Within the innate immune system, natural killer T cells (NKT cells) are involved in the immunosurveillance of cancer due to their cytotoxic properties (Nair and Dhodapkar, 2017). When commensal gut bacteria downregulate the recruitment and concentration of CXCR6+ NKT cells in liver tumors, tumor progression continues and increases (Ma et al., 2018). In a murine liver cancer model, Ma et al. (2018) found that the microbiome could be modulated by removing gram positive bacteria with the use of vancomycin to reverse the effects of these microorganisms and enable NKT cells to repopulate liver tumors to mediate an anti-tumor immune response.

The adaptive immune system hosts CD4+ and CD8+ T cells that secrete IFN-γ, and these cells have been associated with positive clinical outcomes in patients with pancreatic ductal adenocarcinomas (Sethi et al., 2018).

Prior to affecting established tumors, the gut microbiome has been shown to contribute to tumorigenic inflammation in precursor lesions as well. Gaiser et al. (2019) detected an increase of oral microorganisms in tissue specimens that were resected from the human pancreas. The microenvironment included the species Fusarium nucleatum which was significantly denser in patients with invasive pancreatic cancer compared to patients that did not have pancreatic cancer. To further support this theory, Gaiser demonstrated elevated levels of intra-cystic IL-1β in the invasive cancer group which positively correlates with 16S bacterial DNA. This finding suggests that F. nucleatum present within the malignant lesions may have increased the level of inflammatory cytokines recruited to the area creating a tumorigenic environment during the development of the initial tumor (Gaiser et al., 2019).

In contrast to inflammation contributing to cancer, recent studies have also shown positive potential anti-tumorigenic microbial inflammation associated with other microbial species, as opposed to the tumorigenic inflammation caused by Fusobacterium in colorectal cancer. Bacterial families such as Lachnospiraceae and Ruminococcaceae found in biopsies from colon cancer promote a favorable inflammatory response due to high chemokine expression resulting in enhanced T cell infiltration (Cremonesi et al., 2018). Therefore, the gut microbiome exists in a balance where certain microbial species can either positively induce tumor formation or negatively impact tumor initiation, depending on which microbial communities predominate.

Not only do the gut microbiota contribute to tumorigenic inflammation but also they play a key role in common benign gastrointestinal disease such as inflammatory bowel disease, irritable bowel syndrome and celiac disease (Ullah et al., 2025). Autoimmune disorders, metabolic disorders including diabetes, cardiovascular disease, chronic kidney disease and even neurodegenerative diseases are linked to an adverse gut microbiota, likely due to its impairment of immune function (Ullah et al., 2024). The gut microbiota also interact with the central nervous system in the gut-brain axis, a bidirectional system with signaling pathways including chemical neurotrophic factors as well as endocrine and immunologic systems (Ullah et al., 2023). Evidence strongly suggests that gut dysbiosis affects brain-related activities linked to the development and progression of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and autism spectrum disorder (Ullah et al., 2023).

The lungs are routinely presented with environmental microorganisms that colonize the airways and parenchyma. Originally it was thought that localized flora in the lungs contributed to the initiation of regulatory T cells to reduce excessive inflammatory responses due to foreign antigens being continuously inhaled (Gollwitzer et al., 2014). However, recent discoveries have demonstrated that these localized microbial colonies may inadvertently create a pro-tumorigenic environment within the lungs (Segal et al., 2016). In a study in mice, Le Noci et al. (2018) demonstrated that the commensal lung microbiome could induce Foxp3⁺ T_regs that potentially increased growth in melanoma metastases in the lungs through immune suppression. However, aerosolized vancomycin or neomycin reduced lung microbiota resulting in downregulating the immunosuppressive IL-10 producing Foxp3⁺ T_regs populations. This resulted in a reduction of the metastatic nodule growth as well as an increase in T cells and natural killer T cell infiltration.

