Immune-oncology-microbiome axis in lung cancer: from carcinogenesis to therapy—a narrative review

Introduction

Lung cancer remains the leading cause of cancer-related deaths worldwide, with overall survival rates remaining below 20% despite significant advancements in targeted therapies and immunotherapy (1). Bioinformatics is revolutionizing lung cancer researches; the combination of multi-omics data and machine learning is enhancing precision medicine in both prevention and therapy (2). Within this evolving landscape, microbiome studies have emerged as a significant field, offering novel perspectives on the biological foundations of lung cancer. There exists a complex interplay between host and environmental factors that drives the development of lung cancer. Diverse microbial communities that inhabit distinct niches in the human body can be considered a persistent environmental exposure (3). Changes in diet, geographical location, and lifestyle influence the microbiome; furthermore, the use of antibiotics, especially during early life stages, has a particularly profound impact on its composition and function (3,4). Microorganisms form a dynamic microecosystem that maintains homeostasis and modulates the host’s immune response, which is considered a part of the innate immune system. Ecological dysbiosis is commonly observed in lung cancer patients and is characterized by reduced microbial diversity, altered functional composition, metabolic activity, local distribution, and increased pro-inflammatory species (5). There is growing evidence that microorganisms are an essential component of the tumor immune microenvironment and that they directly or indirectly modulate immune cells in tumor tissues by inducing genetic mutations, promoting the development of chronic inflammation, and releasing metabolites (6).

Immunotherapy based on immune checkpoint inhibitors (ICIs) has ushered in a new era in lung cancer treatment. Much evidence points to the microbiome when searching for factors influencing immunotherapy efficacy. In particular, significant achievements have been made in studying gut microbiota in lung cancer immunotherapy. This review focuses on the immune-oncology-microbiome (IOM) axis, describes the microbiota in various anatomical sites of lung cancer patients, addresses the interactions between microbes and the immune system in the tumor immune microenvironment, as well as how those interactions impact immunotherapy efficacy. Finally, we highlight new directions in microbiome research, emphasizing its potential role in improving lung cancer prevention and optimizing therapeutic strategies. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-737/rc).

Methods

This review employed a systematic search strategy using the PubMed and Web of Science databases for English-language articles published from 2014 to 2025. The keyword search terms included “Lung Neoplasms”, “Microbiota”, “Gastrointestinal Microbiome”, “Intratumoral microbiota”, and “Respiratory microbiome”. We also searched the references of the included studies to supplement the acquisition of relevant information. The details of the literature search process are listed in Table S1.

Different microbiome in lung cancer: origin, composition, and functions

Microorganisms are widely present on the mucosal and skin surfaces of the human body. The entire collection of microorganisms in a given ecological niche is called the microbiota, including bacteria, fungi, viruses, and protozoa. The concept of microbiome is much broader, covering the microbiota and its associated genes and genomes (7). As the largest microbiota in the human body, the gut microbiota has been extensively studied. In recent years, the emergence of advanced sequencing technology has led to a gradual focus on lower respiratory microbiota. At the same time, the study of pan-cancer intra-tumoral flora has led to the realization that the intratumoral microbiota is an essential component of tumors rather than just a secondary manifestation of pathogenic infections.

These microorganisms coexist with tumor cells, exhibiting diversity, low biomass, and specificity (3). Their detection, identification, and functional analysis rely on high-throughput sequencing and bioinformatics. While 16S rRNA remains common, newer methods like whole metagenome-based shotgun sequencing (WMS), single-cell RNA sequencing, and spatial transcriptomics allow deeper insight into host-microbe interactions (8,9). Methodological differences greatly affect results, hindering comparison and reproducibility across studies (10). Understanding each method’s strengths and limitations is essential for accurate interpretation. Corresponding bioinformatic approaches are summarized in Table S2.

Gut microbiota

Gut microbiota are communities of microorganisms that primarily inhabit the human colon. Gut microbiota can be broadly classified into three functional groups: commensal, probiotic, and pathogenic, maintaining a delicate balance in the gut (11). The diversity and abundance of commensal microbiota typically increase along the gastrointestinal tract. The composition of microbiota is influenced by physiological changes and host immune activity. Factors such as shifts in pH, oxygen levels, bile acid concentration, intestinal mucus layer, and host defense mechanisms all shape the microbial community (12).

