Convergent evolution of immune evasion in ESKAPE pathogens: A cross-pathogen architecture of conserved host-defense checkpoints

Abstract

Antimicrobial resistance in ESKAPE pathogens is primarily attributed to resistance genes, yet persistent infections despite appropriate therapy implicate immune evasion as an independent driver of treatment failure. Although immune-evasion mechanisms have been extensively characterized in individual pathogens, their shared architecture across the ESKAPE group remains insufficiently integrated. This review synthesizes current evidence to show that phylogenetically diverse ESKAPE pathogens have convergently evolved conserved strategies to evade host immunity under comparable selective pressures. A cross-pathogen immune-evasion framework emerges, encompassing impaired pathogen recognition, complement inhibition, phagocyte dysfunction, immunometabolic reprogramming, biofilm-mediated protection, and persistence-promoting inflammation, together with pathogen-specific virulence mechanisms. These processes intersect with adaptive immune dysfunction and emerging concepts, including quorum-sensing-mediated immunomodulation, trained immunity, and the itaconate–succinate immunometabolic axis, forming an interconnected persistence network rather than isolated virulence traits. This systems-level perspective identifies conserved host-directed therapeutic targets that may complement conventional antimicrobial therapy across species. However, host-directed therapies, immunotherapeutics, and vaccines remain largely preclinical or have shown inconsistent clinical efficacy. Mechanistic evidence is strongest for Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, whereas substantial knowledge gaps persist for Enterococcus faecium, Acinetobacter baumannii, and Enterobacter spp. Overcoming persistent ESKAPE infections will require targeting conserved host–pathogen interactions alongside pathogen-specific antimicrobial resistance mechanisms.

1. Introduction

Antimicrobial resistance (AMR) is now a defining biomedical threat rather than a niche infectious-disease concern. Global burden-of-disease modelling attributes 1.27 million deaths in 2019 directly to drug-resistant bacterial infections, with a further 3.68 million associated deaths, a toll exceeding HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) or malaria, and projections to 2050 show this burden rising without decisive intervention[1, 2]. Healthcare-associated infections disproportionately affect immunocompromised, critically ill, and post-surgical patients, while a stagnant antibiotic discovery pipeline means resistance to newly deployed agents often emerges within a short clinical interval [3, 4]. Conventional antibiotic-centric strategies alone are therefore increasingly unable to contain treatment failure.

This gap is conspicuous through an evolutionary lens. Taxonomically distant bacteria occupying diverse host niches have repeatedly evolved similar mechanisms to evade host defenses, including complement-evasion proteins, antiphagocytic capsules, and toxin repertoires, despite arising through distinct evolutionary pathways rather than shared ancestry [5, 6]. Such convergent evolution suggests that host immune pressure, rather than phylogeny, has shaped a common set of survival strategies [6]. At the same time, lineage-specific adaptations remain important, providing the rationale for organizing this review around shared and pathogen-specific mechanisms. The ESKAPE pathogens, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, are clinically important examples of this convergent evolution [7]. Grouped not simply for shared resistance phenotypes, each has independently acquired the capacity to “escape” therapy via biofilm formation, metabolic and genomic plasticity, and horizontal gene transfer [7, 8]. Their recurrent, chronic infections despite ostensibly adequate antimicrobial regimens imply persistence determinants beyond resistance genotype alone.

This points to immune evasion as mechanistically distinct from, yet functionally entangled with, AMR. Rather than representing isolated mechanisms, ESKAPE immune-evasion strategies function as a coordinated sequence of host-defense disruption. Capsular and surface modifications provide the first barrier by reducing pattern recognition, complement deposition, opsonization, and membrane-attack-complex–mediated lysis [9, 10]. Toxins, proteases, and nucleases further impair innate immunity by degrading neutrophil extracellular traps, eliminating phagocytes, and shifting macrophage responses toward a permissive state [10, 11]. Surviving bacteria can then persist within biofilms that shield pathogen-associated molecular patterns and promote a local immune-tolerant environment [12]. At the adaptive immune interface, superantigens and interference with antigen processing compromise T-cell activation and memory formation [13]. It is this cumulative, self-reinforcing cascade, not any single step, that generates the immunosuppressive niches in which bacteria outlast antibiotics and later relapse, making immune evasion a central, not peripheral, determinant of treatment failure. To our knowledge, existing reviews have not fully addressed this interplay at a comparative, cross-pathogen level, remaining largely organism-specific [7, 8]. Several key gaps remain unresolved. First, a comparison of immune-evasion strategies across all six ESKAPE pathogens is needed to distinguish convergent mechanisms from lineage-specific adaptations. Second, emerging concepts such as biofilm-mediated immunomodulation, quorum sensing, trained immunity, and immunometabolism remain insufficiently integrated into classical immune-evasion frameworks despite increasing mechanistic overlap [14–16]. Finally, a systems-level understanding of shared and pathogen-specific strategies is required to identify broadly applicable therapeutic targets rather than organism-specific interventions.