Tsay et al. (2018), using RNA-seq analysis of lower airway samples in lung cancer patients undergoing diagnostic bronchoscopy, found that translocation of taxa detected predominantly in the supraglottic region to the trachea was associated with upregulation of inflammatory pathways for p53 mutation, PI3K/PTEN, ERK and IL6/IL8. They concluded that enrichment of the lower airway with oral commensals may increase local immune tone with upregulation of IL1, IL6, and ERK/MARK, which in turn promotes tumor progression, thereby suggesting that microaspiration may be involved in the pathogenesis of lung cancer. In a study in human lung cancer patients undergoing tumor resection, Bailey et al. (2024) found that tracheal lavage specimens taken at the time of surgery contained a marked 16-, 6- and 6-fold higher abundance of the oral commensal species Neisseria subflava, Granulicatella adiacens, and the genus Leptotrichia in the lung cancer lavages versus controls, suggesting microaspiration and inflammation occur more significantly in lung cancer patients than in the control lavages.

Despite their different anatomic locations, the gut and lung microbiomes are not isolated but rather entwined sharing molecular signaling pathways and microbial-immune crosstalk dubbed the gut-lung axis (Budden et al., 2017; Dang and Marsland, 2019). The direct microbial connection between these two anatomic areas likely comes from microaspiration of oral contents into the tracheobronchial tree. The gut-lung axis has been found to play a key role in various benign diseases including chronic inflammatory diseases, gastrointestinal disorders and most importantly chronic lung diseases such as asthma, allergy and chronic obstructive lung disease (Zhang et al., 2020). Particular attention has been focused on lung cancer with the gut and lung microbiotas’ modulating influence on the efficacy and response of lung cancer to immunotherapy and its toxicities (Hakozaki et al., 2020; Dora et al., 2023; Hu et al., 2024). Numerous clinical studies have shown correlations between the gut microbiota and the response of lung cancer patients to immunotherapy, although there are marked variations in actual taxa that lead to a positive treatment response (Dora et al., 2024). The differences likely are related to host genetics, diet and geographical location, and antibiotic use (Simpson et al., 2023). Studies are underway to employ various methods including probiotic supplements to modulate the gut microbiota to improve the patient response to immunotherapy (Zhao et al., 2025).

Bacterial immigration, elimination, and replication (regional growth/reproduction rate) are the three major factors that regulate and maintain the composition of the lung microbiome and its abundance ( Table 4 ) (Dickson et al., 2014; Dickson et al., 2015). Bacterial immigration can result from inhalation of air, consistently exposing the lung to air- or droplet-borne bacteria which can move bacteria from the upper respiratory tract into the lungs. Also, bacterial immigration commonly occurs from micro-aspiration of fluids from the oral cavity and these droplets seed the lungs. Elimination of bacterial microorganisms can be from coughing, mucous clearance, and innate or adaptive host immune responses (Dickson et al., 2014; Dickson et al., 2015). Regional Growth and Replication as well as Reproduction Rate depend on pH, temperature, oxygen tension, nutrient availability, local microbial competition, host epithelial cell interactions, activation of inflammatory cells, and concentration of inflammatory cells.

The development of lung dysbiosis can occur rapidly by lung diseases causing a change in the local lung environment, as a result favoring the growth of specific bacterial microorganisms over others (Dickson et al., 2014). Substantial evidence indicates that local lung dysbiosis is linked to chronic pulmonary diseases often causing significant inflammation in the lungs (O’Dwyer et al., 2016). Patients with chronic obstructive pulmonary disease (COPD) had large microbial differences in their bacterial communities within the microenvironment and these were similar to lung samples from patients with cystic fibrosis (Sethi et al., 2007; Gomes et al., 2019). Recovery for these patients is difficult as continuous overgrowth of pathogenic organisms and new commensal strains in the lungs cause exacerbation of the disease (Akinosoglou et al., 2013). The composition of microbiota in the lungs is constantly changing depending on pathological conditions and can contribute to infection and recovery from specific lung diseases including cancer. Other important factors regulating the microbiome include the presence of chronic lung disease and acute infections, medications and environmental exposures, as illustrated in Figure 1 .

