NAMPT/NAD+ signaling drives neutrophil dysfunction and enhances bacterial infection susceptibility in cancer patients

Despite advancements in cancer therapies, bacterial complications remain a major challenge, delaying treatment and worsening outcomes. While immunosuppressive therapies and prolonged hospitalizations contribute, they do not fully explain the elevated infection risk in cancer patients. We observed that elevated G-CSF production by tumors was associated with the persistence of Gram-negative pathogens in head and neck squamous cell carcinoma patients. The presence of Gram-negative pathogens in oral rinse positively correlated with poor prognosis of such patients. As neutrophils are the main cells controlling bacterial infections, we aimed to identify the molecular mechanisms underlying tumor-induced suppression of antibacterial activity of these cells. We identified tumor-driven activation of the NAMPT/NAD+ signaling axis in neutrophils (already at the progenitor level), which induced long-lasting cytoskeletal alterations, impairing phagocytosis and NETosis. Moreover, NAMPT/NAD+ activity accelerated neutrophil senescence and promoted accumulation of tissue-toxic CD62Llow subpopulations, ultimately disrupting lung tissue integrity and facilitating bacterial persistence in tumor-bearing hosts. Targeting the G-CSF/NAMPT signaling effectively reduced the generation of dysfunctional neutrophils and improved bacterial clearance in vivo. These findings reveal tumor-induced, NAMPT-dependent neutrophil reprogramming as a central mechanism driving impaired antimicrobial defenses. Implementing immune-modulating strategies, such as targeting G-CSF/NAMPT signaling, could improve infection control and enhance survival in cancer patients.