Dissecting the intratumoral microbiome landscape in lung cancer

Abstract

The discovery of microbial communities residing within tumors has unveiled a new dimension of cancer biology. In lung cancer, the intratumoral microbiome-comprising bacteria, fungi, and viruses-has emerged as a critical modulator of tumorigenesis, immune evasion, therapeutic response, and metastasis. This review comprehensively examines the landscape of the lung tumor microbiota, highlighting its mechanistic roles in shaping the tumor microenvironment, altering host immune responses, and reprogramming of cancer metabolism. We discuss the influence of specific microbial taxa on immunotherapeutic efficacy, including their interplay with immune checkpoints and pro-inflammatory signaling pathways. Moreover, we evaluate current evidence linking microbial signatures for diagnostic and prognostic applications, emphasizing their potential in biomarker discovery and precision oncology. By integrating findings from molecular epidemiology, multi-omics profiling, and preclinical models, this review provides a translational framework for leveraging the tumor-resident microbiota as both a within tumors, we may develop new microbiome-based strategies. These strategies could improve treatment outcomes and help overcome resistance to immunotherapy.

Keywords: cancer therapy; intratumoral microbiome; lung cancer; microbial interactions; tumor microenvironment.

Figure 1

Components of the tumor microbe microenvironment (TMEM). The tumor microbe microenvironment refers to the dynamic and complex interplay between microbial communities (bacteria, viruses, fungi, and other microorganisms) and tumor cells within the tumor niche, alongside host immune, stromal, and vascular components. The evolution from studying the tumor microenvironment to focusing on the tumor microbe microenvironment marks a significant progress in the field of cancer biology. This shift emphasizes the vital influence of microbial populations, including bacteria, viruses, and fungi, within tumors on cancer progression, metastasis, and treatment responses. It highlights the intricate interactions between these microbial communities and other elements of the tumor microenvironment, such as immune and stromal cells, challenging established perceptions of tumor behavior and therapeutic strategies. Created with BioRender.com .

Figure 2

Key research achievements of intratumoral microbiota, tracing back from 1550 BC to the current era. The infographic presents a historical overview of significant research milestones related to the intratumoral microbiota, tracing developments from ancient times to the present. In 1550 BC, Imhotep utilized surgical methods to induce infections within tumor swellings as a therapeutic strategy, highlighting the historical acknowledgment of the microbial impact on tumors (28). By 1200, Peregrine Laziosi experienced spontaneous tumor regression following an infection, suggesting the potential immune-mediated anti-tumor effects of infections (29). By 1750, initial immunotherapy approaches to cancer began to gain widespread recognition and acceptance, marking the early integration of immunological concepts into cancer treatment (30). In 1800, William Coley developed a vaccine to stimulate the immune system against cancer, leveraging the immune response induced by bacterial products to combat tumors (31). In 1900, Thomas Glover and Virginia Livingston-Wheeler proposed a controversial hypothesis linking bacteria to cancer etiology, though it was later discredited (32). In 1911, discoveries related to CD24 and CD22 began to elucidate their roles in immune evasion within the tumor microenvironment, with CD24 inhibiting the phagocytosis of tumor cells by macrophages and CD22 acting as a phagocytosis inhibitor in microglia (33). The successful isolation of Helicobacter pylori in 1983 and its association with gastric ulcers and subsequently with gastric cancer highlighted the definitive role of specific bacteria in cancer development (34). Most recently, in 2022, G.D. Poore and D. Nejman conducted extensive research on the microbiome across multiple cancer types, further solidifying the critical impact of microbial communities within different tumor environments ¹⁵¹. This progression from mere observations to detailed molecular and immunological insights marks significant advancements in the field of cancer biology and treatment. Moreover, the application prospects of CAR-T cell therapy, ferroptosis, cuproptosis, and alkaliptosis in cancer treatment are promising, as they offer novel mechanisms to target tumor cells through immune modulation, metabolic disruption, and induction of non-apoptotic cell death pathways, potentially overcoming resistance to conventional therapies (–41). Created with BioRender.com .

Figure 3

Microbiome-Mediated Mechanisms in Cancer Development: Inflammation, Genotoxicity, and Metabolic Modulation. The bacterial microbiome modulates tumorigenesis through multiple mechanisms. Firstly, disturbances in microbial composition coupled with impaired host immune defenses can enhance tumorigenesis via inflammation and immune modulation, acting both locally at the tumor site and systemically in distant organs. Secondly, certain bacterial toxins, including colibactin and cytolethal distending toxin (CDT), enter host cell nuclei and directly induce genotoxicity, leading to DNA damage within target cells. Lastly, microbiome-driven metabolic activities may activate or produce carcinogenic metabolites such as acetaldehyde, metabolize dietary pro-carcinogens (e.g., nitrosamines), modulate hormone levels (including estrogen, testosterone), alter bile acid profiles, and influence host energy metabolism. Conversely, some microbiota-driven processes may also exert protective anti-tumor effects. Created with BioRender.com .