Evidence suggests that lung microbiota may regulate pathways that are linked to oncogenic effects and can have a direct effect on driving tumor carcinogenesis. Dysbiosis may result in altered bacteria-derived molecules within the tumor microenvironment, giving rise to lung cancer cells with alterations in metabolic pathways and oncogenic signaling (Yu et al., 2016). These bacterial metabolites prove to be important for regulation of host metabolism and play a large role in signaling pathways (Yu et al., 2016). Providing further evidence, patients with lung cancer had a reported decreased abundance of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database molecules within their lung microbiome, which are important molecules for energy metabolism and ATP-binding cassette (ABC) transport (Gustafson et al., 2010). In contrast, patients with lung cancer had an increase in molecules related to lipid metabolism, amino acid metabolism, and xenobiotic metabolism (Tsay et al., 2018). The dysbiosis shown in these metabolic profiles of lung microbiomes may impact gene expressions of epithelial cells within the airways.

In vitro studies conducted with samples of human lung adenocarcinoma, specifically with the A549 cell line, showed that bacterial products from this cell line resulted in upregulation of PI3K and ERK1/2 gene expression both of which are part of the signaling pathways. Transcriptomics of such cell lines and associated upregulated genes were consistent when lung cancer patients were compared to healthy individuals (Lloyd and Marsland, 2017). Interestingly, upregulation of the PI3K signaling pathway has been linked to early events that occur during promotion of lung tumor development (Tsay et al., 2018). These data, in combination with evidence from in vitro studies, suggest a direct association between the lung microbiome and tumorigenesis.

It has been suggested that microbiota may play a role in shaping the immune microenvironment which could potentially lead to a lung environment that promotes carcinogenesis. Many immune cells that are residents of the lung are important for maintaining homeostasis within pulmonary tissues and are providing immune surveillance against invading pathogens (Palucka and Coussens, 2016). Cancer development is associated closely with chronic inflammation promoted by inflammatory cells that secrete cytokines and chemokines. Another inflammatory cell product comprises prostaglandins which stimulate cell proliferation, tumor remodeling, and metastasis (Jin C. et al., 2019). Although these immune cells have been linked directly to inflammation, and evidence links inflammation to cancer promotion, the source of inflammation and how the immune system contributes to tumorigenesis cellularly and molecularly have yet to been discovered.

Jin Y. et al. (2019) collected lung adenocarcinoma samples that were driven by the KRAS point mutation and had a loss of function of the P53 gene to demonstrate how microorganisms could negatively impact inflammation and tumorigenesis in the lung. The authors found an association between lung tumorigenesis and increased bacterial density with an altered bacterial composition. The microorganisms within the adenocarcinoma samples were shown to stimulate products from myeloid cells such as Myd88-dependent IL-1β and IL-23, which resulted in the activation and the cell proliferation of certain residential lung cells. Such residential lung cells, particularly γδ T cells, began to give rise to immune cells that promote inflammation and neutrophil infiltration within the lung microenvironment, and led to upregulated IL-22 expression which has been shown to directly promote tumor cell proliferation (Fox and Wang, 2007). This study eliminated the commensal bacteria within mice through the administration of antibiotics or by creating germ-free mice. Antibiotic treatment was used to show that elimination of these microorganisms blocks the γδ T cells that downregulate the production of IL-17 which results in the suppression of lung tumor growth (Jin Y. et al., 2019).

In a supporting clinical study, Le Noci et al. (2018) treated patients with an aerosolized combination of vancomycin and neomycin which resulted in a reduced number of lung tumor cell implantation. This patient study also showed that antibiotic treatment results in a decrease of IL-10 and an increase in natural killer cells and anti-tumoral T cells. Therefore, treating a patient with antibiotics may reduce immunosuppression by altering factors within the tumor microenvironment mediated by microbiota that would otherwise foster tumor growth.

