Microbiome-driven Modulation of the Tumor Microenvironment

Emborg Bordi^*
*Correspondence: Emborg Bordi, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA, Email:

Introduction

The human body harbors trillions of microorganisms-collectively termed the microbiome-that reside predominantly in the gut but are also found on the skin, in the oral cavity, and other mucosal surfaces. Far from being passive bystanders, these microbial communities are now understood to play dynamic roles in shaping host physiology, immunity, metabolism, and disease susceptibility. One of the most transformative discoveries in recent oncology research is the intricate and bidirectional relationship between the microbiome and cancer progression. The tumor microenvironment, traditionally viewed as a complex network of cancer cells, immune infiltrates, stromal cells, vasculature, and extracellular matrix, is now recognized to be heavily influenced by microbial signals. Microbiome-driven modulation of the TME affects tumor initiation, progression, immune evasion, angiogenesis, and response to therapy. This article explores the emerging landscape of microbiome-TME interactions, outlining the mechanisms by which microbes influence tumor biology and highlighting therapeutic avenues that leverage the microbiome for cancer treatment [1,2].

Description

The tumor microenvironment is a highly heterogeneous and dynamic milieu comprising not only malignant cells but also fibroblasts, endothelial cells, immune cells (including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells), cytokines, chemokines, and extracellular matrix components. These constituents interact in a symbiotic yet often immunosuppressive fashion that supports tumor survival and growth. Recent studies reveal that microbial signals-particularly those from the gut microbiome-profoundly influence TME composition, behavior, and immunogenicity, extending the concept of the "host factor" to include the microbial community [3].

Microbial metabolites, such as short-chain fatty acids- notably butyrate, acetate, and propionate-are key mediators of microbiome-TME interactions. These metabolites can affect the epigenetic landscape of tumor and immune cells by modulating histone acetylation, DNA methylation, and gene expression. Butyrate, for example, is known to act as a histone deacetylase inhibitor, enhancing the expression of genes involved in T-cell effector function and tumor cell apoptosis. In colorectal cancer, butyrate has been shown to inhibit tumor proliferation and promote antitumor immunity through regulatory effects on T-cell differentiation and macrophage polarization [4].

The microbiome also influences the vascular and metabolic components of the TME. By modulating host metabolism, microbial communities can alter nutrient availability, hypoxia responses, and angiogenesis. Certain gut microbes produce polyamines and nitric oxide, which can enhance tumor vascularization, while others influence hypoxia-inducible factor signaling pathways. Furthermore, microbial regulation of systemic glucose and lipid metabolism affects the metabolic programming of tumor-associated immune cells, influencing their function and polarization. One of the most clinically significant aspects of microbiome-TME interaction is its impact on cancer therapy, particularly immunotherapy. The efficacy of immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 antibodies, has been shown to depend in part on the composition of the gut microbiota. Pioneering studies demonstrated that patients with a higher abundance of Akkermansia muciniphila, Bifidobacterium spp., or Faecalibacterium prausnitzii in their gut had improved responses to ICIs. Mechanistically, these microbes enhance dendritic cell activity, promote effector T-cell recruitment to the tumor, and upregulate MHC class I expression on tumor cells. In contrast, antibiotic use or gut microbial dysbiosis prior to or during treatment is associated with poorer outcomes [5].

Conclusion

The recognition of the microbiome as a critical modulator of the tumor microenvironment marks a paradigm shift in our understanding of cancer biology. Far beyond passive inhabitants, commensal and intratumoral microbes actively shape the immune, metabolic, and structural components of tumors, influencing their progression and response to therapy. The interplay between microbial metabolites, immune pathways, and host signaling networks creates a dynamic interface through which microbes can either support or suppress tumor growth. As research continues to uncover the mechanistic underpinnings of microbiome-TME interactions, new opportunities emerge for diagnostics, prognostics, and therapeutics. By harnessing the microbiomeâ??s potential, we move closer to more personalized, precise, and effective strategies in cancer management. However, realizing this potential will require overcoming biological, technical, and clinical challenges through rigorous investigation and multidisciplinary collaboration. In the coming era of oncology, the microbiome is poised not only as a biomarker but as a powerful ally in the fight against cancer.

Acknowledgement

None.

Conflict of Interest

None.

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