Bacteria: Unsung Players in the Tumor Microbiome

By Deborah Borfitz 

How cancer patients will respond to treatment can be anticipated based on their genetics as well as the tumor microenvironment, although one relevant component is often all but dismissed: the tumor microbiota. This is despite an abundance of evidence that a cancer’s microbial community plays a major role not only in therapeutic effects but also in tumor development, progression, and metastasis formation, according to Maria Rescigno, Ph.D., scientific director of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences.  

Editor’s Note: This article was initially published on Bio-IT World. Visit the original article here.

Every tumor harbors its own unique set of microbes, much like in the gut except in far lower densities, she says. But a multi-layered approach is needed to distinguish genuine biological signals from both host DNA and laboratory contamination of samples during collection and analysis. 

That was the rationale for an international consensus article summarizing what is known in the literature, and the main methodological challenges, and to propose shared standards for more reliable and reproducible detection of tumor-associated microbes, which was published recently in Cancer Cell (DOI: 10.1016/j.ccell.2026.02.011). Part of the mission was to advocate for doing more than a classification of possible bugs based on DNA, says Rescigno. “We want also to show that these are real, live bacteria present there using culturomics.” 

The goal in cultivating the microbes is to enable functional studies demonstrating what they’re doing there, she notes. Although bacteria is the best-known tumor microbiome component, the community also includes viruses and fungi. Next-generation sequencing is the main technology being deployed. Rescigno uses the 16S rRNA DNA-based method that sequences a highly conserved gene that codes for the ribosomal RNA molecule and is ideal for bacterial community profiling in tumor tissues. 

Other broader technologies such as shotgun metagenomic sequencing of the whole DNA that would also allow detecting fungi and viruses is currently not reliable for microbial low-biomass samples like tumor samples because it sequences vast amounts of contaminating human DNA that can cause unreliable results and underestimate the microbial component, she says. 

Leveraging her expertise in the field, Rescigno founded Postbiotica, a biotechnology spin-off of the University of Milan, a decade ago to create “postbiotics” from different strains of bacteria to improve patients’ response to cancer immunotherapies. These are microbiota-derived metabolites that serve as natural pharmaceutical and food supplements. 

Mostly Unmapped Ecosystem 

It remains unknown what proportion of microbes potentially inhabiting a tumor have been catalogued, says Rescigno. What is known is that the composition of microbes, and their relative abundance, can be strikingly different based on cancer type as well as patient to patient. “We have not yet identified a tumor that does not have an intratumor microbiota.” 

In the mix are bacteria that may or may not also be present in healthy tissue, or present in greater or lesser amounts. In the largely unmapped ecosystem, anything is possible, she notes.  

In terms of tumor development, some of these microbes can release genotoxins that induce DNA damage and the amount of mutations within tumor cells, explains Rescigno. Others can activate an inflammatory response, and chronic inflammation is fundamentally associated with cancer development. 

Specific microbes within the tumor microbiota can also induce the transformation of epithelial cells to mesenchymal cells, which is the first step to tumor transformation and metastasis formation, she continues. Other potential troublemakers can induce the release of inflammatory cytokines that in turn lead to senescence cells, which can become more tumorigenic. 

Then there are microbes that can modulate the endothelial cell compartment and thereby increase the permeability of vessels and drive the migration of tumor cells as well as the microbes themselves into other sites where they can generate a pre-metastatic niche, says Rescigno. This creates “the soil for the tumor cells to seed, and to then attach and become metastatic.” In addition, some bacteria within tumor cells make them more resistant to the sheer stress of the blood, so they survive better within the blood circulation and get to the final site of metastasization. 

When it comes to treatment response, the relevant microbes include those that can influence the activity of some chemotherapeutic agents by either reducing or increasing their effectiveness, she says. Other bacterial culprits can negatively affect the utility of cancer immunotherapy, particularly immune checkpoint inhibitors that render T cells ineffective against the tumor. 

It has been demonstrated that when patients receiving cancer immunotherapy are also given an antibiotic because they have an infection, both the gut microbiota and intratumor microbiome are affected and they respond less well to the cancer treatment, Rescigno notes. “The possibility that the microbiota might be responsible for the efficacy of cancer immunotherapy was obviously proposed” and has since been demonstrated in mice as well as human non-responders who received fecal microbiota transplantation from patients who responded well to immunotherapy.  

Seed to Fruit 

Fecal microbiota transplantation is one way to improve cancer treatment by modulating the microbiota, says Rescigno. Retrospective studies also show that patients respond better to immunotherapy if their dietary regimens contain enough fiber. This has also been demonstrated in preclinical studies where the fibers were shown to modulate the tumor microbiota toward the signature associated with positive outcomes. 

Increasing the intake of dietary fiber with a “prebiotic” of this sort can be done easily enough, Rescigno says. Some patients may experience side effects from the treatment, such as diarrhea and abdominal pain, although the unpleasantness pales in comparison to experiencing cancer. But it also takes time for patients’ microbiota to expand to include the new inhabitants. 

Probiotics are another microbiota-based treatment avenue, with a handful of studies showing that bifidobacteria can improve cancer treatment, she continues. But no regulatory-grade dietary supplements have yet to hit the market for this indication, as the trials conducted to date have all been relatively small and not necessarily placebo-controlled. 

In any case, probiotics are not for everyone. For patients having ongoing inflammatory responses, they can potentially exacerbate the problem, says Rescigno.   

Her company, Postbiotica, is thus focused on the metabolites being produced by the probiotics that are actively involved in the treatment-enhancing process. She likens the trio of options as the seed (prebiotics) giving rise to the tree (probiotic) making the fruit (postbiotic).  

The company has three clinical trials ongoing with patients to learn if postbiotics can upregulate the expression of human leukocyte antigen molecules on the tumor cell surface, alerting the immune system to attack, Rescigno shares. The potential was demonstrated in preclinical models, successfully overcoming the immune evasion tactic of tumor cells to downregulate the expression of these molecules. 

‘Sentinel Functions’ 

Among the key recommendations in the newly published consensus article are to integrate different complementary approaches—genetic sequencing, imaging, microbial cultures, and functional tests—to confirm the presence of microbes, their viability, and their causal role. Minimum reporting standards are also suggested to ensure reproducibility of results across laboratories. 

As Rescigno has discovered and will be revealed in forthcoming publications, the intratumor microbiota has many novel and potentially pivotal roles to play in improving cancer treatment which could also help explain the variability in patient outcomes. 

“The tumor microenvironment has been considered one of the most important parts to look at and to target for new therapeutic purposes and strategies, but within this panorama we should also start including the intratumor microbiota because of the sentinel functions it may play,” she says. Some of those bacteria will become new therapeutic targets in the future, joining the vast array of recognized molecular vulnerabilities in cancer that are already being targeted in clinical settings.