Ongoing studies introduce the idea that certain bacterial compositions can contribute to upregulating lung inflammation and as a result contribute to lung cancer tumorigenesis. With antibiotic treatment, a shift in the tumor microenvironment, characterized by a decrease in gram-positive phylum Firmicutes and an increase in gram-negative phylum Proteobacteria, led to an upregulation of anti-tumor immunity (Le Noci et al., 2018). This emphasizes the significance of maintaining homeostasis within the lung microenvironment to promote the equilibrium of various bacterial species. Further evidence suggests that upregulation of oral microorganisms in the lung is associated with inflammatory responses. These oral taxa created increased levels of lymphocytes and expressed more inflammatory cytokines (Segal et al., 2016).

Gollwitzer et al. (2014) showed a shift from phyla Firmicutes to Bacteroidetes in neonates after birth and this shift in the lung tissues began to promote PD-L1 expression within lung dendritic cells. Although they did not specifically determine tumorigenic effects of bacterial shifts, it does suggest that changes in bacterial diversities can impact regulation of immune regulatory molecules, including PD-L1, and can also promote inflammatory factors within the innate and adaptive immune responses.

These diverse studies provided experimental insight to how the lung microbiome may contribute to lung carcinogenesis. More importantly, these studies present novel targets that could potentially be addressed to prevent cancers and even help with the treatment of lung cancers. Of note, while conducted rigorously, sample sizes were modest in these studies with significant variability in the results. Further characterization of the lung microbiome is needed to develop a bacterial biomarker for lung cancer. Also, comparison between lung cancer microbiomes to those of healthy subjects at a larger scale would need to be conducted to determine any significant differences between microbiomes and inform use of antimicrobial therapies in lung cancer patients.

Epidemiologic studies have discovered many relationships between the microbiome and lung cancer, a malignancy with the highest cancer-related death rate worldwide. For example, studies found significant relevance of the species Mycobacterium tuberculosis in early lung cancer studies (Liang et al., 2009). The link of M. tuberculosis infection to lung cancer has been suggested to be due to chronic inflammation-associated carcinogenesis (Christopoulos et al., 2014). Also, persistent infection of M. tuberculosis increases production of tumor necrosis factor (TNF) resulting in chronic pulmonary inflammation. Chronic pulmonary inflammation eventually leads to pulmonary fibrosis which is also linked to the development of lung cancers. In turn, people with lung cancer also have an increased risk of M. tuberculosis reactivation infections as they become immunocompromised during and after their chemotherapy treatments (Morgan and Huttenhower, 2012). As M. tuberculosis is now predominantly present in lower-income countries, its association with lung cancer is less prominent in higher income countries.

Other epidemiologic studies have provided increased evidence that the changes of the microbiome may be significant contributing factors to the development of lung cancer. Between non-malignant and tumor tissues, beta diversity (differences in species composition between different samples) was not significantly different (Yu et al., 2016). However, alpha diversities (species diversity within a specific sample) were significantly lower in lung cancer tumor tissue when compared to non-malignant lung tissues (Laroumagne et al., 2011). Several microorganisms have been analyzed to show their effects in the development and progression in cancer cases when compared to control cases. Bronchoscopic samples from a study by Laroumagne et al. (2011) of 388 cases helped the investigators identify pathogenic gram-negative bacteria that colonized the bronchi in 40% of lung cancer patients including species Escherichia coli, Haemophilus influenzae, and Enterobacter spp (Hosgood et al., 2014). Streptococcus, Granulicatella, and Abiotrophia genera were more abundant in oral and sputum samples from women in China with lung cancer when compared to healthy controls (Yan et al., 2015). In the same study, the alpha diversity in sputum samples from lung microbiota was higher in cases when women used smokey coal for heating and cooking compared to women who used smokeless coal. Interestingly, those same subjects did not show any significant contrast in alpha diversity in the oral samples (Yan et al., 2015).