Evidence of a strong correlation between gut microbiome composition and cancer progression has been well documented by many publications. 16S rRNA sequencing of fecal samples from lung cancer patients and healthy controls revealed distinct microbial patterns (13,14), which also varied by tumor stage and type (15). Additionally, certain bacteria are correlated with serum inflammatory markers (13). However, these studies are all single-center studies with small sample sizes, and the patient cohorts often exhibit highly skewed distributions, potentially limiting the reliability and generalizability of the findings. Notably, several studies have all highlighted that tumor samples tend to show a lower representation of Firmicutes and a higher representation of Fusobacterium, a pattern also observed in colon cancer patients (13,14,16).

Lower respiratory tract microbiota

The lower respiratory tract contains a lower microbial biomass than the upper respiratory tract. Over 90% of the microbial DNA detected in the lungs originates from nonviable microorganisms (17,18). Growing evidence suggests that the healthy lower respiratory tract maintains a dynamic microbial balance. Transient entry and selective elimination of microbiota and relative colonization rates of individual members are major determinants of the microbial composition of the lungs (19,20). Bacterial DNA from oral taxa is sometimes present in healthy individuals (21,22), as is trace microbial content from gastric aspiration (23).

Changes in the microbial composition of the lower respiratory tract have been observed in several chronic respiratory diseases, where specific bacteria often colonize diseased airways (24,25). Chronic inflammation alters the physicochemical environment of the lungs, fostering the growth of specific microbial species that become resident microorganisms (24). Studies indicate a gradual decline in α diversity from healthy lung tissue to non-malignant tissue, and further to tumor tissue in lung cancer patients (26). Significant distinctions exist between the microbiota of nonmalignant and tumor tissues (27,28), with Streptococcus and Veillonella species being more abundant in the lungs of lung cancer patients (28,29), while Staphylococcus species are comparatively reduced (29). Furthermore, the abundance of specific microbial communities varies depending on the tumor histological type, location, stage, and metastatic states (30-33). Current studies of lower respiratory tract microbiota primarily rely on bronchoalveolar lavage fluid, which remains highly vulnerable to contamination from upper airway and environmental microbes during collection. Although sputum samples are sometimes used as an alternative, they introduce even more oral microbiota, further reducing accuracy. These contamination issues cast doubt on the reliability of microbial findings. Moreover, the extremely low microbial biomass in this region exacerbates host DNA interference, undermining the authenticity and precision of sequencing results (34). Another significant challenge is the inconsistency across studies, which may arise from difficulties in pinpointing bacterial species or strains truly involved in carcinogenesis (32,33). Complicating matters further, many microbes exhibit context-dependent behavior, playing either protective or harmful roles depending on the host microenvironment (35).

Intratumoral microbiota

Intratumoral microbiota, or tumor-resident microbiota, are microorganisms that stably colonize tumors and form a vital part of the tumor microenvironment (TME), influencing tumor progression locally. These microorganisms are typically found in low abundance within tumors, exhibit lower community diversity than normal tissues, and are predominantly viable, residing mainly within tumor cells (36). There are three primary hypotheses about the origin of intratumor microbiota: first, enter the tumor via disrupted mucosal barriers; second, migrate from adjacent normal tissues; and third, spread through the bloodstream from other areas of the body, such as the oral cavity or gastrointestinal tract (37,38). Additionally, some microorganisms may travel with the primary tumor to metastatic sites (39).

In lung cancer, the composition of intratumoral microbiota seems to be closely associated with smoking. Tumors from smokers show enrichment of Massilia and Sphingobacterium, both of which can degrade polycyclic aromatic hydrocarbons (PAH) (40). TP53 mutations, which are more common in smokers—especially those with squamous lung carcinoma—are often accompanied by an abundance of PAH-degrading bacteria like Acidovorax (41), suggesting microbes may exploit tobacco-altered niches to promote carcinogenesis. Nejman et al. further confirmed that smoking patients have higher microbial activity in pathways involved in degrading chemicals from cigarette smoke compared to those in nonsmokers (36). Moreover, the metabolic activities of these microbiota also differ based on tumor type (42).

The composition of intratumoral microbiota varies significantly between individuals and even within different regions or growth stages of the same tumor (36,43). This high degree of heterogeneity makes it challenging to identify microbial indicators with consistent and clearly defined roles. Research is further complicated by the fact that many of these organisms are difficult to grow in a lab (44), which hinders the ability to isolate specific strains and experimentally validate their function.

A summary overview of the characterization of different microbiome in lung cancer is shown in Table S3.

