Tumor-microbe transkingdom interactions in cancers at body interfaces: mechanisms of neutrophil lifespan extension and functional reprogramming with therapeutic implications

Neutrophils are central first responders in immune defense. They exhibit a remarkable phenotypic and functional plasticity with time- and context-specific properties and activities. Their short lifespan is tightly controlled, with neutrophils surviving hours in circulation before undergoing apoptosis and clearance. Tissue immigration and exposure to the local cytokine microenvironment can significantly expand the lifetime of neutrophils to several days. Various pathological conditions, such as microbial infections, cancers, and other diseases, can modulate the neutrophil lifespan. This can lead to an accumulation of aged neutrophils with specialized phenotypes and modes of action. In this regard, the host-microbe interaction in cancers at body interfaces generates a transkingdom effect on neutrophil lifetime affecting patient survival and treatment susceptibility. Here, we introduce critical modulators of neutrophil survival, including microbe-associated and cancer-related cues, highlighted as hallmarks of neutrophil survival. In this review, we discuss resulting perspectives on the immunotherapeutic potential of neutrophils and the application of engineered IgA antibodies. Integrating these insights into future research efforts could lead to innovative strategies. Targeted programming of neutrophil function will help to increase the efficacy of immunotherapies and improve outcomes in cancer and other neutrophil-associated diseases.