The current landscape provides an opportunity to address these gaps. Host-directed therapies are increasingly designed to modulate host responses rather than solely enhance antimicrobial killing [17]. Advances in trained immunity have revealed that innate immune cells can acquire epigenetic and metabolic memory, challenging the traditional view that such properties are restricted to lymphocytes [16]. In parallel, immunometabolic studies show that pathogens such as K. pneumoniae and S. aureus can reprogram host metabolism, including through pathways involving itaconate, to promote tolerance and biofilm persistence [15, 18]. Together with advances in systems immunology and next-generation vaccines, these developments enable a more integrated understanding of host–pathogen interactions.

Accordingly, this review moves beyond cataloguing individual mechanisms to define conserved, systems-level principles of immune evasion shared across ESKAPE pathogens. It examines these common strategies as products of convergent evolution driven by shared host pressures while distinguishing them from pathogen-specific adaptations. By integrating biofilm biology, quorum sensing, trained immunity, and immunometabolism into a unified framework, this review proposes a cross-pathogen architecture linking microbial virulence, host immune plasticity, and antimicrobial resistance. This perspective highlights mechanistic vulnerabilities that may guide the development of host-directed therapies, immunotherapeutics, and next-generation vaccines in an era of declining antibiotic effectiveness.

2. Evolutionary and clinical context of ESKAPE pathogens

2.1. Convergent evolution of immune-evasion strategies among taxonomically distinct bacteria

Although the six ESKAPE pathogens span four bacterial phyla and diverge substantially in cell-envelope architecture, metabolism, and genome organization, they converge repeatedly on a narrow set of functional solutions for evading the host immune system. This convergence is not incidental. Bacteria that persist in hospitalized, often immunocompromised, patients encounter a remarkably similar selective environment. Regardless of the infecting species, they must overcome complement activation, phagocyte-mediated clearance, disrupted mucosal barriers, and antibiotic-induced population bottlenecks [19]. Under this reciprocal host-pathogen selection, unrelated lineages are repeatedly pushed toward similar phenotypic outcomes even though the underlying genetic solutions differ, a dynamic increasingly documented through within-host genomic surveillance of bacterial adaptation to human niches [20]. Longitudinal tracking of a single K. pneumoniae clone through a five-year nosocomial outbreak illustrates this directly: strong positive selection repeatedly targeted capsule, lipopolysaccharide, and iron-acquisition loci across genetically independent sublineages, converging on reduced acute virulence and enhanced biofilm formation [21]. This within-species convergence mirrors, at smaller phylogenetic distance, the cross-species convergence this review addresses. Critically, shared clinical behavior does not imply shared ancestry. E. faecium and A. baumannii share almost none of their genomic background, yet both rely on antiphagocytic capsules, biofilm-embedded persistence, and horizontal acquisition of resistance and virulence determinants to survive the same hospital ecology [5–7]. Although quorum-sensing systems differ between Gram-positive and Gram-negative bacteria, they converge functionally to promote biofilm maturation and establish immune-tolerant microenvironments [22]. Likewise, metabolic plasticity enables phylogenetically distinct pathogens, including S. aureus and P. aeruginosa, to survive the nutrient-limited and oxidative conditions of infected tissues [22, 23]. These convergent solutions are rarely cost-free: capsule expression, motility loss, and metabolic remodeling frequently trade acute virulence for chronic persistence, an evolutionary compromise that favors long-term colonization of the healthcare environment over rapid host exploitation [20, 21]. The extent to which such trade-offs generalize beyond Enterobacterales remains debated, as comparable within-host evolutionary data are considerably sparser for Gram-positive ESKAPE organisms and for Acinetobacter [24, 25]. Collectively, the six ESKAPE pathogens provide a natural model of convergent evolution. Despite their phylogenetic diversity, they have independently evolved similar immune-evasion strategies in response to common immunological and clinical pressures. Thus, the conserved immune-evasion mechanisms shared across ESKAPE pathogens are more plausibly explained by convergent evolution than by shared ancestry (Fig. 1).

