Next-Generation Immunotherapies for Pseudomonas aeruginosa: Monoclonal Antibodies and Immune Checkpoint Modulation

Pseudomonas aeruginosa represents a critical healthcare challenge, accounting for 7%-10% of hospital-acquired infections globally, with particularly high prevalence in intensive care, burn, and respiratory units, alongside escalating rates of multidrug-resistant and extensively drug-resistant strains. The bacterium evades host immunity through multiple mechanisms, including Type III Secretion System effector translocation and biofilm formation via polysaccharide matrices (alginate, Psl, Pel). Antibiotic-based therapies are increasingly ineffective, necessitating host-directed immunotherapeutic strategies. This review synthesizes emerging evidence on monoclonal antibody therapy and immune checkpoint modulation for P. aeruginosa infections. Bispecific antibodies targeting PcrV and Psl enhance opsonophagocytic killing and biofilm disruption through Fc-mediated mechanisms. Immune checkpoint inhibitors (anti-PD-1/PD-L1) reverse T-cell exhaustion from chronic antigen exposure and LPS-driven upregulation of inhibitory receptors, restoring antimicrobial function. Combination approaches integrating mAbs with antibiotics and checkpoint blockade show potential for synergistic bacterial clearance in preclinical pneumonia and burn wound models. Clinical translation remains limited by antigen variability (Psl and PcrV epitope polymorphisms), biofilm heterogeneity, and host immunogenetic diversity (Fc receptor polymorphisms, HLA variants, cytokine profiles). Multi-omics profiling may enable personalized treatment selection. Safety concerns regarding immune hyperactivation require carefully dosed, biomarker-guided strategies. Future development demands genomic stratification of responders and optimized therapeutic windows for maximal clinical benefit.