The concept of microecology describes the co-evolved ecosystems formed between humans and their microbial communities, characterized by mutual dependence and constraint. These ecosystems exist at distinct anatomical sites, including the skin, gastrointestinal tract, oral cavity, urogenital system, and respiratory tract, each with its own compositional and functional signature. In healthy individuals, a homeostatic balance prevails between host and microbiota. In lung cancer patients, that balance breaks down in characteristic ways: microbial diversity declines, functional composition shifts, metabolic activity becomes aberrant, spatial distribution is disturbed, and pro-inflammatory species expand. Microorganisms, spanning viruses, bacteria, mycoplasma, chlamydia, and fungi, are now understood to be integral components of the tumor microenvironment itself, capable of inducing genetic mutations, fueling chronic inflammation, and secreting bioactive metabolites that directly and indirectly modulate tumor behavior and therapeutic response.

The gut microbiota, the largest microbial community in the human body, provides some of the clearest signals of this dysbiosis. Researchers have detected significantly elevated levels of Mycoplasma, Veillonella, Clostridium, and Enterococcus species in lung cancer patients compared with healthy individuals, and the proliferation of these genera is closely associated with disease development and progression. Intratumoral bacteria may promote tumorigenesis through multiple mechanisms, including the induction of DNA damage, epigenetic alterations, pro-inflammatory responses, and the modulation of oncogenes and oncogenic signaling pathways. The metabolic specificity is remarkable: in lung tumors, bacteria capable of degrading chemical compounds found in cigarette smoke are significantly enriched, suggesting that the tobacco smoke environment selectively cultivates microbes equipped to exploit it. Laboratory experiments have shown that exposing airway epithelial cells to Veillonella, Prevotella, and Streptococcus activates the ERK and PI3K signaling pathways, which in turn promotes the enrichment of these oral flora in the lower respiratory tract, creating a self-reinforcing loop of microbial colonization and pro-tumorigenic signaling.

The lung’s own microbial residents add another layer of complexity. Since Dickson and colleagues conceptualized the respiratory microbiome in 2014 as a continuum extending from nostrils to lungs, with diversity and abundance gradually decreasing along that axis, molecular techniques have revealed a genuine lower airway ecosystem. Clinical sampling studies have quantified its relevance to cancer: in one analysis of 41 patients with operable lung cancer, 41 percent showed bronchial colonization with potentially pathogenic microorganisms, most frequently Haemophilus influenzae, followed by Streptococcus pneumoniae and Pseudomonas species. Another comparison of 39 lung cancer cases against benign lung disease and healthy controls found higher abundance of Veillonella and Streptococcus in the cancer patients. Animal work has illuminated the immunological consequences: the lung microbiome can stimulate myeloid cells to produce Myd88-dependent IL-1β and IL-23, which induce the proliferation and activation of Vγ6Vδ1 γδ T cells producing IL-17, fostering the growth of both inflammatory and tumor cells. The field does face a serious technical caveat, however, because the lung is a low-biomass environment where contamination from oral micro-aspiration, bronchoscope biofilms, and reagent DNA can generate false positives, demanding protected specimen brushes, negative controls, and rigorous bioinformatic filtering.

The oral cavity, one of the most complex microbial ecosystems in the body, emerges as a major supplier of the lung’s microbial population. Oral microbes continuously migrate into the lower respiratory tract through daily micro-aspiration, and oral-derived bacterial communities can be detected in the lower airways of roughly half of healthy individuals, where they shape baseline pulmonary immune homeostasis through enhanced Th17-type inflammatory responses. In lung cancer patients, salivary analysis reveals a decline in beneficial bacteria such as Actinobacteria and Firmicutes alongside an increase in potentially harmful Clostridium and Proteobacteria. Large-scale epidemiological studies have linked oral overabundance of Lactobacillus to increased lung cancer risk, and in non-smoking female patients, salivary microbial diversity and richness are significantly reduced. The prognostic implications are sobering: patients with early-stage non-small cell lung cancer whose lower airways are enriched with typical oral commensals such as Streptococcus, Prevotella, and Veillonella show significantly lower survival, an effect mechanistically tied to upregulation of pro-tumorigenic signaling pathways including p53, PI3K/PTEN, ERK, and IL-6/IL-8 within the tumor.

