Biofilm–Host Immune Crosstalk at the Diabetic Foot Ulcer Interface: Molecular Mechanisms, Immune Evasion, and Next-Generation Anti-Biofilm Strategies

Yu Han,1 Ye Yang2 1Department of Vascular and Thyroid Surgery, The First Hospital of China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of China; 2Department of Rehabilitation, The First Hospital of China Medical University, Shenyang, Liaoning Province, 110001, People’s Republic of ChinaCorrespondence: Ye Yang, Department of Rehabilitation, The First Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, Liaoning Province, People’s Republic of China, Email [email protected]: Diabetic foot ulcers (DFUs) are chronic wounds in which microbial persistence and defective host defense interact to impair healing. This review examines DFU through the biofilm–host immune interface rather than viewing biofilm as a purely microbiological problem. We summarize how the diabetic wound milieu, including hyperglycemia, impaired perfusion, neuropathy, and polymicrobial community structure, favors persistent biofilm infection, and how DFU-relevant biofilms evade clearance through matrix shielding, altered innate recognition, virulence-associated host modulation, and intracellular Staphylococcus aureus persistence. We further highlight two major immune-dysregulation axes: excessive neutrophil extracellular trap formation with NLRP3-centered inflammatory amplification, and perforin-2 suppression linked to AIM2-mediated pyroptotic injury. We also appraise emerging immune-aware antibiofilm strategies, particularly quorum-sensing interference, enzymatic matrix disruption, phage therapy, and selected immune-directed interventions. Overall, current evidence supports a model in which non-healing DFU reflects failed host–pathogen resolution at the biofilm–immune interface, with important implications for mechanism-guided therapeutic development.Keywords: diabetic foot ulcer, biofilm, innate immunity, immune evasion, neutrophil extracellular traps, pyroptosis, quorum sensing, phage therapy, inflammasome