Microbiome in normal lung immune maturation and regulation

Pulmonary immunity

The respiratory tract plays a crucial role in the host immune response. Pulmonary airway epithelial cells and alveolar macrophages form the first line of defense. Pulmonary epithelial cells express pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) from various pathogens, including viruses, bacteria, fungi, protozoa, and multicellular parasites (45). Lung macrophages, categorized into airway macrophages (AMs) and interstitial macrophages (IMs) based on location, are integral to this defense system. AMs, with their abundant surface receptors, monitor the inhalation environment and work closely with lung epithelial cells to maintain immune homeostasis in the lungs. The second line of defense involves tissue-resident lymphocytes, such as innate lymphoid cells (ILCs), specific memory B and T cell subpopulations, γδ T cells, natural killer T (NKT) cells, and regulatory T (Treg) cells. These cells activate innate and adaptive immune responses with local dendritic cells (46). γδ T cells, the primary T cell component in mucosal epithelial barrier tissues, respond to danger signals and help coordinate the immune response (47). ILCs, divided into ILC1, ILC2, and ILC3, correspond to Th1, Th2, and Th17 cells, respectively, and play significant roles in regulating immunity and tissue repair. Intrapulmonary Treg cells are vital for maintaining immune tolerance to airborne particles by forming inducible Treg cells associated with programmed cell death 1 (PD-1)-programmed death-ligand 1 (PD-L1) expression (48). Dendritic cells in the respiratory mucosa can be recruited to the airways during inflammation, along with monocyte-derived inflammatory cells, primarily macrophages. As antigen-presenting cells (APCs) in the lungs, alveolar macrophages and dendritic cells regulate the activation of pulmonary adaptive immunity, key regulators of the respiratory immune response (49).

Pulmonary immunity is dependent on microbiome

At early life stages, microbial exposure is vital for developing a fully functional pulmonary immune system, preventing immune-mediated diseases, and fostering environmental immune tolerance (50). During the neonatal period, the induction of a specific subset of lung Treg cells depends on Bacteroidetes. These cells mature through interactions with PD-L1, enhancing tolerance to allergens (48). Exposure to various microorganisms alters innate immune cells’ proportion, phenotype, and function in childhood, further shaping immune responses (51). In lung transplants, the lower respiratory microbiota significantly influences the activation of host innate immune cells. Different microbial communities can direct macrophage polarization by varying their stimulatory effects (52). γδ T cells, key players in the innate immune response, rely on pathogen presence to function effectively. For instance, exposure to E. coli promotes γδ T cell recruitment, which helps suppress allergic airway inflammation and protect against respiratory hyperresponsiveness (53-55). Bacterial components such as peptidoglycan, lipopolysaccharide (LPS), and lipophosphatidic acid—collectively known as PAMPs—bind to PRRs on dendritic cells and macrophages. This triggers inflammatory pathways, recruits immune cells, and initiates both innate and adaptive immune responses.

The gut-lung axis (GLA) further regulates pulmonary immunity. Embryologically, lungs, trachea, and intestines share the same origins, and their mucosal immune systems exhibit parallel features and dynamic microbial crosstalk (56,57). Clinically, lung infections can disturb the gut microbial balance (58,59), and lung diseases—including asthma, cancer, and tuberculosis—are associated with significant gut microbiome alterations (15,60,61). On the other hand, gut disorders often coincide with lung conditions, underscoring a bidirectional relationship (62,63). This gut-lung communication occurs via immune cells, cytokines, microbes, and metabolites. Gut-derived metabolites enter the bloodstream and indirectly influence the lung environment by modulating immune cell differentiation and inflammatory signaling (64). For instance, bacterial LPS and short-chain fatty acids (SCFAs) can alter lung macrophage metabolism (65). When infection occurs, gut-associated lymphoid tissue (GALT) can produce immune cells, which will migrate to the respiratory system with the assistance of gut microbiota. This metastatic transfer of immune cells is crucial in building immune tolerance and enhancing resistance to lung infections (66). While sometimes, the host defense is over-activated, it can also provoke autoimmune responses, potentially causing lung injury (67). Additionally, intestinal microbes are closely linked to the production of pulmonary IgA antibodies, profoundly influencing dendritic cell-mediated class-switching recombination (CSR) in the lungs by stimulating the production of transforming growth factor beta (TGF-β) (68).

Mechanisms of microbiome in the tumor immune microenvironment

The tumor immune microenvironment contains diverse immune cells and cytokines they secrete (69). Interactions between these immune cells and cytokines are complex and shape the immune response to tumor growth and metastasis. Both the gut and lung microbiota directly or indirectly influence the activity of immune cells and the production of cytokines, thereby modulating the body immune response to tumors and affecting the progression of lung cancer (Figure 1).

