By Deborah Burwitz
How cancer patients will respond to treatment can be predicted based on their genes, as well as the tumor microenvironment, although one relevant element is often left out: the tumor microorganisms. This is despite the abundance of evidence that the cancer microbial community plays a major role not only in therapeutic effects but also in effect Tumor development, progression, and metastasis, according to Maria Resino, Ph.D., Scientific Director of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.
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Each tumor harbors its own unique set of microbes, just as in the gut, except at much lower densities, she says. But a multi-layered approach is needed to distinguish between true biological signals from both host DNA and laboratory contamination of samples during collection and analysis.
This was the rationale for an international consensus article summarizing what is known in the literature, key methodological challenges, and proposing common criteria for more reliable and reproducible detection of tumor-associated microbes, which was recently published in the journal Cancer cell (doi: 10.1016/j.ccell.2026.02.011). Part of the mission, Recinio says, was to advocate for doing more than just profiling potential bugs based on DNA. “We also want to show that these are real live bacteria out there using cultures.”
She points out that the goal of culturing microbes is to enable functional studies that show what they do there. Although bacteria are the best known components of the tumor microbiome, the community also includes viruses and fungi. Next generation sequencing is the main technology being deployed. Rescigno uses the 16S rRNA DNA-based method It sequences a highly conserved gene encoding a ribosomal RNA molecule, which is ideal for profiling the bacterial community in tumor tissue.
She says other broader technologies, such as metagenomic sequencing of whole DNA, which would also allow detection of fungi and viruses, are currently unreliable for low microbial biomass samples, such as tumor samples, because they sequence huge amounts of contaminated human DNA that can cause unreliable results and underestimate the microbial component.
Drawing on her experience in this field, Resinio founded Postbiotica, a biotechnology subsidiary of the University of Milan, a decade ago to Creating “post-biotics” from different strains of bacteria to improve patients’ response to cancer immunotherapies. These are metabolites derived from microorganisms that serve as natural nutritional and pharmaceutical supplements.
Mostly unmapped ecosystem
It’s still unknown what proportion of potentially tumor-inhabiting microbes are cataloged, says Resinio. What is known is that the composition of microbes and their relative abundance can vary strikingly based on the type of cancer as well as from patient to patient. “We have not yet identified a tumor that does not have microbes within the tumor.”
In the mixture are bacteria that may or may not also be present in healthy tissue, or present in greater or lesser quantities. She points out that in a largely indeterminate ecosystem, anything is possible.
In terms of tumor development, some of these microbes can release genotoxins that stimulate DNA damage and the amount of mutations within cancer cells, Resigno explains. Others can activate the inflammatory response, and chronic inflammation is primarily associated with cancer development.
Specific microbes within the tumor microbiota continue to stimulate the transformation of epithelial cells into mesenchymal cells, which is the first step toward tumor transformation and malignancy. Other potential troublemakers can stimulate the release of inflammatory cytokines that in turn lead to senescent cells, which can become more tumorigenic.
Then there are microbes that can modify the endothelial cell compartment, thereby increasing vascular permeability and driving cancer cell migration, as well as the microbes themselves to other sites, where they can generate a pre-metastatic niche, Reskino says. This creates “the right soil for cancer cells to grow, then they stick to it and become metastasized.” In addition, some bacteria inside cancer cells make them more resistant to the enormous pressure of blood, so they better survive within the circulation and reach the final site of spread.
When it comes to response to treatment, relevant microbes include those that can affect the activity of certain chemotherapy agents by either decreasing or increasing their effectiveness, she says. Other causative bacteria can negatively affect the benefit of cancer immunotherapy, especially immune checkpoint inhibitors that render T cells ineffective against the tumor.
It has been shown that when patients receiving cancer immunotherapy are also given an antibiotic because they have an infection, both their gut microbiota and the microbiome inside the tumor are affected, and they respond less well to cancer treatment, Recinio notes. “The possibility that the microbiota may be responsible for the effectiveness of cancer immunotherapy was clearly suggested” and has since been demonstrated in mice as well as non-responder humans who received fecal microbiota transplants from patients who had responded well to immunotherapy.
From seed to fruit
Fecal microbiota transplantation is one way to improve cancer treatment by modifying the microbiota, Reskino says. Retrospective studies also show that patients respond better to immunotherapy if their diets contain enough fiber. This has also been proven in preclinical studies where fibers have been shown to modulate the tumor microbiota toward a signature associated with positive outcomes.
Increasing your dietary fiber intake with “prebiotics” of this type can be done easily enough, says Resinio. Some patients may experience side effects from treatment, such as diarrhea and abdominal pain, although the pain pales in comparison to that of cancer. But it also takes time for patients’ microbiomes to expand to include new populations.
She continues, saying that probiotics are another treatment method that relies on microbes, as a group of studies have shown that bifidobacteria can improve cancer treatment. But no regulatory-grade supplements have been on the market yet for this indication, as the trials conducted so far have all been relatively small and not necessarily placebo-controlled.
However, probiotics are not right for everyone. For patients with persistent inflammatory responses, this will likely exacerbate the problem, Recinio says.
Hence, her company, Postbiotica, focuses on the metabolites produced by probiotics that are actively involved in the treatment enhancement process. They liken the trio of options to the seeds (prebiotics) that give rise to the tree (probiotics) that make the fruit (postbiotics).
The company has three ongoing clinical trials with patients to see if the antibiotic can regulate the expression of human leukocyte antigen molecules on the surface of cancer cells, alerting the immune system to attack, Resigno shares. The potential has been demonstrated in preclinical models, successfully overcoming the immune evasion tactic of cancer cells to downregulate the expression of these molecules.
“Guardian Jobs”
Among the key recommendations in the newly published article that reached consensus was the integration of different complementary approaches – genetic sequencing, imaging, microbial cultures, and functional tests – to confirm the presence of microbes, their viability, and their causal role. It also suggests minimum reporting standards to ensure reproducibility of results across laboratories.
As Rescigno has discovered and will be revealed in upcoming publications, the microbiome within a tumor has many new and potentially pivotal roles to play in improving cancer treatment that can also help explain variation in patient outcomes.
“The tumor microenvironment is one of the most important parts to look at and target for new therapeutic purposes and strategies, but within this jigsaw we must also begin to include the microbiota within the tumor because of the sentinel functions they may play,” she says. Some of these bacteria will become new therapeutic targets in the future, joining the wide range of recognized molecular vulnerabilities in cancer that are already being targeted in clinical settings.
