Multicellular crosstalk in neutrophilic asthma: unraveling the pathogenic web of steroid resistance and emerging precision therapies

Neutrophilic asthma (NA) is a severe, glucocorticoid-resistant phenotype. Although it represents a small proportion of asthma cases, it imposes a disproportionate burden due to its poor responsiveness to conventional therapies. Challenging the traditional view of isolated molecular defects, emerging evidence positions steroid resistance in NA as a product of dynamic, self-perpetuating pathogenic networks involving neutrophils, airway epithelial cells, T helper cells, macrophages, and B cells.

This review synthesizes the cellular crosstalk underlying NA, emphasizing how convergent interactions impair glucocorticoid receptor function, a final common pathway to steroid resistance. We critically examine emerging therapeutic strategies that disrupt key network nodes, highlighting a shift from single‑target to rational combination regimens. In parallel, we propose a biomarker‑anchored endotyping framework for precision patient stratification, an essential step toward translating network‑targeted interventions into clinical practice. Finally, we identify major knowledge gaps in NA pathogenesis and steroid resistance, and outline priority directions for future research.

This review provides an integrated perspective on the pathogenesis of steroid-refractory NA and offers actionable insights for precision management, aiming to improve clinical care for this severe asthma subtype.