Figure 1 The gut, lower respiratory tract, and intratumoral microbiota, which inhabit different regions of the body, play critical roles in the development of lung cancer. They influence lung immune cells—such as Tregs, airway macrophages, dendritic cells, innate lymphoid cells, and γδT cells—by releasing metabolites that contribute to chronic inflammation and create an immune-suppressive microenvironment, favorable to cancer progression. The GLA forms a bidirectional communication network between the intestine and the lungs. This network is mediated by immune cells, cytokines, microbes, and their metabolites, demonstrating how the immune system and microbiome are closely linked across different body systems. Created with biogdp.com. AM, airway macrophage; ILC, innate lymphoid cell; GLA, gut-lung axis; PAMP, pathogen-associated molecular pattern; SCFA, short-chain fatty acid; TLR, Toll-like receptor; Treg, regulatory T.

Microbial regulation of immune cells

In a previous study, researchers categorized the lung microbiota into two distinct pneumotypes: one with high bacterial load and supraglottic-predominant taxa (SPT), and another with low bacterial load and background-predominant taxa (BPT) (22). The pneumotypes-SPT correlated with elevated lymphocytes and neutrophils in bronchoalveolar lavage fluid (22), Th17-mediated inflammation, and reduced TLR4 response in alveolar macrophages (70). In ex vivo experiments, exposure of airway epithelial cells to oral bacteria led to upregulating IL-17, PI3K, MAPK, and ERK signaling pathways, with Veillonella being a key player (31). These pathways influence cell proliferation, apoptosis, and survival while also promoting PD-L1 expression and fostering a Th17-rich inflammatory TME in early lung cancer (31,71). Similarly, Pseudomonas aeruginosa LPS-driven chronic inflammation in mice enhanced tobacco carcinogen-induced tumorigenesis via T-cell depletion, elevated PD-1/PD-L1, and accumulation of myeloid-derived suppressor cells (MDSCs) and Treg cells (72).

γδ T cells, a unique class of T cells, play a dual role in maintaining immune balance and exhibiting anti-tumor properties. In mice treated with antibiotics, γδT17 cells, a subset that produces IL-17, showed impaired anti-tumor responses, indicating the critical role of lung microbiota in maintaining local immune homeostasis (73). In a Kras-mutated and p53-deficient mouse model of lung adenocarcinoma, Tyler et al. found that lung commensal bacteria stimulated myeloid cells to produce MyD88-dependent IL-1β and IL-23, which, in turn, activated γδ T cells to produce IL-17. This promoted inflammation and tumor growth, while germ-free or antibiotic-treated mice were protected from Kras-driven lung cancer development (74). Additionally, Le Noci et al. observed a significant reduction in lung metastases in mice treated with inhaled antibiotics, which was linked to a decrease in intra-tumoral Treg cells and an increase in natural killer (NK) cell activity (75). Toll-like receptors (TLRs) also mediate inflammatory responses by recognizing microbial products in lung cells. For instance, Streptococcus pneumoniae infection activates TLR2 in bronchial epithelial cells, leading to upregulation of IL-6, which enhances stromal adhesion of lung adenocarcinoma cells and increases liver metastasis (33). Non-typable Haemophilus influenzae has been shown to promote tumor growth by upregulating genes involved in inflammatory cell recruitment, particularly IL-6, and activating immune-regulatory pathways like nuclear factor kappa B (NF-κB) and STAT3 in lung epithelial cells (76,77).

Macrogenomic sequencing has shown that specific intratumoral microbiota are linked to the composition of immune cells within tumors, which in turn influences lung cancer prognosis. For example, in patients with Bacillus megaterium-positive tumors, the TME tends to have higher levels of Th2 cells but fewer activated dendritic cells (aDC), natural killer T (NKT) cells, and plasma cells (78). Mycobacterium franklinii, which is commonly found in patients with underlying lung diseases, has been associated with higher levels of CD4⁺ T cells. The presence of these microorganisms may contribute to a shift in immune cell populations that could impact tumor progression (78). Mao et al. observed decreased Propionibacterium acnes in tumor tissues (79). This bacterium has been shown to stimulate immune responses by triggering Th17 and Th1-type cytokine pathways, leading to inflammation (80). Its reduction suggests that cancer cells may exploit microbial dynamics to evade immune surveillance.

