Comprehensively dissecting onco‐microbiome: Intriguing connection of the microbiome to cancer metastasis

In a recent paper published in Cell, Battaglia et al. provide a valuable pan-cancer analysis of the microbiome in metastatic cancer,1 which identified the specific preferences of microbes for different organs and demonstrated the correlations between diversity of microbes and neutrophils invasive into tumors, the anaerobic bacterial enrichments in hypoxic tumors, and the relationship between Fusobacterium and immune checkpoint blockade resistance in nonsmall cell lung cancer. For over a century, researchers have observed the presence of bacteria in human tumors. However, the pathophysiological impact of intratumor microbiomes has been consistently ignored. Because of this overlook, despite our extensive knowledge of cancer and our array of treatment options, the microbiome has just been linked to cancer studies in the recent 20 years. Even though only a small number of bacteria are known to be directly carcinogenic, there has been a consistent rise in the number of bacteria that have an indirect impact on cancer. The microbiome has been found to be linked to the tumor microenvironment, the initiation of innate immune sensing pathways, the tumor-infiltrating immune compartment, and the effectiveness of immunotherapy. The presence of microbes in local tissue, adjacent locations, and tumors themselves has been demonstrated to foster and inhibit the onset and growth of cancer. Moreover, these microbes have demonstrated the ability to influence the effectiveness of many cancer treatments, such as radiation, chemotherapy, and immunotherapy, which play a vital part in regulating the host immune system and influencing the body's response to anticancer treatments (Figure 1). Primary tumors contain intricate microbial communities, and current research indicates that certain types of cancer are significantly influenced by these microbes. In our view, it is crucial to comprehend the impact of the bacteria that exist in tumors on tumor biology, immunology, and therapeutic response. However, little is known about the existence and significance of the microbiome in relation to cancer, including the distinction in the microbial composition between the primary tumor and its metastases, the preferential colonization of bacteria in certain tumor types or organs, and the resilience of the microbial population during therapeutic interventions. To this end, Battaglia et al. combined metagenomics, genomics, and transcriptomics techniques to examine the microbiota of metastatic tumors and their tumor-resident microbiome. They employed a bioinformatics methodology for data analysis, utilizing computational approaches such as Kraken2 and PathSeq, and also used high-throughput sequencing technology and various bioinformatics analysis approaches, including the STAR RNA-seq comparison tool and MutationalPatterns analysis, to enhance the precision and comprehensiveness of data processing and analysis. They analyzed 4164 samples of whole-genome sequencing and pretreatment tumor biopsies from the Hartwig Medical Foundation cohort to characterize tumor-resident microbiome communities in metastatic cancer types. Battaglia and colleagues attempt to make a comprehensive account of the microbiome in metastatic malignancies across different types of cancer, aiming to reveal the range of microorganisms present and their relationship with tumor physiology and immune function. The authors methodically analyzed the microbiome in many types of cancer by pan-cancer analysis, a somewhat uncommon approach in current research. Their study investigated the correlation between microbial diversity and cancer and delved into the intricate connections between microorganisms and tumor immune evasion, invasion of cancer-related fibroblasts, and immunological rejection. They developed a comprehensive collection of the microbiome observed in metastatic tumors across different types of cancer, which could potentially facilitate the development of treatment approaches and offer valuable biological knowledge. Even though frontier areas in the investigation of the relationship between cancer and microbiota are yet to be explored, there is still inspiring research presenting new possibilities for cancer diagnosis and treatment. Detecting sample host and microbiome RNA signatures has potential for aiding the diagnosis of cancer. Research shows that by utilizing a metatranscriptomic approach to analyze saliva samples and training a classifier with machine learning techniques, it is possible to achieve a wide-ranging ability to detect oral squamous cell carcinoma and oropharyngeal squamous cell carcinoma at an early stage.2 The microbiome is also beneficial for the classification of diseases. The interaction between the microbiome and metabolome has been found to be different in early-onset colorectal cancer and late-onset colorectal cancer. It is found that multiomics signatures of early-onset colorectal cancer are characterized by enriched flavonifractor, whereas those of late-onset colorectal cancer seem to be related to Fusobacterium nucleatum enrichment.3 Microbiome-derived biomarkers have the potential to serve as noninvasive tools for accurately detecting and distinguishing individuals with early-onset colorectal cancer. Furthermore, it is beneficial for enhancing patient stratification. Analyzing human RNA sequencing data can identify bacterial signals and differentiate between several factors such as survival, anatomic location, microsatellite instability, consensus molecular subtype, and immune cell infiltration.4 Meanwhile, modulating the microbiome could be a potential adjuvant therapy for cancer immunotherapy. Administration of Fusobacterium nucleatum can downregulate the interleukin 17 signaling pathway by targeting the nuclear receptor of indole-3-lactic acid, which inhibits the growth of colorectal tumors.5 These aforementioned research findings, if supported by a pan-cancer analysis similar to Battaglia's or even a large-scale database, will undoubtedly have a significant impact on clinical tumor treatment and provide valuable guidance for future research directions. Limited clinical laboratory technology: The primary clinical examination is to determine tumor location, size, or characteristics. Advanced techniques were rarely devised to detect the microbiome within tumors. The extent and diagnostic implications of microbial contributions to various types of cancer are yet to be determined. Lack of procedural controls: Procedural controls are seldom utilized in cancer genomics investigations. Utilizing a newly developed bioinformatics methodology can enhance the efficacy of genomics projects. Sample bias: Even with a high sequencing depth, under sampling of lowly numerous bacteria may occur due to the little biomass presence. We may disregard the impact of lowly abundant bacteria. Sample contamination: The investigations are limited by the potential for sample contamination during collection, processing, and sequencing. An approach for sample selection should be devised to limit the impact of contaminants in microbiological signatures. In conclusion, the first comprehensive pan-cancer atlas of intratumor microbiomes in metastatic tumors was created by Battaglia et al., and this is considered a noteworthy achievement. They minimize errors arising from samples or computational processes by utilizing emerging high-throughput technologies and bioinformatics methods, providing innovative results for current tumor microbiome research. Progress in this field will necessitate cooperation between cancer biologists and microbiologists. To further investigate the molecular mechanisms linking microorganisms to cancer, as well as their impact on tumor development, tumor immunity, tumor transfer, and tumor treatment, it is imperative to employ advanced technologies like high-throughput sequencing and single-cell sequencing in large-scale cohort studies. Application of immune checkpoint blockage and immune sensing pathways in personalized medicine holds promise for future therapeutic approaches. Comprehensive studies, analysis of various tumors, and the establishment of strong follow-up systems are essential for facilitating future investigations into the complex and potentially manipulable functions of the intratumor microbiome in cancer. Lan Yang wrote the manuscript and drew the figure. Hailin Zhang and Min Wu initiated, supervised, and revised the manuscript writing. All authors have read and approved the final manuscript. The authors thank Yongye Huang of College of Life and Health Sciences, Northeastern University for his help in reading the manuscript. Figure 1 was created with Biorender.com. The authors declare no conflict of interest. The ethics statement is not applicable to this article. Data sharing is not applicable to this article.