For decades, the battle against cancer has revolved almost exclusively around the tumor itself—its genes, mutations, growth rate, and mechanisms of resistance. But now, a new and unexpected player is entering the field with transformative potential: the microbiome. This complex and dynamic ecosystem of bacteria, viruses, fungi, and archaea—along with their genetic material and bioactive byproducts—is not only shaping our general health but is increasingly recognized as a powerful influencer in cancer development, progression, treatment response, and even therapy-associated toxicity. Understanding and manipulating the microbiome may be one of the most promising frontiers in the future of precision oncology.
The gut microbiome, in particular, has garnered significant attention due to its intimate crosstalk with the immune system. Far from being a passive community of microbes, it acts as a master regulator of immune function, shaping both local mucosal immunity and systemic antitumor responses. A state of eubiosis, characterized by a diverse and balanced microbial ecosystem, supports immune surveillance and epithelial integrity. Beneficial microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and members of Clostridiales metabolize dietary fibers into short-chain fatty acids (SCFAs) like butyrate, which exert anti-inflammatory effects, strengthen the mucosal barrier, and enhance T cell function. In this balanced state, the immune system is better equipped to recognize and attack tumor cells, while also avoiding overactivation that could lead to autoimmunity or adverse effects.
In contrast, dysbiosis—an imbalanced or pathologically altered microbiome—can promote systemic inflammation, disrupt mucosal immunity, and impair the body’s ability to mount effective antitumor responses. This altered microbial state is marked by reduced diversity, loss of beneficial commensals, and overgrowth of pro-inflammatory or pathogenic taxa such as Enterobacteriaceae or oral-derived microbes. These dysbiotic changes not only weaken the host’s immune defenses but can also directly interfere with cancer therapies. Alarmingly, studies have shown that administering broad-spectrum antibiotics—especially prior to immunotherapy—can deplete beneficial microbial populations and lead to significantly poorer outcomes, including shorter overall survival and higher rates of immune-related toxicities.
The impact of the microbiome extends beyond the gut. Emerging evidence reveals that intratumoral microbes, residing within the tumor microenvironment, can influence tumor biology and therapy resistance. For example, Fusobacterium nucleatum, commonly found in colorectal cancer, has been shown to suppress immune cell activity by binding to inhibitory receptors on T and NK cells. Moreover, this bacterium can persist in both primary and metastatic tumor sites, highlighting its potential role in cancer progression. Other microbes, such as Gammaproteobacteria in pancreatic tumors, have been found to metabolize chemotherapeutic agents like gemcitabine, rendering them inactive and contributing to treatment failure.
In contrast, some tumors with high microbial diversity show more robust immune infiltration and better long-term outcomes. A study on pancreatic cancer revealed that patients who survived more than five years after surgery had significantly higher intratumoral microbial diversity and greater abundance of cytotoxic T lymphocytes. When fecal microbiota from these long-term survivors was transplanted into mice, it conferred improved antitumor immunity and reduced tumor growth, suggesting a causative role for the microbiota in modulating therapy response.
This has sparked growing interest in therapeutic modulation of the microbiome. Fecal microbiota transplant (FMT), initially developed for recurrent Clostridioides difficile infections, is now being investigated as an adjunct to cancer immunotherapy. Early-phase clinical trials in patients with metastatic melanoma have shown that FMT from responders—patients who experienced durable responses to checkpoint inhibitors—can restore sensitivity to these therapies in patients who were previously resistant. Responders to FMT not only showed altered gut microbial composition but also exhibited improved mucosal immunity and T cell activation.
Other microbiome-based strategies include the use of targeted probiotics, prebiotics (such as dietary fibers that nourish beneficial bacteria), and even engineered microbial consortia designed to boost immune function or deliver antitumor compounds directly within the tumor microenvironment. Novel bacteriophage therapies are being explored to selectively eliminate harmful bacterial species like F. nucleatum, while preserving or enriching those that support immune function.
Diet and lifestyle factors also play a crucial role in shaping the gut microbiota. Diets rich in dietary fiber promote the growth of SCFA-producing bacteria, which are associated with better responses to immunotherapy. In contrast, low-fiber or highly processed diets have been linked to poorer outcomes and increased tumor progression. Physical activity, too, has been shown to enhance microbial diversity and modulate immune responses in patients at high risk of cancer.
The microbiome is even being studied as a biomarker for treatment prediction. High-throughput sequencing and machine learning have enabled the development of predictive scores such as TOPOSCORE, which classifies patients based on microbial signatures associated with survival outcomes following immunotherapy. In the near future, analyzing a patient’s gut microbiota could guide oncologists in selecting the most appropriate therapeutic strategy—ushering in a new era of microbiome-informed precision medicine.
Figure 1. The illustration compares eubiosis (left), where commensal microbes enhance dendritic cell function and activate cytotoxic T cells, supporting tumor control, versus dysbiosis (right), where pathogenic bacteria promote chronic inflammation (IL-6, TNF-α), impair immune responses, and enable tumor progression. Diet, exercise, and antibiotics influence these microbial states and cancer outcomes.
Still, this field faces critical challenges. The heterogeneity of individual microbiomes, variability in sequencing methods, and risk of introducing infections in immunocompromised patients must be carefully addressed. Moreover, while early clinical trials are promising, large-scale, randomized studies are needed to validate the safety, efficacy, and reproducibility of microbiome-targeted interventions.
In conclusion, the microbiome is not merely a silent companion in the cancer journey—it is a powerful modulator of fate. By shaping immunity, influencing drug metabolism, and altering the tumor microenvironment, microbes within and beyond the gut are rewriting the rules of cancer therapy. As we continue to unravel this intricate relationship, the promise of microbiome-informed oncology grows stronger. Treating cancer may no longer mean targeting the tumor alone—but restoring harmony within the body’s microscopic ecosystem.
Main Reference:
Fernandez E, Wargo JA, Helmink BA. The Microbiome and Cancer: A Translational Science Review. JAMA. 2025;333(24):2188–2196. (S/f). Jamanetwork.com. Recuperado el 2 de julio de 2025, de https://jamanetwork.com/journals/jama/article-abstract/2833859
Other References:
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