Microbe-derived metabolites modulate the tumor immune microenvironment

SCFAs, such as acetate, propionate, and butyrate, are vital metabolites that intestinal microorganisms produce through fermentation. After being released into the intestinal lumen, these SCFAs can enter the bloodstream and influence local immune responses in the gut and systemic immune regulation and inflammation (81-83). Bacteroides phylum primarily produces acetate and propionate, while butyrate is derived chiefly from the Firmicutes phylum (65). Lung cancer patients often exhibit a disrupted gut microbiome, with a low ratio of Firmicutes to Bacteroides, leading to a decreased concentration of circulating SCFAs (13,14,84). This imbalance influences pro- and anti-inflammatory responses and modulates the tumor immune microenvironment. Butyrate and propionate inhibit histone deacetylases (HDACs), promoting the production of Treg cells outside the thymus (85). Butyrate also exerts anti-inflammatory effects by inhibiting NF-κB activation in various immune cells, reducing the proliferation of ILC2s, and suppressing the production of cytokines such as IL-13, IL-5, and IL-17a. These actions help alleviate ILC2-mediated airway inflammation and hyperresponsiveness (86,87). In vitro, propionate and butyrate increase the expression of E-cadherin in lung adenocarcinoma cells, curbing epithelial-mesenchymal transition (EMT) and impeding cancer progression. Propionate also enhances epithelial gene expression through chromatin remodeling, reducing tumor invasiveness (88). The role of acetate in lung cancer is dual and context-dependent. Some acetic acid-producing bacteria in the lower airways, such as Paenibacillus odorifer, can suppress lung cancer cell growth in vitro, suggesting possible anticarcinogenic effects (89). However, these findings require in vivo validation. In contrast, recent metabolomic analyses of non-small cell lung cancer (NSCLC) samples revealed that tumor tissues were enriched in acetate, which upregulates c-Myc expression, enhances glycolysis, and promotes tumor proliferation. This is accompanied by increased PD-L1, cyclin D1, and lactate dehydrogenase A (LDHA) levels, along with lactate production (90). In mice, acetate supplementation reduced intratumoral CD8⁺ T cells, Th1 cells, and M1 macrophages, while increasing Th2 cells and MDSCs, resulting in immunosuppression and accelerated tumor progression (90).

Tryptophan is a vital protein biosynthesis component and raw material for immune cell antibody production. It is derived from the host’s metabolic pathways and microbial breakdown of undigested proteins in the gut (91,92). The primary metabolic pathway of tryptophan involves its degradation into kynurenine (Kyn) via the enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Kyn and its metabolite, 3-hydroxy anthranilic acid (3-HAA), play crucial roles in promoting lung cancer progression by increasing the proliferation of Treg cells, enhancing T cell apoptosis, and suppressing Th17 cells. This process facilitates the immune escape of tumor cells (93). Key enzymes in the tryptophan metabolism pathway contribute to an immunosuppressive TME. In lung adenocarcinoma, high IDO1 expression is significantly associated with a lack of CD8⁺ tumor-infiltrating lymphocytes (TILs) and with mutations in the epidermal growth factor receptor (EGFR) (94). IDO1 overexpression has also been linked to increased tumor cell migration and invasion (95). Similarly, TDO promotes tumor cell proliferation and migration by stimulating the release of Kyn from lung fibroblasts. Inhibiting TDO2 has been shown to reduce tumor metastasis and improve the infiltration of immune cells into the tumor (96).

Microbial-derived peptides from pathogens or commensal bacteria also regulate anti-tumor immunity (97,98). Firstly, some antimicrobial peptides (AMPs) have been shown to directly kill tumor cells by inducing apoptosis and disrupting cell membranes, such as colicin N, which can mediate apoptosis in lung cancer cell lines (99). Due to the high selectivity of cancer cells, some AMPs are termed anticancer peptides (ACPs) and hold great promise for their application in cancer treatment (98). Secondly, some tumor-associated microorganisms are processed and assembled into human leukocyte antigen (HLA) molecules to form immunopeptidome-derived bacterial peptides (IPdBPs). Naghavian et al. found that HLA molecules of glioblastoma present bacteria-specific peptides, which can be recognized by TILs and stimulate peripheral blood memory cells (100). A parallel process in melanoma shows that bacterial peptides presented on HLA-I and HLA-II molecules can elicit reactive T-cell responses, thereby modulating immune function through canonical CD8⁺ and CD4⁺ T cell immunity pathways (101). In addition, certain Gram-negative bacteria produce quorum-sensing peptides, which act as signaling peptides. For instance, Bart et al. confirmed quorum-sensing peptide Phr0662 promotes tumor progression by targeting EGFR and enhancing angiogenesis (102).

Other metabolites, including branched-chain amino acids and bile acids, also play roles in lung cancer. The roles of various microbial metabolites in lung cancer are summarized in Table 1.

