Despite the revolutionary impact of immune checkpoint inhibitors on cancer therapy, 60% to 80% of patients with NSCLC still show suboptimal responses. PD-L1 expression, the most widely used clinical biomarker, fails to predict benefit even in patients with high expression levels—approximately 40% to 50% of them do not respond to single‑agent immunotherapy. Tumor mutational burden and microsatellite instability have shown potential but face significant hurdles in lung cancer due to the disease’s histological and molecular heterogeneity. Given these challenges, there is an urgent need for in‑depth investigation into the role of the microbiome as a predictive and functionally relevant biomarker.
A research team from Peking University People’s Hospital in Beijing, China, has published (DOI: 10.20892/j.issn.2095-3941.2025.0177)a comprehensive review in Cancer Biology & Medicine (August 2026) that systematically evaluates the microbiome’s role in lung cancer immunotherapy. Led by Dr. Kezhong Chen from the Department of Thoracic Surgery, the authors synthesized evidence from multiple cohorts and clinical trials, covering microbial communities in the oral cavity, airways, lung tumors and gut, and their connections to treatment efficacy and immune‑related adverse events.
The review reveals that the microbiome operates as an interconnected ecosystem spanning the oral cavity, airways, lungs and gut, with each site contributing distinct predictive information. Individuals with higher oral microbial diversity show lower lung cancer risk, while specific bacteria such as Streptococcus, Veillonella and Fusobacterium are consistently enriched in oral and airway samples from patients with lung cancer. In the gut, high abundance of butyrate‑producing bacteria—including Fusicatenibacter, Butyricicoccus and Blautia—correlates with longer survival, whereas genera like Ruminococcaceae UBA1819 predict poorer outcomes. Akkermansia muciniphila (AKK) has emerged as a particularly promising biomarker: AKK‑positive patients show significantly higher objective response rates and 12‑month survival of 59% versus 35% in AKK‑negative patients. Notably, the relationship follows an inverted U‑shape—moderate AKK abundance works best, while levels exceeding 5% may paradoxically diminish benefit. The intratumoral microbiome exhibits striking spatial heterogeneity, with pro‑inflammatory bacteria clustering at invasive margins alongside activated CD8+ T cells, while immunosuppressive bacteria associate with regulatory T cells and M2 macrophages in tumor cores. Short‑chain fatty acids, tryptophan metabolites and bile acids have emerged as functional biomarkers that may predict treatment outcomes more accurately than taxonomic composition alone.
“The microbiome is not just a passive bystander in cancer treatment—it actively shapes the immune landscape,” the authors said. “We are seeing that the bacterial communities in a patient’s gut, their airways and even within the tumor itself can tell us a great deal about whether they are likely to benefit from immunotherapy. The real opportunity now is to move beyond describing these associations and start developing practical, clinically useful tools. But we also have to be cautious—these are complex ecological networks, and we are only beginning to understand which changes are causes and which are effects.”
These findings open multiple pathways for clinical translation. Microbiome-based prediction models have reported accuracy above 80%, outperforming PD-L1 expression alone, and integrating multiple body sites further improved predictive performance over single-site analysis. Non‑invasive sampling through fecal or saliva collection enables longitudinal monitoring, potentially allowing real‑time treatment adjustments. Intervention strategies—including probiotic supplementation, fecal microbiota transplantation (FMT), dietary modification and engineered bacteria—are being actively investigated to boost immunotherapy efficacy and reduce immune‑related adverse events. FMT from immunotherapy‑responsive donors has shown particular promise, with ongoing trials evaluating its role in non‑small cell lung cancer. However, the authors emphasize that most current evidence remains associative rather than causal, and rigorous randomized controlled trials are needed before microbiome‑based interventions can be widely adopted in routine practice.
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References
DOI
10.20892/j.issn.2095-3941.2025.0177
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0177
Funding information
This work was supported by the Beijing Natural Science Foundation (Grant Nos. Z240013, L234002, and L222021), the Beijing Research Ward Excellence Program (Grant Nos. BRWEP2024W034080200 and BRWEP2024W034080204), the Chinese Academy of Medical Sciences (Grant No. 2021RU002), the National Natural Science Foundation of China (Grant Nos. 92259303, 82388102, 82450111, 82373416, and 82573950), the CAMS Medical and Health Science and Technology Innovation Project (Grant No. 2021-I2M-5-002), and the Peking University People’s Hospital Research and Development Funds (Grant No. RZG2024-02).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world.