Perhaps the most frontier-defining discovery is that tumors themselves harbor resident microbial communities. These intratumoral microbiota, typically low in biomass and diversity and primarily located inside tumor cells, exhibit high spatial and temporal heterogeneity, varying between patients, between regions of the same tumor, and across stages of development. They may arrive through breaches in mucosal barriers, migration from adjacent tissues, or hematogenous spread. In lung cancer, their composition is closely linked to smoking: tumor tissues from smokers show significant enrichment of bacteria capable of degrading tobacco carcinogens such as polycyclic aromatic hydrocarbons, including Massilia and Sphingomonas. Particularly notable is the frequent enrichment of Acidovorax, which can metabolize nicotine derivatives, in TP53-mutant lung squamous cell carcinoma, a subtype common among smokers. This suggests that the chemical environment created by tobacco smoke may selectively recruit microbes with matching metabolic capabilities, which then participate in shaping a local pro-carcinogenic niche. Two obstacles hamper this research: profound heterogeneity complicates the identification of universal markers, and the difficulty of culturing many of these organisms in vitro limits causal validation.

The most clinically consequential findings concern therapy resistance, and here the evidence is causal rather than merely correlational. In landmark experiments using germ-free and antibiotic-treated mouse models, Iida and colleagues demonstrated that commensal microbiota are required for the optimal antitumor activity of the platinum chemotherapy oxaliplatin and of CpG-based immunotherapy. In microbiota-depleted mice, tumor-infiltrating myeloid cells produced fewer reactive oxygen species and mounted weaker inflammatory responses, significantly diminishing treatment efficacy. Similarly, Viaud and colleagues showed that cyclophosphamide induces the translocation of specific Gram-positive bacteria from the gut into secondary lymphoid organs, where they stimulate Th17 and memory Th1 immune responses essential for the drug’s anticancer effects. Follow-up work identified Lactobacillus johnsonii, Lactobacillus murinus, Enterococcus species, and segmented filamentous bacteria as crucial for cyclophosphamide’s response, while the Gram-negative Barnesiella intestinihominis boosts the drug’s activity by increasing interferon-gamma-producing T cells within tumors. These discoveries blur the traditional boundary between chemotherapy and immunotherapy and point toward adjuvant therapies built on beneficial bacteria or their immunomodulatory metabolites.

For immunotherapy, the stakes are even higher. Primary resistance to immune checkpoint inhibitors affects 45 to 85 percent of non-small cell lung cancer patients, and the microbiota appears to be a key regulator of who responds. Favorable responders often harbor enriched gut populations of Bifidobacterium longum, Aeromonas species, and Enterococcus faecium, while the abundance of Akkermansia muciniphila correlates positively with stronger Th1 and Tc1 immune responses and improved outcomes. Conversely, broad-spectrum antibiotic use is associated with significantly shorter overall and progression-free survival, and higher gut microbial diversity generally predicts longer progression-free survival with more circulating memory T cells and NK cells. Microbial metabolites matter too: butyrate can enhance anti-PD-1 efficacy by modulating T cell receptor signaling in CD8-positive T cells, and patients who develop immune-related colitis show significant reductions in butyrate-producing bacteria. Local ecosystems count as well, since Neisseria is more common in patients with low PD-L1 expression and poor response, whereas Veillonella is enriched in high-PD-L1 responders, and intratumoral Fusobacterium is associated with poorer checkpoint inhibitor response through reduced cytotoxic T cell infiltration. Even targeted therapy is implicated: patients responding to EGFR tyrosine kinase inhibitors show higher abundance of Actinobacteriota, particularly the genus Rothia, and greater gut microbial diversity correlates with reduced severity of treatment-induced diarrhea.

The path forward, as the review outlines, requires confronting microbial heterogeneity across individuals, establishing causality from observational data, and perfecting contamination-free sampling of low-biomass sites. Integrated multi-omics approaches will be essential to move beyond simple taxonomic surveys and unravel the functional dynamics of host-microbiome interactions, while spatial microbiology techniques will map exactly where microbes reside within tumor architecture. The ultimate goal is clinical translation: reliable microbial biomarkers for diagnosis and prognosis, and therapeutic modulation of the microbiota through precision probiotics, postbiotics, or engineered bacterial consortia designed to enhance treatment efficacy and overcome resistance. Fecal microbiota transplantation experiments, in which transferring stool from immunotherapy responders restored anti-PD-1 sensitivity in germ-free mice while non-responder microbiota failed to confer benefit, hint that such interventions may one day become routine. If the lung cancer microbiome can be reliably read and deliberately rewritten, prevention, diagnosis, and treatment paradigms that have remained stubbornly static for decades may finally be transformed.

Subject of Research: The role of microecological dysbiosis in lung cancer progression and therapy resistance

Article Title: The role and mechanisms of microecological dysbiosis in lung cancer therapy

Article References: Shuai, Y., & Tang, M. (2026). The role and mechanisms of microecological dysbiosis in lung cancer therapy. Holistic Integrative Oncology, 5(1), Article 50. https://doi.org/10.1007/s44178-026-00269-6

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00269-6

Keywords: lung cancer, microbiome, dysbiosis, immunotherapy resistance, chemotherapy, gut microbiota, intratumoral microbiota, oral microbiota, PD-1, EGFR-TKI, tumor microenvironment, microbial metabolites