The tumor microenvironment (TME) is composed of three categories of cells: tumor cells, extracellular matrix, and immune cells all of which are important in the development of the tumor (Abers et al., 2016, Aggarwal et al., 2023). In the TME, the extracellular matrix (ECM) comprises a complex network of proteins, glycoproteins, and polysaccharides synthesized by various cell types (Winkler, Abisoye-Ogunniyan, Metcalf, & Werb, 2020). Key contributors to the ECM include fibroblasts, which produce collagen, fibronectin, and proteoglycans, all of which contribute to the structural framework that supports tumor growth and invasion (Aggarwal et al., 2023, Ahmed and Tait, 2020). Endothelial cells form the vascular basement membrane, crucial for angiogenesis and nutrient supply to the tumor (Aggarwal et al., 2023, Ahmed and Tait, 2020). Immune cells in the TME play dual roles; they can either attack tumor cells or support tumor growth (Gajewski, Schreiber, & Fu, 2013). Within the TME, the immune cell population consists of immunosuppressive types including macrophages associated with tumors (TAMS), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) (Demuytere, Ernst, van Ovost, Cosyns, & Ceelen, 2022). Additionally, there are anti-tumor effector cells present, such as B cells, mast cells, CD4 + T helper 1 (Th1) cells, cytotoxic CD8 + T cells, dendritic cells (DCs), natural killer (NK) cells, and granulocytes (specifically neutrophils) (Demuytere et al., 2022). DCs are key antigen-presenting cells that initiate and regulate the adaptive immune response by presenting antigens to T-cells. Microbial metabolites can activate DCs through pattern recognition receptors or PRRs, enhancing their maturation and ability to present antigens effectively (Wilson, Gressier, McConville, & Bedoui, 2022). Activated DCs can present both microbial and tumor antigens to T-cells, thus bridging innate and adaptive immunity and potentially enhancing anti-tumor immune responses (Del Prete, Salvi, & Soriani, 2023). The presence of certain microbial components can modulate the cytokine milieu within the TME, influencing DC function and the type of immune response (e.g., Th1, Th2, or regulatory) (Terhune, Berk, & Czerniecki, 2013). Specific microbial-derived molecules can enhance the antigen-presenting capability of DCs, improving the efficacy of cancer vaccines or checkpoint inhibitor therapies (Griffin & Hang, 2022). (TAMs), can be polarized into different states: M1 (pro-inflammatory and anti-tumor) or M2 (anti-inflammatory and pro-tumor) (Pan, Yu, Wang, & Zhang, 2020). Microbial components, such as lipopolysaccharides (LPS) from bacteria, can bind to Toll-like receptors (TLRs) on macrophages, leading to their activation and polarization (Le Noci et al., 2021). LPS and other microbial metabolites often induce M1 polarization, characterized by the production of pro-inflammatory cytokines (e.g., interleukin 12 or IL-12, tumor necrosis factor or TNF-α) and increased phagocytic activity, enhancing anti-tumor responses (Zhao, Wu, & Yan, 2021). Conversely, certain chronic infections or microbial metabolites can promote an M2 phenotype, which supports tumor growth by producing anti-inflammatory cytokines (e.g., IL-10, transforming growth factor or TGF-β), promoting tissue repair, and angiogenesis (Bahu et al., 2013, Bhatt et al., 2017). MDSCs are immunosuppressive cells that accumulate in the TME and inhibit anti-tumor immune responses, primarily by suppressing T-cell activity (Li, Shi, & Zhang, 2021a). Microbes and their metabolites can influence the expansion and activation of MDSCs (Zhang, Ma, & Duan, 2021a). Chronic infections or persistent microbial stimulation can lead to the accumulation of MDSCs, which secrete immunosuppressive cytokines (e.g., IL-10, TGF-β) and reactive oxygen species (ROS) (Zhao et al., 2021). Microbial-induced MDSCs can enhance tumor growth by creating an immunosuppressive microenvironment, inhibiting T-cell and NK cell functions, and promoting tumor angiogenesis (Blevins et al., 2022, Burke et al., 1990, Cao et al., 2024). For instance, persistent bacterial infections can lead to an increase in MDSCs within the TME, reducing the effectiveness of immunotherapies and promoting tumor progression (Blevins et al., 2022, Burke et al., 1990, Cao et al., 2024). Dysbiosis of the microbiome, such as that in the TME, can cause a buildup of ROS in the microbiome (Bahitham, Alghamdi, & Omer, 2024). This is because a healthy microbiome produces antioxidants such as butyrate, GSH, and folate (Riaz Rajoka, Thirumdas, & Mehwish, 2021). These antioxidants prevent the buildup of ROS and the damage to cellular structures such as mitochondria (Dominic, Hamilton, & Abe, 2021). Stress-induced premature senescence (SIPS) involves excessive ROS production, driving various senescent traits (Dominic, Banerjee, Hamilton, & Abe, 2020). Some senescent cells escape cell cycle arrest, gain “stemness,” and show increased proliferation while producing ROS, inflammatory cytokines, and growth factors (Dominic et al., 2020). This process, known as the senescence-associated secretory phenotype (SASP), promotes inflammatory and proliferative signaling, leading to aggressive growth and resistance to cancer treatments (Dominic et al., 2020).