Lee et al. (2016) looked at the microbiome of bronchoalveolar lavage fluid in squamous cell carcinoma (SCC) and adenocarcinoma patients compared to benign nodules and discovered that there were significant variations in the presence of the organisms. The genera Capnocytophaga, Selenomonas, Veillonella, and Neisseria were found in malignant samples when compared to the benign mass-like lesion controls. Because of these findings, they posited that lung cancer screenings for bacterial biomarkers of genera Capnocytophaga and Veillonella may show promise in the prediction of SCC and adenocarcinoma. In that pilot study, Lee et al. (2016) discovered that phyla Firmicutes and Saccharibacteria (TM7), and genera Veillonella and Megasphaera in bronchoalveolar lavage fluid were relatively more abundant from patients with lung cancer. Of the patients with lung cancer, the phyla Firmicutes and Bacteroidetes were present at a significantly higher ratio in the smoking group compared to the non-smoking group (Man et al., 2017).

Phylum TM7 was notably higher in lung cancer and COPD cases which suggests that COPD may contribute to development of lung cancer possibly from chronic inflammation. With this discovery, Man et al. (2017) suggested a potential biomarker for lung cancer would have significantly high AUC values due to the combination of increased genera Megasphaera and Veillonella (Lee et al., 2016).

Lung microbiome research is typically done by analyzing saliva, sputum, and trans-bronchoscopic bronchoalveolar lavage fluids samples, since lung biopsies are obviously not practical for healthy subjects. This makes categorizing the normal lung microbiome more difficult as these samples can be easily contaminated by the upper respiratory tract, and more accurate analysis and assessments of the lung microbiome would need to come from lung tissues (Yu et al., 2016). Researchers also discovered that the lung microbiota was different when compared to the digestive tract microbiota within healthy subjects (Liu et al., 2018). In lung tumor tissue, lower alpha diversity was observed compared to normal lung tissue which is analogous to results observed when comparing other respiratory diseases to healthy lung tissues.

Liu et al. (2018) compared the lung microbiome of SCC and adenocarcinomas and observed decreased abundance of the genus Ralstonia and increased abundance of the genus Thermus in adenocarcinoma compared to SCC. They suggested that microbiota composition and abundance could be associated with cancer histology. The same study further revealed that in metastasis, the genus Legionella was abundantly higher suggesting that tumor progression may be mediated through this microorganism (Liu et al., 2018). They reported that patients with lung cancer had a significant decrease in their lung microbial diversity in comparison to the controls. Also, they observed a steady decline of alpha diversity from the healthy noncancerous site compared to the cancerous site by testing healthy controls that underwent a bronchoscopy versus lung cancer patients with unilateral lobar masses (Walters et al., 2013). In control samples without cancer, the genus Staphylococcus was more abundant, while the genus Streptococcus was more abundant in samples from patients with cancer. This suggests that the development of lung cancer could correlate with microenvironmental changes (Walters et al., 2013), although there are significant differences in the actual genera that are most important, which is a common weakness of these studies.

Currently, our understanding of the relationship between gut microbiota and lung cancer is primitive, with many treatment studies limited to in vitro and non-clinical approaches. The close bidirectional interaction of the gut-lung axis suggests why interventions for the gut microbiome result in significant effects in the lungs and its malignancies. Clinical studies have included the increased use of probiotics, anti-inflammatory diets, and more invasive options including fecal microbiota transplants (FMT). With the understanding of the relationship between the gut microbiota and lung cancer, an approach for new early-stage detection methods may increase the number of treatment options available for lung cancer and improve outcomes for patients managed with current treatment options. Figure 3 summarizes the following microbiome effects.

Products that target the microbiome have been commercially available for decades, such as probiotic and prebiotic supplements, and recent advances in microbiome research have suggested potential clinical benefit and safety of these products. Clinical data from the use of probiotics and prebiotics suggest improved integrity of the gastrointestinal tract while promoting microbial homeostasis, metabolism regulation through vitamins and short-chain fatty acids, and even neutralization inflammatory agents and carcinogens. Hemarajata and Versalovic (2013) concluded that maintaining diversity and relative concentrations of the phyla Bacteroidetes, Actinobacteria, Proteobacteria, and others in the gut microbiome through the administration of probiotics and prebiotics promotes optimal homeostasis of the host immune system.

