Engineered Listeria Bacteria Shows Promise as Cancer Immunotherapy

After nearly 40 years of research on how Listeria bacteria manipulate cells and battle the immune system to cause listeriosis, researchers have discovered ways to turn the bacteria into potent boosters of the immune system and potential weapons against cancer.

Three years ago, a startup called Laguna Biotherapeutics was cofounded to work with scientists at the University of California, Berkeley to eliminate the bacteria's ability to cause disease while retaining its ability to rev up production of gamma delta T cells, a type of immune system cell associated with increased survival in cancer patients. These gamma delta T cells are general-purpose killers of cancer cells or any cell infected by a pathogen—bacteria, virus, or fungus.

Laguna Bio will soon ask the FDA for clearance to evaluate the therapy in children with leukemia who have received unmatched bone marrow transplants. Doctors at Stanford University Medical Center hope that the engineered Listeria will boost gamma delta T cells in pediatric patients and help them stave off graft-versus-host disease, fight potentially deadly infections that take advantage of a transplant patient's compromised immune system, and prevent the cancer from returning.

In a separate approach, researchers at Stony Brook University have developed an oral vaccine candidate based on a genetically modified, attenuated strain of Listeria monocytogenes that stimulates powerful anti-tumor immune responses directly in the gut. The research shows that the vaccine generates tumor-specific CD8+ T cells in the gastrointestinal tract.

In mouse models of colorectal cancer, the oral vaccine significantly improved tumor control, especially when combined with immune checkpoint inhibitors. This combination increases the infiltration of cancer-killing T cells into tumors. Published on February 5, 2026, in the Journal for ImmunoTherapy of Cancer, the study presents a potential new strategy to overcome immunotherapy resistance in colorectal cancer, which is one of the leading causes of cancer-related deaths worldwide.

The oral immunization combined with immune checkpoint inhibitors induced the accumulation of tumor-specific CD8 T cells within the tumor microenvironment. These specialized immune cells remain stationed in the gut and provide immediate and long-lasting protection against cancer cells, a response not achieved by vaccination or immune checkpoint inhibitors alone.

The Listeria therapy is unique among cancer therapies in stimulating the body's innate immune system to eliminate essentially any cell that puts out a distress signal indicating it's been compromised. Today's immunotherapies for cancer typically activate the "adaptive" immune system, boosting cells that recognize and kill cancer cells.

Researchers at UC Berkeley and Laguna Bio published details of the successful use of the attenuated Listeria therapy in mice in the journal mBio late last year. In another study posted last year on the BioRxiv preprint server, they reported that Listeria can also be engineered to boost another type of innate immune cell—mucosal-associated invariant T cell, or MAIT—that helps defend against infections and possibly cancer.

Listeria monocytogenes is a foodborne pathogen that causes gastrointestinal disease and fever in some people but occasionally spreads from the intestines to cause deadly sepsis or meningitis. Researchers have documented how, after infection, the bacteria are engulfed by scavenger cells called phagocytes, where they are captured by an organelle called a phagosome that digests invaders. But research showed nearly 40 years ago that before that can happen, the bacteria escape the phagosome and set up shop in the cell interior, hiding out from the host's immune system until they reproduce and spread to infect new cells.

To construct a version of Listeria that would not make people sick, researchers deleted two genes required for the bacteria to exit a cell and spread. The bacteria normally do this by hijacking host cell actin, a protein from the cell's cytoskeleton, and using it to construct finger-like protrusions, which are internalized by neighboring cells. This strain—dubbed LADD, for Listeria attenuated double deleted—will still get into the cytosol of cells, still grow and induce a potent immune response, but since it doesn't spread, it's a thousandfold less virulent.

Aduro Biotech combined this strain with a cancer antigen and used it to treat nearly 1,000 patients with pancreatic cancer and mesothelioma in the 2000s. While the results are promising in preclinical models for the newer approaches, human trials will be necessary to assess safety and efficacy.