Profiling tumor bacteria: Bacteria are well-known residents in human tumors, but whether their presence is advantageous to the tumors or to the bacteria themselves has been unclear. As an initial step toward addressing this question, Nejman et al. produced an exhaustive catalog of the bacteria present in more than 1500 human tumors representing seven different tumor types (see the Perspective by Atreya and Turnbaugh). They found that the bacteria within tumors were localized within both cancer cells and immune cells and that the bacterial composition varied according to tumor type. Certain biologically plausible associations were identified. For example, breast cancer subtypes characterized by increased oxidative stress were enriched in bacteria that produce mycothiol, which can detoxify reactive oxygen species. Science , this issue p. 973 ; see also p. 938

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD_L), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD_L expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.

BACKGROUND: Historical accounts linking cancer and microbes date as early as four millennia ago. After establishment of the germ theory of infectious diseases, clinical research of microbial influences on cancer began in 1868, when William Busch reported spontaneous tumor regressions in patients with Streptococcus pyogenes infections. Over the next century, poor reproducibility, erroneous microbiological claims, and severe toxicity led many to discount the role of bacteria in carcinogenesis and cancer therapy. However, these studies provided the first crude demonstrations of cancer immunotherapy. Contemporaneously, the viral theory of cancer flourished, spurred by the 1911 discovery of Rous sarcoma virus, which transformed benign tissue into malignant tumors in chickens. The decades-long search to find viruses behind every human cancer ultimately failed, and many cancers have been linked to somatic mutations. Now the field is encountering intriguing claims of the importance of microbes, including bacteria and fungi, in cancer and cancer therapy. This Review critically evaluates this evidence in light of modern cancer biology and immunology, delineating roles for microbes in cancer by examining advances in proposed mechanisms, diagnostics, and modulation strategies. ADVANCES: Few microbes directly cause cancer, but many seem complicit in its growth, often acting through the host’s immune system; conversely, several have immunostimulatory properties. Mechanistic analyses of gut microbiota–immune system interactions reveal powerful effects on antitumor immunity by modulating primary and secondary lymphoid tissue activities. Many of these pathways invoke Toll-like receptor–initiated cytokine signaling, but microbial metabolic effects and antigenic mimicry with cancer cells are also important. In preclinical models, microbial metabolites also regulate phenotypes of tumor somatic mutations and modulate immune checkpoint inhibitor efficacy. Emerging evidence suggests that intratumoral bacteria exist and are active, with overlapping immunohistochemistry, immunofluorescence, electron microscopy, and sequencing data in ~10 cancer types. Preliminary studies further suggest that fungi and bacteriophages contribute to gastrointestinal cancers. However, the abundance of intratumoral microbial cells is low relative to cancer cells, and knowledge of their functional repertoire and potency remains limited. Further validation of their prevalence and impact is needed in diverse cohorts and therapeutic contexts. The immunomodulatory effects of host microbiota have reinvigorated efforts to change their composition as a form of immunotherapy. Despite extensive preclinical evidence, translation of microbiota modulation approaches into humans has not yet materialized into commercialized therapies. Synthetic biology approaches are also gaining traction, with engineered bacterial cancer therapies in preclinical and clinical trial settings. OUTLOOK: A better understanding of the roles of microbes in cancer provides an opportunity to improve each stage of the cancer care cycle, but major challenges remain. Concerted efforts to characterize cancer-associated microbiota among tumor, stool, and blood samples with gold-standard contamination controls would tremendously aid this progress. This would be analogous to The Cancer Genome Atlas’s role in characterizing the cancer somatic mutation landscape. Large-scale clinical trials are currently testing the efficacy of microbiota modulation approaches, ranging from dietary modifications to intratumorally injected, engineered bacteria. These bacterial cancer therapies, if safe and effective, could tremendously expand the cancer therapy armamentarium. Altogether, integrating the host-centric and microbial viewpoints of cancer may improve patient outcomes while providing a nuanced understanding of cancer-host-microbial evolution. Opportunities for microbes to affect cancer care.: Diagnosis: Cancer-specific, blood-borne microbial DNA may complement cell-free tumor DNA (ctDNA). Prognosis: Gut and intratumoral microbiota may stratify patient outcomes (NR, nonresponder; R, responder; TME, tumor microenvironment). Therapy: Intratumor injection of CD47 nanobody (CD47nb)–producing Escherichia coli may create systemic antitumor immunity by enhancing dendritic cell (DC) phagocytosis, lymph node (LN) antigen (Ag) presentation, and cytotoxic T lymphocyte (CTL) activity.

Another benefit of dietary fiber: The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Spencer et al . add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fiber (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fiber consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response. —PNK

Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice, hematogenous F. nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc. Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F. nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels. We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc. Intravascularly inoculated Fap2-expressing F. nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization. Inoculation with F. nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment. Thus, targeting F. nucleatum or Fap2 might be beneficial during treatment of breast cancer.

Cancer-microbe associations have been explored for centuries, but cancer-associated fungi have rarely been examined. Here, we comprehensively characterize the cancer mycobiome within 17,401 patient tissue, blood, and plasma samples across 35 cancer types in four independent cohorts. We report fungal DNA and cells at low abundances across many major human cancers, with differences in community compositions that differ among cancer types, even when accounting for technical background. Fungal histological staining of tissue microarrays supported intratumoral presence and frequent spatial association with cancer cells and macrophages. Comparing intratumoral fungal communities with matched bacteriomes and immunomes revealed co-occurring bi-domain ecologies, often with permissive, rather than competitive, microenvironments and distinct immune responses. Clinically focused assessments suggested prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers, and synergistic predictive performance with bacteriomes.