The Gut–NET–ICB Axis: Microbial Metabolite-Mediated Regulation of NETosis and Implications for Cancer Immunotherapy

Abstract

Background: Immune checkpoint blockade (ICB) has transformed oncology, but its efficacy is limited by primary and acquired resistance. The gut microbiome is a established determinant of ICB response, while neutrophil extracellular traps (NETs) have recently emerged as key mediators of an immunosuppressive tumor microenvironment (TME) and ICB resistance. The mechanistic link between these two phenomena remains elusive. We hypothesize that gut microbial metabolites serve as critical systemic messengers that modulate NET formation (NETosis), thereby influencing ICB outcomes. Methods & Findings: Through a synthesis of recent literature, we delineate a novel "gut-NET-ICB" axis. We provide evidence that specific microbiota-derived metabolites directly regulate NETosis. Short-chain fatty acids (SCFAs) like butyrate and polyamines such as spermidine suppress NET formation by inhibiting histone deacetylases (HDACs), reactive oxygen species (ROS) production, and peptidyl arginine deiminase 4 (PAD4) activity. Conversely, certain secondary bile acids can promote NETosis. We propose a model wherein a favorable gut microbiome generates a metabolite profile that systemically suppresses pathological NETosis, thereby remodeling the TME to enhance CD8+ T-cell infiltration and function, creating a state permissive to ICB. Conversely, dysbiosis fosters a pro-NETotic environment that drives resistance. Conclusion: The modulation of NETosis by gut microbial metabolites represents a crucial mechanism underlying the microbiome's impact on cancer immunotherapy. This mechanistic insight positions the gut microbiome and NETosis as complementary therapeutic targets. Strategies to promote a NETosis-suppressive metabolite profile through dietary interventions, pre/probiotics, or postbiotic supplements or to directly inhibit NETosis (e.g., with PAD4 inhibitors) hold significant promise for overcoming ICB resistance and improving patient outcomes.