Fig. 1.

Convergent evolution of immune-evasion programs among ESKAPE pathogens. Shared host-selective pressures drive phylogenetically distinct ESKAPE pathogens toward conserved immune-evasion programs while preserving lineage-specific adaptations, collectively promoting persistence, antimicrobial resistance, and treatment failure

2.2. Clinical epidemiology and resistance burden of the six ESKAPE organisms

This convergence is best appreciated clinically rather than taxonomically (Table 1). Rather than six separate epidemiological profiles, ESKAPE organisms collectively dominate a shared set of healthcare-associated ecological niches: ventilator circuits, central and urinary catheters, surgical sites, and chronic wounds, each providing an abiotic or devitalized surface conducive to biofilm establishment and immune-privileged persistence [7, 26]. A multi-year bloodstream infection surveillance study spanning 2018–2024 confirmed that all six organisms remain persistent contributors to nosocomial bacteremia, with resistant phenotypes disproportionately represented among device-associated and intensive care unit (ICU)-acquired isolates, and with recurrence rates that track closely with biofilm-forming capacity rather than with resistance genotype alone [27]. Comprehensive surveys of ESKAPE resistance mechanisms similarly emphasize that clinical persistence and treatment failure are rarely explained by resistance determinants in isolation, reinforcing the need to consider immune evasion as a co-equal driver of outcome [28]. This distribution is not coincidental: the same ecological features that favor biofilm formation and immune evasion, prolonged device dwell time, disrupted mucosal barriers, and antibiotic selection pressure, simultaneously favor recurrence and treatment failure, linking epidemiological persistence mechanistically to the evasion strategies addressed in later sections. Differences in relative syndrome burden, enterococcal and staphylococcal dominance of device-associated and bloodstream infection, Klebsiella- and Enterobacter-driven urinary and respiratory disease, and Acinetobacter- and Pseudomonas-associated ventilator-associated pneumonia in critically ill patients, reflect lineage-specific tropism layered atop the shared, conserved evasion chassis described above. This combination of convergent and lineage-specific adaptations makes the ESKAPE pathogens a valuable comparative model. Unlike single-pathogen studies, cross-pathogen analyses can distinguish immune-evasion mechanisms shaped by shared host selective pressures from those unique to individual pathogens. This evolutionary framework provides the basis for comparing how ESKAPE pathogens manipulate innate immunity through both conserved and pathogen-specific mechanisms.

Table 1.

Comparative clinical and evolutionary characteristics of the ESKAPE pathogens [5, 6, 20, 21, 27, 28]

Organism	Taxonomy	Major clinical syndromes	Dominant resistance mechanisms	Principal immune-evasion/Persistence strategy	Typical hospital reservoir
Enterococcus faecium	Gram-positive coccus; Firmicutes (Bacillota); Enterococcaceae	Bloodstream infection, infective endocarditis, catheter-associated UTI, surgical-site infection	Acquired vancomycin resistance (vanA/vanB); intrinsic low-level β-lactam and aminoglycoside resistance	Biofilm formation on indwelling devices; GI-tract colonization as a persistent reservoir	Gastrointestinal tract, urinary catheters, central venous lines
Staphylococcus aureus	Gram-positive coccus; Firmicutes (Bacillota); Staphylococcaceae	Bacteremia, infective endocarditis, skin/soft-tissue infection, device-associated infection, pneumonia	mecA-mediated methicillin resistance (MRSA); reduced vancomycin susceptibility (VISA/hVISA)	Biofilm formation; toxin/superantigen repertoire; small-colony-variant persistence	Nasal and skin colonization, central lines, prosthetic devices
Klebsiella pneumoniae	Gram-negative bacillus; Proteobacteria (Pseudomonadota); Enterobacteriaceae	Pneumonia, bacteremia, urinary tract infection, liver abscess (hypervirulent clones)	Carbapenemases (KPC, NDM, OXA-48); extended-spectrum β-lactamases	Capsule/lipopolysaccharide-mediated complement resistance; biofilm; hypermucoviscosity	Gastrointestinal tract, ventilator circuits, urinary catheters
Acinetobacter baumannii	Gram-negative coccobacillus; Proteobacteria (Pseudomonadota); Moraxellaceae	Ventilator-associated pneumonia, bacteremia, wound infection, meningitis	Carbapenemases (OXA-23/24/58); extensive multidrug and pan-drug resistance	Desiccation tolerance; biofilm on abiotic surfaces; complement-resistance surface proteins (e.g., CipA)	Hospital surfaces and equipment, ventilator circuits
Pseudomonas aeruginosa	Gram-negative bacillus; Proteobacteria (Pseudomonadota); Pseudomonadaceae	Ventilator-associated pneumonia, bacteremia, chronic wound/burn infection, cystic fibrosis lung infection	Efflux-pump overexpression; AmpC/carbapenemase production; porin loss	Quorum-sensing-coordinated biofilm; alginate-mediated immune shielding	Water systems, ventilator circuits, chronic wounds
Enterobacter spp.	Gram-negative bacillus; Proteobacteria (Pseudomonadota); Enterobacteriaceae	Bacteremia, urinary tract infection, respiratory infection, surgical-site infection	AmpC β-lactamase derepression; carbapenemase acquisition	Biofilm formation; rapid horizontal gene transfer of resistance plasmids	Gastrointestinal tract, urinary catheters, central lines