Based on this information, researchers have investigated potential microbial drug targets as therapies for lung cancer. Microbial drug targets have the potential to be addressed by targeted therapies, thereby decreasing adverse events that are a result of chemotherapy treatment.

A clinical trial by de Jong et al. (2006) suggested that irinotecan treatment of small cell lung cancer with concurrent administration of neomycin was of clinical benefit in decreasing the adverse events caused by the chemotherapy drug. A preclinical study treating mice with colon cancer by inhibiting a bacterial enzyme, β-glucuronidase, also alleviated chemotherapy drug toxicity by protecting the mice from irinotecan-mediated diarrhea (Wallace et al., 2010).

Despite such medical breakthroughs, the current gaps in knowledge and lack of investigational support to study how beneficial microorganisms and their molecular mechanisms can benefit the host prevent researchers from understanding how the microbiome interacts with its host. It is unknown whether changes in the microbiome will result in imbalance of homeostasis and cause disorders, or even cause inflammatory responses that could result in the formation of precancerous lesions. Also, FDA recently issued a safety alert regarding fecal microbiota transplantation (FMT) due to potential risks of serious or life-threatening infections resulting from pathogenic organisms being disseminated from the original donor (FDA, 2020).

Radiation therapy for early and advanced stage lung cancer, despite its many side effects, has been widely accepted as routine treatment in clinical practice. Unfortunately, radiotherapy can result in unexpected adverse events due to radiation toxicities and damage the host immune system. Studies of the effects of radiotherapy on the gut microbiome remain scarce and research in this field has not progressed significantly. Cui et al. (2017) had a particular interest in the relationship of gut microbiota and radiation-induced side effects. In their preclinical study of mice receiving a FMT, results showed a decrease in radiation damage that did not promote tumor cell proliferation in vivo. However, Gerassy-Vainberg et al. (2018) showed radiation-induced proinflammatory dysbiosis with enhanced TNF-α, IL-1β, and IL-6 within microbial signature expressions in post-radiated mice when compared to microbiota in radiation naïve mice. These studies are important in predicting microorganisms that are hypersensitive to radiation. By identifying these microorganisms, they can then be targeted to improve curative radiation effects. Although such studies are very preliminary, in the future microbiota may be able to serve as a premise for therapeutic strategies to help reduce radiotherapy-mediated toxicities and even to improve the prognosis of lung cancer patients post-radiation treatment (Raza et al., 2019).

Recent studies have implied that the gut microbiome is vital to drug metabolism, host response sensitivity, and chemotherapy toxicities (Roy and Trinchieri, 2017). Microorganisms and microbial enzymes within the gut microbiota have proven to directly modulate the host response to drug absorption and metabolism (Montassier et al., 2015). Gut microbiota can additionally regulate gene expression thereby indirectly affecting the rate of drug metabolism both with oral and IV administrations, as well as modulating the mucosal barrier response and changing the physiology of distant organs (Selwyn et al., 2016). In vivo and in vitro experiments demonstrated a complex relationship between human microorganisms and chemotherapy drugs. Of note, certain microbial species are able to promote the alkylating agent CB1954 in blood circulation and inhibit gemcitabine demonstrating that local bacteria can in fact change the efficacy of chemotherapeutic agents (Lehouritis et al., 2015).

Genotoxic platinum drugs are another class of antineoplastic therapeutics that contribute to anti-cancer treatment outcomes by inhibiting DNA replication (Wagner and Karnitz, 2009). This subset of drugs targets the plasma membrane and mitochondria of tumor cells, but are destructive to the host as well, leading to serious side effects including deafness, and compromising the blood-brain barrier’s integrity (Abuzeid et al., 2009). A contributing factor to the side effects of genotoxic platinum drugs may derive from the destruction of the mucosal layer which results in pathogenic microorganisms’ invasion of mesenteric lymph nodes and possibly entry into the bloodstream as well (Hooper and Macpherson, 2010). Additionally, a number of studies have shown that antibiotic misuse may not only aggravate the side effects from the administration of antineoplastic drugs, but they may potentially cause severe systemic adverse events (Zitvogel et al., 2018).

