Gut commensal Bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Although immunotherapy such as anti-programmed death-1 and its ligand 1 (PD-1/L1) is a standard treatment for advanced non-small cell lung cancer (NSCLC), many patients do not derive benefit directly. Several studies have elucidated new strategies to improve the antitumor immune response through gut microbiota modulation. However, it remains largely debatable regarding how gut microbiota remotely affect lung cancer microenvironment and subsequently modulate immunotherapy response. Here we show that commensal Bifidobacterium-derived extracellular vesicles (Bif.BEVs) can modulate the therapeutic effect of anti-PD-1 therapy in NSCLC. These Bif.BEVs are up-taken by lung cancer cells predominantly via dynamin-dependent endocytosis and upregulate PD-L1 expression through TLR4-NF-κB pathway. They also efficiently penetrate murine intestinal and patient-derived lung cancer organoids. Oral gavage of these Bif.BEVs result in their accumulation in tumors in mice. Using a syngeneic mouse model, Bif.BEVs are found to synergize the anti-tumor effect of anti-PD-1 via modulation of key cytokines, immune response and oncogenic pathways, and increase in tumor-infiltrating CD8⁺ T cells. Our study therefore identifies a link between Bif.BEVs and the tumor microenvironment, providing an alternative mechanism to explain how gut microbiota can influence immunotherapy response, particularly in tumors located anatomically distant from the gut.