Bidirectional neutrophil–macrophage interactions as therapeutic leverage points in sepsis

Abstract Sepsis is a life-threatening condition driven by a dysregulated host response to infection, in which the innate immune axis—particularly the crosstalk between neutrophils and macrophages—plays a central role in dictating disease trajectory. This review delineates the functional, metabolic, and spatial characteristics of these two phagocytic cell types and highlights their bidirectional interactions across distinct immunological phases of sepsis. Multiple intercellular conduits, including extracellular vesicles, cytokine–chemokine axes, extracellular traps, and efferocytosis, mediate context-specific reprogramming of effector states, with extracellular vesicle cargo and trap degradation products emerging as diagnostic and therapeutic targets. Advances in nanomedicine now enable phase-specific manipulation of this myeloid crosstalk, attenuating pathogenic inflammation in the early phase and restoring antimicrobial competence during immunosuppression. Dissecting the spatiotemporal, metabolic, and molecular logic of neutrophil–macrophage communication offers a framework for precision immunomodulation in sepsis, with potential to recalibrate the immune landscape toward controlled inflammation and durable resolution.