Reconsidering immunotherapy resistance: the emerging role of the tumor microbiome in head and neck and lung cancers

Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized treatment for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), yet resistance limits durable responses in many patients. Emerging evidence implicates the intratumoral microbiome – comprising bacteria, fungi, and viruses within tumor tissues – as a key modulator of tumor biology, immune infiltration, and ICI sensitivity, beyond traditional tumor-intrinsic and immune factors. In HNSCC, human papillomavirus (HPV)-negative tumors exhibit higher oncobacteria abundance than HPV-positive ones, with elevated levels linked to worse survival in HPV-positive oropharyngeal cases, suggesting an immunosuppressive tumor microenvironment that may influence ICI outcomes. In NSCLC, intratumoral taxa such as Fusobacterium nucleatum and Bacteroides fragilis promote progression and evasion via immune checkpoint modulation (PD-1/PD-L1), pro-inflammatory pathways (toll-like receptors and cytokines like interleukin-6/tumour necrosis factor-alpha), metabolic reprogramming (PI3K/AKT), and recruitment of suppressive cells (neutrophils and myeloid-derived suppressor cells). Pan-cancer studies show microbial enrichments and compositional shifts in responders versus non-responders to ICI, with metabolites (e.g., lactate and succinic acid) driving M2 macrophage polarization, T-cell suppression, and resistance. The gut–tumor axis further exacerbates refractoriness through systemic dysbiosis and immune alterations. Preclinical models indicate that targeted microbiome interventions – such as fecal microbiota transplantation, specific probiotics (e.g., Bifidobacterium spp. and Akkermansia muciniphila ), or selective antibiotics – can restore antitumor immunity, enhance ICI efficacy, and minimize broad dysbiosis risks. Integrating intratumoral microbial profiling into HNSCC and NSCLC clinical trials could refine patient stratification, uncover predictive biomarkers, and accelerate microbiome-directed adjunct therapies, advancing precision oncology and expanding immunotherapy benefits.