Most studies of the microbiome and chemotherapy drug administration remain within animal models and only a few trials have been conducted in humans to explore the alterations of the gut microbiome and its functions during chemotherapeutic treatment and post-chemotherapy surveillance of patients being treated for lung cancer. Moreover, large clinical trials are required to investigate if modulation of gut microorganisms will aid in the treatment of lung cancer during chemotherapy and determine if those microorganisms contribute to minimizing drug toxicities.

Several potentially effective ways to prime the gut microbiome may serve to influence outcomes for patients treated with immunotherapies ( Table 6 ). Some studies have contributed to the hypothesis that dysbiosis within the intestinal microbiota may also affect the outcomes of immunotherapies for patients with cancer (Routy et al., 2018). For example, a study in France by Routy et al. (2018) was conducted with 249 lung cancer patients receiving immunotherapy to target a PD-1 mutation. Of the 249 patients, 69 were treated with antibiotics because they had underlying diseases with onset before the first cycle of treatment which disrupted their intestinal microbiome. Upon follow up, it was determined that the 69 antibiotic-treated patients had shorter progression-free survival and overall survival compared to patients that did not receive antibiotics during immunotherapy treatment. These findings suggest that antibiotic use could negatively impact the efficacy of immunotherapy treatment and reduce the effectiveness of the drug (Routy et al., 2018). Nyein et al. (2022) also found that antibiotics administered prior to or during immunotherapy or chemotherapy treatment of advanced lung cancer resulted in a worse response rate and worse overall survival, likely resulting from a disruption of the eubiotic gut microbiome.

The species Akkermansia muciniphila is a probiotic organism that has been shown in recent studies to prevent obesity and diabetes, but has also demonstrated positive contributions to cancer immunotherapy (Li and McAllister, 2022). A recent review described a comparison of the gut microbiota for two groups of patients after isolating Akkermansia muciniphila from their stool samples. The investigators then performed a FMT into germ free mice and treated them with PD-1 inhibitors. They found that mice receiving feces from a probiotic-treated patient were able to respond rapidly to the PD-1 inhibitors when compared to mice that received a FMT from a patient without the probiotic treatment. Additionally, the researchers determined that immunotherapy response can be restored by using oral Akkermansia muciniphila probiotics as well (Gopalakrishnan et al., 2018; Li and McAllister, 2022). This outcome could be explained by the higher diversity of the microbial community, which positively correlates with cancer cells to being targeted and killed more effectively due to increased T cell activity. In contrast, increased regulatory T-cell activity within a host with unfavorable bacteria may suppress the immune response in that patient.

Jin Y. et al. (2019) conducted a clinical study in China focusing on patients diagnosed with advanced stage non-small cell lung cancer and treated with immunotherapy targeting the PD-1 checkpoint inhibitor. Patients with greater diversity in their gut microbiota responded better to the anti-PD-1 immunotherapy checkpoint inhibitors. Patients with higher microbial diversity, which is considered a favorable microbiome, exhibited an enhanced microbial signature specifically for memory T cells and natural killer cells in their blood samples. Similarly, the systemic administration of a certain bacterium from the genus Bifidobacterium, can stimulate signaling in the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and increase the performance of dendritic cells after anti-PD-1 treatment. Bifidobacterium administration successfully converted mice that were non-responders into mice that responded to immunotherapy (Shi et al., 2020).