Microbiota optimize immune-related therapy in lung cancer

The occurrence of ICIs has expanded treatment options for patients with advanced driver mutation-negative lung cancer. Despite their success, not all patients benefit equally, with 45–85% of NSCLC patients exhibiting primary resistance to ICIs (110). Microbiota modulate the immune response within the TME through metabolites, inflammatory factors, and interactions with immune cells. This can either enhance or hinder the effectiveness of immunotherapy. In parallel, there is growing interest in microbiome-based immunotherapies, with researchers exploring the potential of live bacteria to enhance cancer treatment (Figure 2).

Figure 2 Promising microbiome-based cancer therapy including the combination of immunotherapy, engineered bacteria, oncolytic viruses, and PTT/PDT, hold significant promise for advancing lung cancer treatment. These innovative approaches leverage the unique interactions between microbes and the immune system to enhance anti-tumor responses. Created with biogdp.com. ICI, immune checkpoint inhibitor; PDT, photodynamic therapy; PTT, photothermal therapy; ROS, reactive oxygen species.

Microbiome signatures are associated with the efficacy of ICI immunotherapy

Numerous studies have uncovered the impact of antibiotics on the effectiveness of ICIs, largely due to their influence on gut microbiota composition (111,112). Routy et al. observed that patients treated with antibiotics before receiving ICIs had significantly shorter overall and progression-free survival (PFS) compared to those who did not receive antibiotics. The study also found that patients who responded favorably to ICIs had higher fecal concentrations of Akkermansia muciniphila. This bacterium was associated with a more robust immune response, particularly involving Th1 (helper T cells) and Tc1 (cytotoxic T cells) activity against interferon-gamma (IFN-γ), which is crucial for the efficacy of ICIs (113). Another retrospective study revealed that the impact of antibiotics on ICI efficacy in advanced NSCLC patients varied depending on PD-L1 expression levels. The negative effect of antibiotics was pronounced in patients with PD-L1 expression ≥50% but not in those with PD-L1 expression <50% (114). A prospective study by Jin et al. further emphasized the association between gut microbiome composition and ICI outcomes. They found that patients with higher baseline gut microbial diversity had significantly longer PFS and higher proportions of peripheral memory T cells and NK cells. Importantly, unlike other treatments such as radiotherapy, the gut microbiome remained stable during immunotherapy, underscoring its potential as a consistent biomarker (115). Gut microbial metabolites also play a critical role in enhancing ICI efficacy. Zhu et al. demonstrated that butyrate can enhance the effectiveness of anti-PD-1 therapy by modulating TCR signaling in CD8⁺ T cells. Other metabolites like lysine and niacin have also been linked to long-term positive outcomes in NSCLC patients undergoing immunotherapy (116). Interestingly, gut microbiota composition is also associated with the occurrence and severity of immune-related adverse events (irAEs). Functional analysis revealed that the development of immune-related colitis might be connected to the metabolic pathways of certain microorganisms. Notably, butyrate-producing bacteria were significantly reduced in patients who developed irAEs, further highlighting the importance of gut microbial metabolites in immunotherapy (117).

Beyond the gut microbiome, recent research has begun to explore the roles of lower respiratory and intratumoral microbiota in influencing immunotherapy outcomes. Jang et al. found that specific microbial profiles in the lungs are associated with PD-L1 expression levels and the response to immunotherapy in lung cancer patients. Their study revealed that Neisseria was more prevalent in patients with low PD-L1 expression and poor responses to immunotherapy. At the same time, Veillonella was more abundant in those with high PD-L1 expression and better therapeutic responses (118). However, it was previously mentioned that Veillonella can induce an inflammatory microenvironment that promotes tumorigenesis and development, though further studies are needed to understand its role in lung cancer, specifically. Meanwhile, through multi-omics analysis, Battaglia et al. demonstrated that Fusobacterium correlates with poor response to immunotherapy in NSCLC. Higher abundance of Fusobacterium was significantly linked to decreased cytotoxic T-cells, IFN-γ, and major histocompatibility complex (MHC) class II gene expression (119). Sequencing NSCLC patients prior to receiving immunotherapy revealed that the Proteobacteria phylum was significantly associated with PFS and OS in patients receiving immunotherapy, with the presence of Gammaproteobacteria being associated with low PD-L1 expression and adverse response to ICIs-based immunotherapy, resulting in low survival rates (120). Interestingly, regardless of the responsiveness to immunotherapy, patients with greater microbial diversity tend to experience longer overall survival (120). This may be partly due to these patients’ better overall health or lower disease burden, which naturally supports a more diverse microbiome. Additionally, a diverse tumor microbiome might enhance the likelihood of protective immune cross-reactivity between microbe-derived peptides and tumor neoantigens, potentially improving responses to current or future immunotherapies (121).

