Immune exhaustion in bacterial infections: mechanisms, consequences, and therapeutic implications

• Bacterial pathogens can drive immune exhaustion, a concept traditionally studied in viral and oncologic contexts but increasingly recognized in chronic bacterial infections. • Biofilms, immune-privileged niches, and regulatory T-cell expansion are major contributors to persistent immune dysfunction, creating barriers to effective immune responses. • Immune exhaustion exacerbates secondary infections, antibiotic resistance, and microbiome dysbiosis, underscoring its broader impact beyond direct bacterial persistence. • Targeting exhaustion pathways through immune checkpoint blockade, metabolic reprogramming, and microbiome modulation offers promising therapeutic strategies beyond conventional antimicrobial approaches. T-cell exhaustion, a well-characterized phenomenon, has historically been studied in the context of viral and oncological diseases. However, its relevance to chronic bacterial infections has only recently garnered attention. This review summarizes emerging evidence suggesting that bacterial pathogens can induce immune exhaustion through a variety of mechanisms. Additionally, we explore how bacterial biofilms, immune-privileged niches, and regulatory T-cell expansion contribute to persistent immune dysfunction. The article further examines the consequences of immune exhaustion, including secondary infections, antibiotic resistance, and microbiome dysbiosis, which are often underappreciated aspects of chronic immune impairment. Therapeutic strategies targeting these exhaustion pathways, such as immune checkpoint blockade, metabolic reprogramming, and microbiome modulation, are also discussed. We emphasize the need to consider chronic bacterial infections not as static conditions but as dynamic processes that interact with and suppress the immune system. Thus, understanding the mechanisms behind immune exhaustion highlights the importance of developing therapies that restore immune function, rather than solely relying on traditional antimicrobial treatments.