Most recently Lin et al. (2025) reported that they isolated a new strain of the bacteria genus Hominenteromicribium from the feces of 50 patients who responded to PD-1 blockade therapies. This strain Hominenteromicrobium Mulieris YB328 was instilled into mice treated with anti-PD-1 had higher abundances of activated CD8⁺ T cells and cytokine-producing CD8⁺ T cells in the tumor microenvironment than mice treated with the common commensal species Phocaeicola vulgatus (found in non-responder feces) and anti-PD-1 or control mice. YB328 administration alone did not inhibit tumor growth. However, “patients with elevated YB328 abundance had increased infiltration of CD103⁺CD11b⁻ cDCs in tumours and had a favourable response to PD-1 blockade therapy in various cancer types.” They also analyzed “whether the bacterial species Akkermansia muciniphila and Bifidobacterium longum, which reportedly improve responses to cancer immunotherapy, possessed properties similar to those of YB328.” A. muciniphila, but not B. longum, demonstrated a marked anti-tumor effect when combined with anti-PD-1 treatment (Lin et al., 2025). Further studies are needed to discern whether any particular bacterial genus or species will provide reproducible benefit if given prospectively as a microbial “adjuvant” in humans. Nevertheless, numerous preclinical and early clinical studies have identified bacterial taxa including Ruminococcaceae, Akkermansia, and Bifidobacterium that are associated with improved response to immune checkpoint inhibitors. Numerous microbiome-focused interventions are undergoing clinical evaluation, although the field is in early stages now and will require large-scale trials before microbiome interventions enter routine clinical practice (Barragan-Carrillo et al., 2025).

The gut microbiome can also be primed to support an immune response via TLR4-signaling (Paulos et al., 2007). Commensal bacteria in the host gut could potentially activate myeloid cells associated with a tumor. This would result in a production of inflammatory cytokines and tumor-necrosis factor (TNF) that help modulate the tumor microenvironment and the anti-tumor effect during immunotherapeutic treatments (Iida et al., 2013). Each of these studies helped reveal the close relationship between gut flora and cancer immunotherapeutic treatment outcomes which informs potentially improved efficacy for immunotherapies. Understanding the positive and negative associations of the intestinal microbiome with cancer immunotherapy can inform study designs that explore cancer treatment outcomes by limiting or increasing certain microbiota. Nevertheless, understanding the relationship between the gut microbiome and cancer treatments needs to be explored in a microbe specific manner and in larger studies.

Lung cancer is typically found through chest x-rays or by screening low-dose chest CT scans. Risk stratification factors that group patients into low-risk and high-risk include age, gender, smoking history, and occupational or environmental exposures. Although these guidelines for screening high-risk individuals have been recommended for the last decade (U.S. Preventive Services, 2021), many patients who develop lung cancer fall outside of these demographics. For that reason, finding specific high-risk microorganisms, microbial signatures, or microbial alterations that are associated with lung cancer would provide a better risk stratification for high- or low-risk patients, thus improving the high-risk screening population. As sequencing capabilities expand, comparison of microbiomes between different patients, exposures, and multiple diseases have piqued the interest of researchers and physicians. It has been documented that microbial flora alterations and the development of lung cancer display significant correlation (Hosgood et al., 2014), as shown by various epidemiological studies with long-term observations and where relevant samples were provided (Lee et al., 2016; Chalmers et al., 2018; Liu et al., 2018).

Prior studies have demonstrated that alterations in the microbiome have been linked to the development and exacerbation of various lung diseases. These diseases are characterized by high inflammatory responses and have the potential to progress to lung cancer (Garcia-Nuñez et al., 2014; Taylor et al., 2017; Zheng et al., 2020). Zheng et al. (2020) discovered microbial signatures within the gut microbiome that predicted early-stage detection in lung cancer. Similarly, Yan et al. (2015) observed that concentrations of the genera Neisseria, Streptococcus and Porphyromonas in saliva from lung cancer patients were significantly higher than those in samples provided by patients without lung cancer, potentially serving as a biomarker for early-stage disease detection. Pilot studies using 16S rRNA sequencing have determined greater abundance of certain microorganisms including the families Bacteriodaceae, Lachnospiraceae, and Ruminococcaceae in lung tissues that correlate with a decreased rate of recurrence-free survival and disease-free survival rates (Peters et al., 2019). The importance of conducting additional clinical studies to establish sensitive and specific microbial biomarkers for lung cancer is a desirable focus. Such research will determine whether microbial biomarker tests can be developed that meet clinically valid criteria for sensitivity, reliability, and reproducibility.