Promising microbiome-based cancer therapy

Combined immunotherapy

Due to the recognized importance of gut microorganisms in immunotherapy, there is growing interest in combining probiotics with ICIs. Probiotics, including Bifidobacterium, Lactobacillus, and Clostridium butyricum, are beneficial microorganisms that help maintain the host’s microecological balance (122,123). In mouse models, oral Bifidobacterium improves dendritic cell function and increases CD8⁺ T cell accumulation, enhancing ICI efficacy (124). A phase I clinical trial in metastatic renal cell carcinoma also yielded promising results, with the combination of probiotics and ICIs significantly improving PFS in patients (125). However, translating these benefits to human studies has been challenging, likely due to differences in the ability of probiotic strains to survive and function in specific environments.

Beyond probiotics, Listeria monocytogenes infection in mice leads to upregulation of PD-L1 on immune cells, suppressing effector T cell activity. A Listeria-based vaccine conjugate (Lm-LLO-E7) combined with an anti-PD-1 antibody reduced (126). Further, pairing a glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonist with a Listeria monocytogenes-based vaccine effectively eliminated tumors in 60% of mice by modulating Tregs and MDSCs, demonstrating a strong anti-tumor immune response (127). Similarly, an attenuated Listeria monocytogenes-based vaccine, ADXS-503, targets NSCLC antigens and, with pembrolizumab, shows promising response and durable disease control in metastatic NSCLC (128).

Engineered bacteria

The “cold” TME, characterized by a lack of immune cell infiltration, makes some patients less responsive to ICIs (129). Engineered bacteria modified using synthetic biology and nanotechnology offer a unique potential to penetrate deeply into tumors, delivering therapeutic proteins, cytokines, and chemotherapeutic agents. This ability allows them to remodel the “cold” environment into an immunologically “hot” one, thereby enhancing the response to ICIs (130). Facultative or specialized anaerobic bacteria, such as Salmonella typhimurium and Escherichia coli, are particularly effective in colonizing tumor environments’ hypoxic and acidic conditions, making them ideal delivery vectors (131). Zhao et al. construct attenuated Salmonella typhimurium VNP20009 carrying Sox2 shRNA, which, when combined with an antiangiogenesis agent, enhanced anti-tumor activity and increased apoptosis (132). In another study, Salmonella typhimurium A1-R combined with recombinant methionine and cisplatin successfully eradicated pulmonary osteosarcoma metastases in mice (133). Research into this targeting mechanism has found that Escherichia coli is attracted to lung cancer cells by specific biochemical signals, including the protein clusterin (134). Beyond their delivery potential, bacteria possess immune-activating properties. Deb et al. screened theta toxins from NSCLC cell lines and observed significant inhibition of NSCLC growth when combined with AKT inhibitors (135).

Cancer vaccines represent another promising avenue in immuno-oncology; however, tumor neoantigens alone often elicit insufficient immune responses. The use of immune adjuvants or bacterial-derived delivery vectors is a powerful strategy to enhance the immunogenicity of these vaccines (136,137). Researchers have developed nanocarriers based on bacterial outer membrane vesicles (OMVs) and hybrid membrane nanomaterials (HM-NPs). OMVs allow for the rapid presentation of multiple tumor neoantigens, facilitating the quick construction of tumor nano vaccines. HM-NPs, composed of E. coli-derived membranes and tumor cell membranes, are particularly useful for preventing postoperative recurrence in cases where tumor antigens may be unavailable after surgery (138).

Oncolytic viruses (OVs)

OVs are a class of viruses that can selectively infect and kill tumor cells while also activating the body’s anti-tumor immune response. The primary OVs used in lung cancer include adenovirus, herpes simplex virus (HSV), and measles virus (139). He et al. developed a recombinant adenovirus YSCH-01, which carries the anticancer gene L-IFN. Once inside tumor cells, the virus replicates and produces L-IFN protein, which directly kills the cells and activates the immune system. A clinical trial demonstrated its promise in treating advanced solid tumors, including lung cancer (140).

For patients resistant to ICIs, OVs could be a novel treatment option. CAN-2409 is a replication-defective adenovirus that delivers the herpes simplex thymidine kinase (HSV-tk) gene to cancer cells. When combined with valacyclovir and ICIs, CAN-2409 has demonstrated effectiveness in treating unresectable stage III/IV NSCLC in patients who did not respond adequately to first-line anti-PD(L)1 therapy. The combination therapy has shown good tolerability and significantly prolonged overall survival in these patients (141).

