Cancer immunotherapy has made major strides with engineered immune cells designed to destroy tumors, but challenges remain in making these treatments faster, safer, and more broadly available. One major hurdle is immune rejection, which limits the use of donor-derived therapeutic cells that could otherwise be produced “off the shelf” for rapid treatment. A new approach has now shown how to engineer immune cells to evade rejection while enhancing their cancer-killing power.

Researchers at the Massachusetts Institute of Technology (MIT, Cambridge, MA, USA) and Harvard Medical School (Boston, MA, USA) have developed an engineered form of natural killer (NK) immune cells, known as CAR-NK cells, that are designed to target cancer cells more effectively. The team modified the cells using a one-step engineering process that integrates several genetic features to make them immune-evasive and more potent. The study, published in Nature Communications, demonstrates a method that may enable large-scale, ready-to-use CAR-NK cell therapies.

To create these cells, the scientists used a DNA construct carrying genes that silence HLA class I proteins, which normally mark the cells for destruction by a patient’s immune system. The construct also encodes chimeric antigen receptors (CARs) that guide NK cells to specific cancer targets, and includes either PD-L1 or single-chain HLA-E (SCE), which enhances NK cell activity. This combination allows the donor-derived cells to remain undetected by the host immune system while efficiently attacking cancer cells.

The team tested the engineered CAR-NK cells in mice with human-like immune systems and injected them with lymphoma cells. In treated mice, the CAR-NK population persisted for at least three weeks and nearly eliminated the cancer, whereas in control mice, unmodified NK cells were quickly destroyed and failed to stop tumor growth. The modified cells also demonstrated a lower risk of cytokine release syndrome, a potentially life-threatening immune overreaction seen in some immunotherapy treatments.

These results suggest that immune-evasive CAR-NK cells could provide a safer, faster alternative to CAR-T cell therapy for blood cancers such as lymphoma and leukemia. The genetic engineering strategy can be applied to future CAR-NK therapies targeting different cancers, potentially paving the way for universal, donor-derived treatments. The researchers plan to initiate clinical trials and are also exploring applications of this technology in autoimmune diseases such as lupus.

“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,” said MIT Professor Jianzhu Chen, senior author of the study.

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