Immunotherapies that harness a patient’s immune system to fight cancer have become a cornerstone of treatment. CAR T-cell therapy received approval from the Food and Drug Administration in 2017 and has since shown promising results for certain cancers, particularly blood cancers. This therapy involves removing T-cells, a type of white blood cell, from a patient, and re-engineering them to produce a protein on their surface that binds to a specific target protein found on cancer cells. Once infused back into the patient, the CAR T-cells effectively kill cancer cells bearing that target protein. However, CAR T-cell therapy has had limited success in treating solid tumors, which account for about 90% of adult cancers and 40% of childhood cancers. The dense network of proteins and other cells surrounding these tumors prevents immune cells from infiltrating, and the hostile environment inhibits their ability to fight tumors. Additionally, the significant diversity among solid tumors complicates the targeting of specific proteins for attack. To enhance cell-based immunotherapies for solid tumors, it is crucial for immune cells to bypass these defenses. Researchers have now re-engineered immune cells to penetrate and destroy solid tumors grown in laboratory settings.

A team, led by researchers from the Penn State College of Medicine (Hershey, PA, USA), has developed a light-activated switch that regulates protein functions related to cell structure and shape, integrating it into natural killer (NK) cells, which are immune cells that attack infections and tumors. When exposed to blue light, these NK cells undergo morphological changes, enabling them to migrate into tumor spheroids—three-dimensional tumors cultivated in the lab from mouse or human cell lines—and effectively kill tumor cells. The researchers believe this innovative method could enhance cell-based immunotherapies. The results of their study were published in the Proceedings of the National Academy of Sciences.

Using computational modeling, the team designed and tested a light-controlled variant of septin-7, a crucial internal protein that supports the cytoskeleton of a cell, which maintains cellular shape and organization. They introduced a light-sensitive domain into septin-7, creating what they refer to as “an allosteric regulator.” This light-sensitive segment is positioned away from the protein’s active site and does not interfere with the protein's structure or function until activated. The domain responds to blue light, toggling the protein's function on and off. The researchers then re-engineered human natural killer immune cells to express the light-sensitive septin-7 protein.

In the presence of blue light, the researchers noted that the typical function of septin-7 was disrupted. The cells also adopted a more elongated, spindle-like appearance with increased outward protrusions, which facilitate interaction with their surroundings and aid in cellular movement. The re-engineered natural killer immune cells were tested against two types of solid tumor spheroids, one created from human breast cancer cells and the other from human cervical cancer cells. Within seven days, they successfully eliminated the tumor cells. In contrast, unmodified natural killer cells attacked the tumor spheroids externally but could not penetrate the tumor, allowing it to continue growing. The researchers also re-engineered immune cells from mice and evaluated them against tumor spheroids made from mouse melanoma cells.

“This technology is totally out of the box. It’s akin to CAR T-cell therapy, but here, the guiding principle is the ability of cells to infiltrate the tumor,” said senior author Nikolay Dokholyan, G. Thomas Passananti Professor at the Penn State College of Medicine and professor of biochemistry and molecular biology. “I don't know of another approach that is anything close to this.” 

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