Microbes include bacteria, yeast, fungi, protozoa, archaea, and viruses that live in or on the human body (Matson, Chervin, & Gajewski, 2021). These microorganisms play a crucial role in maintaining health by aiding digestion, producing vitamins, regulating the immune system, and protecting against harmful pathogens. Bacteria are the most abundant type of microbe in the human microbiome and therefore have more prominent effects on the TME (Matson et al., 2021). The largest and most studied microbiome is the gut microbiome, though distinct microbiomes are also present in the skin, mouth, respiratory tract, urogenital tract, and nasal passages (Cheok et al., 2022, Ciernikova et al., 2022). Microbes are also abundant across many diverse types of cancers in areas with a natural microbiome, such as Colorectal Cancer (CRC), Gastric Cancer, Breast Tumors, Pancreatic Ductal Adenocarcinoma (PDAC), Cervical Cancer, Liver Cancer (HCC) (Matson et al., 2021). Even tumors such as glioblastoma, which is located in the brain have been shown to host microbes (Ciernikova, Sevcikova, Stevurkova, & Mego, 2022). Research has provided compelling evidence that certain microbes, including bacteria and viruses, can utilize the bloodstream or lymphatic system to migrate to tumor sites within the body (Chen, Wu, Wu, Xing, & Ma, 2022). Bacteria like Salmonella Enterica and Escherichia coli have been observed accumulating in solid tumors after entering the bloodstream, taking advantage of the TME’s hypoxic conditions and leaky vasculature (Duong, Qin, You, & Min, 2019). Moreover, microbial metabolites derived from the gut microbiota, such as lipopolysaccharides (LPS), can translocate into the bloodstream through compromised intestinal barriers, potentially influencing cancer progression through systemic inflammation (Sampsell, Hao, & Reimer, 2020). Cancer can also damage mucosal barriers such as the intestine, and further enhance microbes’ ability to transmit their metabolites, and even themselves to different locations in the body (Xue, Li, & Chen, 2023). The lymphatic system serves as a route for microbial dissemination (enters the lymphatic system from the blood), allowing microbes associated with chronic infections or inflammation to travel to nearby or distant tumors using the lymphatic vessels (Siggins & Sriskandan, 2022).

Microbes can affect the immune system and TME by directly interacting with the immune system (metabolites, adjuvants, signaling, Immunogenic cell death), or first interacting with the tumor which then interacts with the immune system (Microbial mimicry, presentation of microbial antigens by tumor cells) (Ma et al., 2021). The way microbes stimulate the immune system may be different depending on the cell types, method of interaction, stage of the tumor, and location of the tumor (Ma et al., 2021). in various cancers such as the lung, ovarian, pancreatic, and breast cancers, generally, the more diverse the microbiome is, the better the functional diversity of the immune system which results in a lower risk of cancer developing (Luu, Schütz, Lauth, & Visekruna, 2023). There are three categories, mechanisms of microbial interaction with the TME and immune system (refer to Table 1). First, is cancer caused by microbes. The second category is cancers that cause infections by obstructing openings or damaging mucosal barriers (like the intestine) (Yusuf, Sampath, & Umar, 2023). This category includes a subcategory known as fungating or ulcerated Tumors. The third is tumors located in organs where there is an established natural microbiome such as the GI tract, and pancreas (Schepis, De Lucia, & Nista, 2021). This third category is the most important for this review because these organs host a rich and diverse microbiome that plays a crucial role in both maintaining health and influencing disease processes (Matson et al., 2021). Furthermore, areas with a natural microbiome (such as the gut microbiome) are where the microbiome’s influence on tumor biology has been most abundant and extensively studied, providing a wealth of data and insights that are critical for understanding the broader implications of microbial involvement in cancer (Elagan et al., 2021, Fernandes et al., 2018, Gajewski et al., 2013). This established body of research makes the third category particularly relevant for the chapter, as it allows for a detailed exploration of how the microbiome contributes to cancer dynamics in these specific environments.

While significant work has been done to look at the TME and understand its evolution during the process of tumorigenesis, metastasis, and necrosis, the interactions of microbes and the immune system within the TME have just in the past half-decade to decade become more well-researched. The purpose of this chapter is to bring attention to the role the microbiome plays in TME. This chapter is essential for the reader as it delves into the intricate relationship between the TME and the diverse array of microbes inhabiting the human body, highlighting their impact on cancer development and progression. By focusing on organs with an established natural microbiome, such as the gastrointestinal tract and pancreas, the chapter emphasizes the critical role that these microbial communities play in influencing cancer dynamics. Understanding how microbes can modulate the immune response, produce metabolites, and interact directly with cancer cells provides valuable insights into the complex mechanisms driving tumor growth and metastasis. These insights can then be used to improve and create cancer treatments.

Table 1: on the left side of the table there is each category of microbe interaction with cancer. The first categories are microbes that are known to increase the risk of cancer and are not natural to the body. To the right is the detailed layout of this category with three subtypes of microorganisms that contribute to cancer. The second category involves cancers causing infections, creating environments suitable for microbes. These microbes might not necessarily support cancer but may still cause harm in their own way. The third category focuses on areas where dysbiosis of the natural microbiome might cause or support cancer. This means that microbes that are usually harmless in homeostasis could become contributing factors to cancer outside of homeostasis ranges. The fourth category is a subcategory of the second and refers to cancer and microbe interaction when the cancer is exposed to the outside environment (open air).