Efforts to enhance the therapeutic effects of OVs have led to exploring their combination with radiotherapy and immunotherapy. A phase III clinical trial showed that combining the modified poxvirus vaccine TG4010 with chemotherapy improved PFS in patients with advanced NSCLC (142). Beyond bacteria, viruses also serve as effective microbial vectors for targeting tumors. Ji et al. developed a chimeric antigen peptide influenza virus (CAP-Flu) system to deliver tumor antigen peptides directly to the lungs via influenza A virus (IAV). In mice, an attenuated IAV fused with the immune stimulant cytosine-phosphate-guanine (CpG) increased immune cell infiltration into lung tumors after intranasal administration. Moreover, IAV engineered to express anti-PD-L1 nanobodies further suppressed lung metastasis and extended survival upon tumor re-challenge (143).

Bacteria-based photothermal therapy (PTT)/photodynamic therapy (PDT)

Phototherapy, including both PTT and PDT, employs light and specific absorbers to increase local temperature or generate cytotoxic reactive oxygen species (ROS). These techniques are gaining recognition as promising options for lung cancer treatment due to their minimally invasive nature, low toxicity, and high specificity (144). One of the primary challenges in PTT is ensuring sufficient accumulation of photothermal agents within the tumor. Recent research has addressed this issue by using bacteria to deliver near-infrared (NIR) absorbers directly to the tumor, enabling more effective photothermal ablation (145,146). Yi et al. developed a bacteria-mediated photothermal immunotherapy approach without additional delivery agents. Injection of an attenuated Salmonella ΔppGpp strain into tumor-bearing mice led to bacterial proliferation within the tumor, triggering immune activation, pro-inflammatory factor release, and vascular disruption. This resulted in tumor-specific thrombosis and darkening, enhancing photothermal immunotherapy efficacy (147). Moreover, PDT has been improved by incorporating photosensitizer (PS)-containing nanoparticles into live bacteria, showing great promise in preclinical colorectal cancer and melanoma models (148-150). Table 2 summarizes microbiome-based therapy clinical trials.

Conclusions

Investigating the complex interplay between the immune system, cancer cells, and microbes is a promising but challenging frontier in lung cancer research. A primary set of obstacles relates to study design and data consistency, particularly as the microbiome is highly influenced by diet, lifestyle, and genetics. Multicenter studies and cross-regional validation are needed to improve the representativeness and reliability of findings (10). Furthermore, inconsistent bioinformatic approaches limit the ability to compare results across different studies. Without consistent data standards and open sharing, comparisons across studies remain limited. Clear reporting guidelines and unified workflows, including those leveraging federated learning architectures, are therefore critical for transparency and reproducibility (173).

The nature of the research sample itself presents another significant hurdle. Microbial communities often exhibit low biomass, and results are susceptible to contamination from environmental or reagent-derived sources. Although strict wet-lab protocols can reduce such risks, they should be combined with bioinformatic filtering to ensure data quality. Techniques such as enzymatic digestion, filtration, and commercial extraction kits are increasingly used to minimize host DNA interference and improve microbial signal detection (34).

When considering biomarker development, the use of whole microorganisms as biomarkers faces challenges due to high interindividual variability, sampling complexity across different body sites, difficulties in standardization, and strong environmental influences. In contrast, microbial metabolites—such as SCFAs, peptides, certain amino acids and their derivatives—offer greater clinical potential for diagnosis and treatment guidance thanks to their stability, quantifiability, and functional relevance.

In addition, translating microbiome-based interventions into clinical practice remains difficult. The primary challenge is standardization. Microbial therapies are difficult to standardize in terms of strain specificity, manufacturing consistency, dosing protocols, and colonization capacity within complex host environments. This lack of reproducibility is evident in the variable efficacy of probiotics combined with ICIs. Secondly, regulatory frameworks for these novel therapeutics are still evolving, requiring new safety, efficacy, and production standards. Most critically, treatment success depends heavily on individual patient variables—including baseline microbiota, diet, concomitant medications (especially antibiotics), and genetic background—which collectively shape a unique microecological niche. To realize their full potential, future efforts must advance toward personalized precision medicine through well-designed trials integrated with multi-omics analyses. Interdisciplinary collaboration will be essential to account for moderating factors like lifestyle and physical activity, which may interact with the microbiome and influence cancer outcomes (174).

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-737/rc

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Funding: This work was supported by grants from National Natural Science Foundation of China (#8217272, #82370096) and Jinling Hospital Management Project (#22LCYY-LH3).

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