Much of cancer research and therapy focuses on the direct impacts on cancer cells. However, understanding the broader context of cancer as a component of a patient, rather than an isolated invader, has opened a variety of insights and treatments for patients with cancer. Investigations of how the microbiome impacts cancer and immunotherapy was the prime focus of the second session on June 23, 2026 at the Frontiers in Cancer Immunotherapy Symposium hosted by The New York Academy of Sciences.
GVHD and the microbiome
Opening the discussion, Marcel van den Brink, MD, PhD, president of City of Hope Los Angeles and City of Hope Medical Center spoke about the role of the intestinal microbiome in cancer immunotherapy.
He began by describing the history of graft versus host disease (GVHD), pointing out that while early work from the 1970s suggested that germ free mice had reduced instance of GVHD following transplants, more current work has pointed to the intestinal microbiome as an immune system modulator.
“Protection of the commensal anaerobes is beneficial,” he said. He explained that Enterococcus has a habit of dominating a population with reduced diversity, pointing out that it “happens very frequently within the context of allogenic transplant, and again is linked with graft versus host [disease].”
“So we try to understand how that happens, why do you get that domination?” van den Brink described how damage to the internal lining of the gut by chemotherapy or XRT conditioning can lead to alloreactivity of immune cells. Damaged enterocytes are less able to produce lactase, leading to increase in lactose availability, which can help drive the growth of Enterococcus species, including E. faecillis—a primary species found in patients who develop GVHD. Concurrently, bile acids can have an immune suppressive effect.
He went on to share results of two published studies exploring the role of immune cells in this cycle and potential interventions. He summarized this work saying, “The protection of the commensal anaerobes is critical.
“That’s probably the easiest point that I can make, if you think about using the gut microbiome as a target to improve outcomes for cancer patients.”
As the gut is a complicated ecosystem, and there are many angles of research, the van den Brink lab is also now exploring other avenues of research that do not involve antibiotics in addition to their work with antibiotics and other therapies.
Probiotic engineering
The second talk in this session, presented by Nicholas Arpaia, PhD, associate professor of microbiology and immunology at Columbia University, explored the possibility of personalized cancer immunotherapy with the use of engineered probiotics.
His work has focused on exploring the interactions between bacteria and the tumor microenvironment (TME) and how bacteria can act as a sort of Trojan horse to access the inner tumor environment.
In terms of cancer immunotherapy, Arpaia began by saying, “hopefully I’ll be able to convince you that utilizing bacteria is a potential path forward.” Bacteria, he argues, have a bright future in the field with a strong and growing research background based on the publications, companies formed, and clinical trials over the last 20 to 30 years.
He continued describing the wide scope of the field, both in how bacteria are engineered, and in how those bacteria are delivered. While the immune-oncology space has tended towards engineering payloads that modify the TME or deliver neoantigens, there are other approaches aimed at delivering toxins or modifying the metabolism within the TME. Further, Arpaia shared details on the differences between intravenous (IV), intratumor, or oral delivery. He pointed out that bacteria injected intravenously have been found in the cores of tumors. “It’s been speculated that this occurs because of the amenable conditions within the tumor.”
The question then arises, how can this behavior be beneficial to cancer therapy? “Features of bacteria themselves can activate the innate immune system,” Arpaia said. “If you then couple that with something that’s going to help activate the adaptive immune system, it gives us all the signals we need to really get long-term durable and effective responses.”
While many bacterial strategies involve the bacteria bringing specific payloads to the TME, much of his work explores a strategy of quorum-based lysis or a synchronized lysing circuit.
“Essentially what we should observe is that there’s growth, they hit a quorum threshold, so this synchronized lysis event occurs, a few of the bacteria remain, and the entire population undergoes these cyclic events again.”
Following the lysis event, what remains is “just a massive bag of innate immune stimulatory ligands.” The payload is released over and over through this synchronized lysis of the bacteria. Arpaia summed the process: “They grow, they undergo a lytic event, they grow back, and the entire process again occurs again and again.”
Tumor-associated bacteria in space
The final talk seamlessly transitioned from the discussion of bacterial lysis deep within the tumor to a discussion on how the location of tumor-associated bacteria within the TME can impact therapy approaches.
Susan Bullman, PhD, associate professor of immunology at the University of Texas MD Anderson Cancer Center began her discussion by taking a step back from cancer. “What I’m going to talk about is the native colonization of tumors by bacteria, by members of our microbiome,” she said.
She explained that her group is “particularly interested in oral gastrointestinal cancers and understanding how microbes disseminate from our microbiome and can infiltrate human tumors to modulate the TME.”
Bullman described how certain bacterial that or typically restricted to the oral cavity can migrate and infiltrate cancers throughout the gastrointestinal (GI) tract. She focused specifically on Fusobacterium nucleatum, which not only has been consistently identified in GI tract tumors, but has also been found to negatively impact patient outcomes.
“When this microbe is enriched in the tumor, patients tend to have an increased risk for relapse, metastases and overall poor prognosis,” she said. Bullman explained that there is variability between tumor types and likelihood of tumor infiltration by microbes—with GI tract tumors having a higher instance of bacterial infection. Further, there is a heterogenous distribution of the bacteria within the tumor itself and while this bacterium is not the only microbe within the tumor tissue, her work aims to understand how this species modulates the TME.
She asked, “When these microbes get into a tumor tissue or infiltrates the tumor tissue, what exactly are they doing?” She pointed out that in healthy tissue, bacteria will interact with epithelia cells and interact with the immune system, but it’s unclear what they do within the TME.
Through the use of sequencing of both tumor and bacterial cells, her lab was able to identify details on the genetic expression of tumor cells and have a better understanding of the TME. They found that just the mere presence of bacteria at all in the tumor also has a physical impact on the tumor. The bacteria have been shown to impact tumor cell density, increasing space between the human tumor cells. As a result, these cells become stressed and stay in temporary quiescence until the bacteria are removed.
“This is interesting for a range of perspectives, from an immunotherapy perspective and an immunology perspective,” she shared.
“We see that these quiescent cells, they reduce metabolism, they reduce gene expression, and they have reduced antigen presentation. So when the cancer epithelial cells are pushed into this dormant state, they become somewhat invisible to the immune system.”
From a chemotherapy perspective, this was an interesting discovery. “We know that many anti-metabolite chemotherapies that are used in the clinic, they are targeting hyperproliferative cells,” she explained.
Currently, the team is working to map the host-bacterial interactions within the TME, looking for co-localization of cells and function to better understand how the tumor responds to bacterial infection. While they are still trying to understand the mechanisms, Bullman is encouraged by the current data.
“There [are] hints towards impacts of microbes, the amount, the load of these microbes, the immune cells, the monoid cells that they’re recruiting, and their impact on immune checkpoints within the tumor microenvironment.”
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