The gut microbiota influences anti-tumor immunity and can induce or inhibit response to immune checkpoint inhibitors (ICIs). Microbiome features are being studied as predictive/prognostic biomarkers of patient response to ICIs, and microbiome-based interventions are attractive adjuvant treatments in combination with ICIs. Specific gut-resident bacteria can influence the effectiveness of immunotherapy; however, the mechanism of action on how these bacteria affect anti-tumor immunity and response to ICIs is not fully understood. Early bacterial-based therapeutic strategies have demonstrated that targeting the gut microbiome through various methods can enhance the effectiveness of ICIs, resulting in improved clinical responses in patients with a diverse range of cancers. Understanding the microbiota-driven mechanisms of response to immunotherapy can augment the success of these interventions, particularly in patients with treatment-refractory cancers. The gut microbiota can impact carcinogenesis by disrupting signaling pathways involved in inflammation, DNA repair, and stability. Depending on the organ, bacterial-driven carcinogenesis is either caused by organ-specific microbiota or by effects of a distant bacterial community. For instance, Helicobacter pylori, which infects almost half of the world's population, has a significant role in the onset of atrophic gastritis and the development of gastric cancer. On the other hand, several organs, such as the liver and pancreas, lack a recognized microbial community; therefore, exposure to bacterial components or metabolites can contribute to carcinogenesis in these organs. In contrast, bacteria can have anti-tumor effects through bacterial-derived ligands that bind to toll-like receptors (TLRs) and NOD-like receptors (NLRs) on various immune cells responsible for triggering innate immunity and, as a result, promoting anti-tumor immune responses. Immune mediators such as type I interferons (IFNs) are produced upon activation of TLRs and NLRs, redirecting tolerogenic immune responses toward anti-tumor immunity. TLRs, including TLR2 and TLR3, are being investigated in clinical trials as adjunctive therapies and primary treatment options. For example, it was found that a ligand associated with TLR1/TLR2 can inhibit T regulatory cells (Tregs), which in turn amplifies the activity of cytotoxic T lymphocytes. In addition, several research studies have verified the anti-cancer properties of TLR3 through its direct role in inducing apoptosis in malignant cells. Front-line cancer treatments are surgery, radiotherapy, chemotherapy, and immunotherapy. However, radiation and chemotherapy have limited specificity and may harm healthy tissues along with cancerous ones, whereas most immunotherapies activate T cells and eliminate cancer cells, leaving healthy bystander cells intact. Immune checkpoint inhibitors (ICIs) are among immunotherapy approaches that block immune inhibitory molecules on T cells. In particular, lymphocyte-associated antigen 4 (CLTA-4), programmed cell death protein 1 (PD-1), and programmedThe gut microbiota influences anti-tumor immunity and can induce or inhibit response to immune checkpoint inhibitors (ICIs). Microbiome features are being studied as predictive/prognostic biomarkers of patient response to ICIs, and microbiome-based interventions are attractive adjuvant treatments in combination with ICIs. Specific gut-resident bacteria can influence the effectiveness of immunotherapy; however, the mechanism of action on how these bacteria affect anti-tumor immunity and response to ICIs is not fully understood. Early bacterial-based therapeutic strategies have demonstrated that targeting the gut microbiome through various methods can enhance the effectiveness of ICIs, resulting in improved clinical responses in patients with a diverse range of cancers. Understanding the microbiota-driven mechanisms of response to immunotherapy can augment the success of these interventions, particularly in patients with treatment-refractory cancers. The gut microbiota can impact carcinogenesis by disrupting signaling pathways involved in inflammation, DNA repair, and stability. Depending on the organ, bacterial-driven carcinogenesis is either caused by organ-specific microbiota or by effects of a distant bacterial community. For instance, Helicobacter pylori, which infects almost half of the world's population, has a significant role in the onset of atrophic gastritis and the development of gastric cancer. On the other hand, several organs, such as the liver and pancreas, lack a recognized microbial community; therefore, exposure to bacterial components or metabolites can contribute to carcinogenesis in these organs. In contrast, bacteria can have anti-tumor effects through bacterial-derived ligands that bind to toll-like receptors (TLRs) and NOD-like receptors (NLRs) on various immune cells responsible for triggering innate immunity and, as a result, promoting anti-tumor immune responses. Immune mediators such as type I interferons (IFNs) are produced upon activation of TLRs and NLRs, redirecting tolerogenic immune responses toward anti-tumor immunity. TLRs, including TLR2 and TLR3, are being investigated in clinical trials as adjunctive therapies and primary treatment options. For example, it was found that a ligand associated with TLR1/TLR2 can inhibit T regulatory cells (Tregs), which in turn amplifies the activity of cytotoxic T lymphocytes. In addition, several research studies have verified the anti-cancer properties of TLR3 through its direct role in inducing apoptosis in malignant cells. Front-line cancer treatments are surgery, radiotherapy, chemotherapy, and immunotherapy. However, radiation and chemotherapy have limited specificity and may harm healthy tissues along with cancerous ones, whereas most immunotherapies activate T cells and eliminate cancer cells, leaving healthy bystander cells intact. Immune checkpoint inhibitors (ICIs) are among immunotherapy approaches that block immune inhibitory molecules on T cells. In particular, lymphocyte-associated antigen 4 (CLTA-4), programmed cell death protein 1 (PD-1), and programmed