer, scientists have just sharpened a new blade, one that’s faster, stealthier, and potentially safer than its predecessors. A team of researchers from MIT and Harvard Medical School has unveiled a breakthrough in engineering CAR-NK cells, a type of immune cell that can be programmed to target and destroy cancer cells. Their innovation could revolutionize how quickly and effectively patients receive treatment.
Natural killer (NK) cells are the immune system’s frontline warriors, designed to detect and eliminate rogue cells, whether infected by viruses or transformed into cancer. But in recent years, scientists have been upgrading these cells with a powerful tool: the chimeric antigen receptor, or CAR. This molecular add-on acts like a GPS, guiding NK cells directly to cancer targets.
CAR-T cells, which use a similar strategy, have already made headlines for their success in treating blood cancers. But CAR-NK cells offer a tantalizing alternative: they’re less likely to trigger dangerous immune reactions. They could be made from healthy donors, creating a ready-to-use arsenal for newly diagnosed patients.
There’s a catch. When CAR-NK cells are derived from donors, the patient’s immune system often perceives them as invaders and attacks. This immune rejection has been a major roadblock until now.
In a study published in Nature Communications, researchers led by Jianzhu Chen of MIT and Rizwan Romee of Harvard revealed a new method to cloak CAR-NK cells from the host immune system. Their approach uses a one-step genetic engineering technique that silences a set of surface proteins called HLA class 1, molecular ID tags that can trigger T-cell attacks if they’re unfamiliar.
By using siRNA to suppress these proteins and introducing genes for CAR, PD-L1, or single-chain HLA-E (SCE), the team created a stealthy, cancer-killing cell that could evade the body’s defenses. All these genetic instructions were packed into a single DNA construct, making it easy to transform donor NK cells into immune-evasive warriors.
To test their creation, the researchers injected these engineered CAR-NK cells into mice with human-like immune systems and lymphoma. The results were dramatic: the modified cells survived for at least three weeks and nearly wiped out the cancer. In contrast, unmodified NK cells were quickly eliminated by the host immune system, allowing the cancer to spread.
Even more promising, the new CAR-NK cells showed a lower risk of cytokine release syndrome, a dangerous side effect of some immunotherapies that can cause severe inflammation and organ damage.
“This enables us to do one-step engineering of CAR-NK cells that can avoid rejection by host T cells and other immune cells,” said Chen. “And, they kill cancer cells better and they’re safer.”
Traditional CAR-NK and CAR-T therapies require weeks of preparation, starting with a patient’s own blood sample. But the new method could pave the way for off-the-shelf treatments, pre-made CAR-NK cells that are ready to deploy as soon as a diagnosis is made.
That speed could be life-saving, especially for aggressive cancers like lymphoma. The team’s construct, which targets CD19 (a protein found on many cancerous B cells), could also be adapted for use in other cancer types.
The researchers aren’t stopping at cancer. They’re now collaborating with a biotech company to explore CAR-NK cells as a treatment for lupus, an autoimmune disorder where the immune system attacks healthy tissues. If successful, this could mark a new chapter in immunotherapy, one where engineered cells not only fight disease but restore balance to a misfiring immune system.
The study’s lead author, Fuguo Liu, a postdoc at MIT’s Koch Institute and a research fellow at Dana-Farber, helped drive the innovation from concept to mouse trials. Now, the team is preparing for clinical trials in humans, hoping to bring their stealthy immune assassins into hospitals and oncology wards.
In the battle against cancer, speed, precision, and safety are everything. With this new generation of CAR-NK cells, scientists may have found a way to deliver all three: turning natural killers into programmable protectors, and giving patients a fighting chance from day one.
Journal Reference:
- Liu, F., Tarannum, M., Zhao, Y. et al. Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection, enhancing safety and anti-tumor responses in xenograft mice. Nat Commun 16, 8809 (2025). DOI: 10.1038/s41467-025-63863-8
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