In the fight against cancer, chimeric antigen receptor T cell (CAR-T) therapy has achieved notable success in treating blood cancers. However, it has been largely ineffective against solid tumors.

Now, a newly published study by UNC Lineberger Comprehensive Cancer Center researchers demonstrates that a different immunotherapy approach utilizing natural killer T (NKT) cells produced significant antitumor activity in preclinical models of solid tumors.

Gianpietro Dotti, MD, professor of microbiology and immunology at UNC School of Medicine and co-leader of the UNC Lineberger immunology research program, Xin Zhou, Ph.D., a postdoctoral fellow in the Dotti lab, and their colleagues report that CAR-natural killer T cells (CAR-NKT) utilize a multimodal approach, combining direct tumor cell killing, reprogramming of the tumor microenvironment, and promotion of systemic immune responses, to create a more immunogenic environment in tumors.

Their findings are published in Nature Cancer.

“CAR-T cells are very potent cells. However, the most surprising finding in our work is that these potent cells are strongly inhibited in tumor models that recapitulate the complexity of the tumor microenvironment,” said Dotti, the paper’s corresponding author. “In particular, tumor-associated macrophages seem to have a potent inhibitory effect on CAR-T cells. CAR-NKTs seem capable of avoiding the inhibitory effects of macrophages since they can directly target them.”

Previous research has shown that CAR-T cells’ limited ability to penetrate and function within solid tumors is primarily due to the physical barriers within tumors and the suppressive nature of the tumor microenvironment. Natural killer T cells possess innate-like properties that make them uniquely equipped to fight solid tumors. Specifically, they express a T cell receptor that recognizes glycolipid antigens presented by CD1d molecules.

Dotti, Zhou and their colleagues demonstrated that CAR-NKT cells effectively eliminated CD1d-expressing M2-like macrophages within the tumor microenvironment. These macrophages promote tumor growth and suppress immune responses, making their removal a critical aspect of enhancing antitumor immunity. By targeting these cells, CAR-NKT therapy effectively reprograms the tumor microenvironment from a pro-tumor to an anti-tumor environment.

They also reported that CAR-NKT cells promoted epitope spreading—a process by which the immune system recognizes and attacks new targets—leading to the activation of T-cell responses.

“Our findings demonstrate that CAR-NKT cells not only effectively eliminate CD1d-expressing M2-like macrophages within the tumor microenvironment but also stimulate endogenous immune cells,” said Zhou, the paper’s first author. “This dual function—overcoming suppressive immune cells and promoting sustained immune activity—represents a crucial advancement in improving CAR-based therapies for solid tumors and achieving long-term tumor control.”

The researchers also report that they were able to help CAR-NKT cells overcome therapeutic exhaustion, a known shortcoming of CAR-T therapies that have had extended exposure to tumor antigens. Signs of exhaustion include co-expression of the immune checkpoint markers PD1 and TIM3, which dampen the immune cells’ effectiveness. However, the researchers demonstrated that combining CAR-NKT cells with PD1 blockade—an immune checkpoint inhibitor commonly used in cancer treatment—significantly boosted their antitumor activity.

The researchers also reported that combining CAR-NKT cells with vaccination approaches, such as those using alpha-galactosylceramide-loaded dendritic cells, further enhanced the antitumor response. Alpha-galactosylceramide is a known potent stimulator of NKT cells.

Looking ahead, Dotti said his team is focused on developing approaches to simplify the process for producing CAR-NKT cells. “CAR-NKT cells have already been safely used in clinical trials. However, the manufacturing of CAR-NKT for clinical use is more complex than the manufacturing of CAR-T cells. We are working on simplifying the manufacturing of CAR-NKT.”