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. Here we show that tumors producing high levels of granulocyte colony-stimulating factor (G-CSF) promote the persistence of Gram-negative pathogens in head and neck squamous cell carcinoma. We identify tumor-driven activation of the nicotinamide phosphoribosyltransferase (NAMPT)- nicotinamide adenine dinucleotide (NAD) signaling axis in neutrophil progenitors, resulting in impaired phagocytosis and neutrophil extracellular traps formation, accelerated neutrophil aging, and buildup of tissue-damaging neutrophil subsets. This disrupts lung tissue integrity and facilitates bacterial persistence. Importantly, targeting the G-CSF-NAMPT pathway prevents the generation of dysfunctional neutrophils and improves bacterial clearance in vivo. Our findings reveal tumor-induced, NAMPT-dependent neutrophil reprogramming as a central driver of compromised antimicrobial defenses in cancer. Therapeutic strategies aimed at modulating G-CSF-NAMPT signaling could enhance infection control and survival for cancer patients