Tumors Are Not Sterile: How Microbes Living Inside Cancers Reshape Immunity and Immunotherapy

For more than a century, tumors were taught to medical students as sterile masses—islands of rogue cells surrounded by immune and stromal bystanders. That picture has now collapsed. A comprehensive review published in Molecular Cancer by Zhiyong Xiang, Weishi Cheng, Yijun Wu, Ting Niu, Ailin Zhao, Kai Kang and colleagues at West China Hospital, Sichuan University, synthesizes a decade of evidence showing that living microorganisms—bacteria in particular, but also fungi and other microbes—reside within tumor tissue itself. Far from being incidental contaminants, these intratumoral microbiota behave as dynamic ecological regulators that shape how tumors evolve, how the immune system reads the tumor microenvironment, and how patients respond to some of the most celebrated drugs in modern oncology: immune checkpoint inhibitors.

The technical case for intratumoral microbes rests on several converging methodologies. Bacterial 16S ribosomal RNA gene sequencing has detected microbial signatures in resected tumors across cancer types, including pancreatic ductal adenocarcinoma, non-small cell lung cancer, triple-negative breast cancer, hepatocellular carcinoma, and squamous cell carcinomas of the head, neck, and oral cavity. More decisive have been spatially resolved techniques: fluorescence in situ hybridization, which places bacterial signals inside tumor cells and immune cells under the microscope, and single-cell RNA sequencing analyses that computationally recover microbial reads from individual cells. Studies of pancreatic cancer, for example, reported intracellular bacteria within cancer-associated fibroblasts and immune populations, while work on breast tumors suggested that bacteria can even exploit host cell trafficking pathways, such as the cytoskeletal machinery that normally drives cell migration, to spread within the tumor.

What makes the new review distinctive is its insistence that microbial identity alone explains little. The same bacterial taxon can be associated with tumor suppression in one context and tumor promotion in another. The authors argue that biological function is determined by a combination of microbial traits—such as whether an organism is immunogenic or immunosuppressive, metabolically active or dormant—its spatial localization within the tumor, the characteristics of the host tumor, and the therapeutic pressure applied to the system. This context-dependence reframes the field: instead of asking simply which microbes are present, researchers must ask where they sit, what they are doing, and what the tumor and the treatment are doing to them at that moment.

That framing leads to the review’s central organizing concept, a tripartite framework the authors call microbiota–immunity–therapy. Under this model, the tumor is treated as an ecosystem with three interacting layers. Microbes alter the immune landscape; immunity determines whether cancer cells are eliminated or tolerated; and therapy—particularly immunotherapy—feeds back on both. The framework is designed to replace the older, linear view in which microbes were either passenger bystanders or simple biomarkers. It positions intratumoral microbiota as a dynamic variable that can be measured, monitored, and potentially manipulated to improve treatment outcomes.

The immune reprogramming arm of the framework is where the biology becomes most striking. Intratumoral microorganisms carry pathogen-associated molecular patterns that engage pattern-recognition receptors on innate immune cells, setting off cascades that can either amplify antitumor inflammation or entrench immunosuppression. Tumor-associated macrophages, myeloid-derived suppressor cells, tumor-associated neutrophils, dendritic cells, and natural killer cells all shift their behavior in response to local microbial signals. Bacterial metabolites, including short-chain fatty acids, can diffuse through the microenvironment and reprogram cell states. Outer membrane vesicles shed by bacteria deliver cargo—DNA, proteins, lipids—directly into host cells, adding another channel of communication. The net effect is a microenvironment whose immune tone is partly written by its microbial residents.

Adaptive immunity is equally entangled. Microbial antigens presented within the tumor can recruit and activate T cells, and in some settings bacterial signals enhance dendritic cell maturation and T cell priming against tumor antigens. In others, microbial stimulation drives exhaustion phenotypes in T cells, expands regulatory populations, or skews the balance toward immune escape. The review emphasizes that these effects are not fixed properties of a microbe but outcomes of its ecological position: a bacterium sequestered inside cancer cells may behave very differently from the same species sitting in the extracellular matrix adjacent to a high endothelial venule or a tertiary lymphoid structure.