Figure 4

Commensal Microbiota Drive Lung Cancer via γδ T Cell-Mediated Inflammation. The indigenous microbial community incites inflammation linked to lung adenocarcinoma through the stimulation of resident γδ T cells within the lungs. Mice devoid of microbiota or those treated with antibiotics exhibited a marked resistance to the progression of lung cancer triggered by Kras mutation and p53 deficiency (119). On a mechanistic level, resident bacteria prompted myeloid cells to generate IL-1β and IL-23 in a Myd88-reliant manner, which in turn spurred the multiplication and stimulation of Vγ6+Vδ1+ γδ T cells. These cells secreted IL-17 along with additional effector molecules, fostering an environment conducive to inflammation and the proliferation of tumor cells. A definitive connection has been established between the interplay of local microbiota and the immune system in the emergence of lung tumors, pinpointing crucial cellular and molecular agents that could be pivotal in the strategic intervention of lung cancer. Left Under normal physiological conditions, lungs maintain a balanced microbiota and immune cell homeostasis, involving alveolar macrophages, neutrophils, and γδ T cells that collectively contribute to tissue immune surveillance and microbial balance. Right In lung cancer conditions, local dysbiosis occurs with altered microbiota composition and increased bacterial burden. This microbial dysbiosis activates lung-resident myeloid cells (alveolar macrophages and neutrophils) to produce pro-inflammatory cytokines IL-1β and IL-23. Subsequently, these cytokines stimulate the proliferation and activation of local γδ T cells (predominantly the Vγ6+ subset), promoting their differentiation into IL-17-producing γδ T cells (γδ T17). Activated γδ T17 cells then recruit additional neutrophils and secrete tumor-promoting cytokines (IL-17, IL-22, and amphiregulin [Areg]), contributing to tumor cell proliferation and growth. This positive feedback loop amplifies inflammation and fosters a tumor-supportive microenvironment in the lung, ultimately facilitating lung adenocarcinoma development. Created with BioRender.com .

Figure 5

The bacterial microbiome influences NSCLC development via various pathways. The image illustrates the potential role of microbial pathogens and commensal bacteria in promoting NSCLC progression via epithelial barrier disruption and immune modulation. Specifically, microbes such as Streptococcus, Veilonella, and Chlamydia pneumoniae induce Toll-like receptor (TLR)-mediated signaling, stimulating the secretion of pro-inflammatory cytokines (IL-1β, IL-23), subsequently activating γδ T cells and Th17 cells to release IL-17 (–125). This inflammatory cytokine cascade leads to epithelial cell changes, immune cell infiltration, and contributes to the tumor-promoting inflammatory microenvironment associated with lung cancer pathogenesis. Mechanistically, these microbiota can directly stimulate the activation of the PI3K–PDPK1 (PDK1)–AKT signaling pathway (96, 126). This microbial-driven signaling promotes oncogenic processes. Additionally, these microbes trigger immune responses characterized by enhanced inflammatory cytokine production, contributing further to tumorigenesis in the lung microenvironment. Created with BioRender.com .

Figure 6

Mechanisms of Intratumoral Bacteria in Lung Cancer Development. The relationship between intratumoral bacteria and cancer cells involves complex mechanisms that are not yet fully elucidated. Current understanding suggests three primary pathways through which these bacteria may influence cancer progression: firstly, the production of genotoxic substances that induce genetic mutations; secondly, the engagement with host cellular signaling pathways implicated in carcinogenesis; and thirdly, the promotion of inflammatory responses and immune system modulation, which can facilitate cancer initiation. These interactions highlight the multifaceted role of intratumoral microbiota in oncogenesis. Created with BioRender.com .

Figure 7

Clinical Implications of the Microbiome in Lung Cancer Diagnostics and Therapy. The bacterial microbiome has important clinical applications in oncology, facilitating lung cancer diagnosis and treatment through multiple strategies. These include detection of circulating microbial DNA in peripheral blood for cancer diagnosis, surveillance of micro-metastatic disease progression, prognostic assessment, tailoring personalized therapeutic regimens, and integration with artificial intelligence approaches to anticipate treatment responses and potential treatment-related adverse events.