Nowhere is this context-dependence more consequential than in immunotherapy. Immune checkpoint inhibitors targeting PD-1 and PD-L1 have transformed outcomes in melanoma, lung cancer, and many other malignancies, yet most patients do not respond durably. A growing body of work links intratumoral microbial composition to checkpoint inhibitor efficacy, and the review catalogues examples in which specific organisms or microbial signatures correlate with response, resistance, or immune-related toxicity. Crucially, the authors highlight that microbial effects on immunotherapy can appear paradoxical: the same microorganism may sensitize a tumor to PD-1 blockade under one set of ecological and therapeutic conditions and undermine it under another. Tumor bacterial burden—the overall load of bacteria within the tumor—emerges as a variable that may stratify patients in ways that conventional genomic biomarkers do not capture.

These insights are already generating microbiota-targeted therapeutic strategies. Fecal microbiota transplantation, which reprograms the gut ecosystem that indirectly shapes systemic immunity, has shown early promise in rescuing responses to checkpoint inhibitors in small clinical studies. More directly, researchers are exploring intratumoral approaches: engineering bacteria to deliver therapeutic payloads, deploying bacterial outer membrane vesicles as adjuvant-like immunostimulants, combining antibiotics with immunotherapy to deplete immunosuppressive microbes, and designing probiotic or oncolytic microbial constructs that reprogram the tumor microenvironment from within. Each strategy inherits the same caveat that runs through the entire review—manipulating an ecosystem whose rules are only partially understood carries the risk of unintended immune consequences.

The authors are candid about the methodological fragility of the field. Intratumoral microbial ecosystems are low-biomass environments, which makes them exquisitely vulnerable to contamination from reagents, surgical equipment, and sequencing pipelines. Distinguishing genuine tumor-resident microbes from environmental noise requires rigorous negative controls, careful sample handling, orthogonal validation by imaging and culture, and standardized reporting. Spatial heterogeneity adds another layer of difficulty: a single biopsy may miss microbial niches concentrated in hypoxic or necrotic regions. The review argues that emerging technologies—spatial transcriptomics, single-cell multi-omics, and improved culture-independent methods—will be essential to move the field from cataloguing microbes to understanding their functions in situ.

Even so, the trajectory is clear. The discovery that tumors host their own microbiomes has added a previously unrecognized layer of complexity to cancer biology, and the West China Hospital team’s synthesis argues that this layer belongs at the center of immunotherapy research rather than at its margins. If the microbiota–immunity–therapy framework holds up under experimental scrutiny, the next generation of cancer immunotherapy trials may routinely profile intratumoral microbes alongside tumor mutational burden and PD-L1 expression, and microbial manipulation may become a legitimate lever for converting non-responders into responders. For a field that long treated tumors as sterile, the message is blunt: the ecosystem inside a cancer is crowded, active, and consequential—and learning to manage its microbial residents could reshape how the immune system is aimed at cancer.

Subject of Research: Intratumoral microbiota and their role in tumor immune reprogramming and immunotherapy response

Article Title: Intratumoral microbiota: spatiotemporal dynamics, microenvironmental immune reprogramming, and immunotherapeutic implications

Article References: Xiang, Z., Cheng, W., Wu, Y., Niu, T., Zhao, A., & Kang, K. (2026). Intratumoral microbiota: spatiotemporal dynamics, microenvironmental immune reprogramming, and immunotherapeutic implications. Molecular Cancer. https://doi.org/10.1186/s12943-026-02811-6

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02811-6

Keywords: intratumoral microbiota, tumor microenvironment, cancer immunotherapy, immune checkpoint inhibitors, PD-1/PD-L1, tumor-associated macrophages, bacterial metabolites, fecal microbiota transplantation, tumor bacterial burden, microbial ecology, single-cell sequencing, Molecular Cancer