3. Innate immune evasion: a sequential disruption cascade

Having established that ESKAPE pathogens evolve similar survival strategies through convergent evolution rather than shared ancestry, this section examines why this convergence is particularly evident in innate immunity. The innate immune system presents a limited number of defensive barriers, including pattern recognition, complement activation, phagocyte-mediated killing, and macrophage polarization. Consequently, bacteria have only a restricted set of effective strategies to overcome these defenses without compromising fitness. From this perspective, convergent evolution reflects shared selective constraints rather than close evolutionary relatedness. To facilitate comparison, we organize immune-evasion mechanisms into four functional checkpoints: interference with pattern recognition and complement, suppression of neutrophil and phagocyte effector functions, modulation of macrophage polarization, and biofilm-mediated immune shielding. These checkpoints are intended as a conceptual framework rather than a strict biological sequence, as they frequently overlap and operate simultaneously during infection. Nevertheless, success at one stage can alter the immune environment and influence subsequent host–pathogen interactions. A second pattern also emerges from the available evidence. Mechanistic studies are heavily concentrated on S. aureus, K. pneumoniae, and P. aeruginosa, whereas E. faecium, A. baumannii, and especially Enterobacter species remain comparatively understudied. This imbalance reflects current research priorities rather than lower biological complexity. Accordingly, evidence gaps are highlighted throughout this review instead of being discussed only in sections where data are limited. Figure 2 illustrates the four-checkpoint conceptual framework, whereas Table 2 summarizes the principal experimentally supported molecular effectors across all six ESKAPE pathogens, providing the comparative reference for the mechanistic discussion that follows.

Fig. 2.

Sequential innate immune-evasion cascade in ESKAPE pathogens. Taxonomically distinct ESKAPE pathogens employ diverse molecular effectors that converge on four conserved checkpoints of innate immune evasion, collectively promoting persistence, antimicrobial resistance, and treatment failure while identifying potential targets for host-directed therapies

Table 2.

Principal experimentally supported molecular effectors by checkpoint across ESKAPE pathogens

Organism	Checkpoint I (PRR/Complement)	Checkpoint II (Phagocyte)	Checkpoint III (Macrophage)	Checkpoint IV (Biofilm)
Enterococcus faecium	Capsule (C3b/LTA masking) [29]	Not well characterized	Not well characterized	PIA-independent biofilm; Esp, Ace adhesins [14]
Staphylococcus aureus	SCIN, Efb, ClfA, capsule (5/8) [13]	Nuc, LukAB/leukocidins, catalase [13, 31]	Itaconate-driven reprogramming [15]	PIA/PNAG matrix [14]
Klebsiella pneumoniae	Capsule (K-antigen), O-antigen LPS [8]	Capsule-mediated ROS resistance [8]	Metabolic-stress-induced tolerance [18]	Capsule-associated matrix; hypermucoviscosity [8, 14]
Acinetobacter baumannii	CipA, capsule (K-locus) [9]	Catalase; capsule-linked oxidative resistance [9]	Not well characterized	Biofilm-associated persistence, abiotic surfaces [14]
Pseudomonas aeruginosa	Complement proteases, alginate/Psl/Pel [10]	LasB elastase, pyocyanin [10, 32]	Preliminary evidence only	QS-coordinated alginate/Psl/Pel; eDNA [10, 36]
Enterobacter spp.	Capsule, LPS modification (less characterized) [28]	Not well characterized	Not well characterized	Biofilm formation (limited mechanistic data) [28]

Effectors are grouped by checkpoint rather than by organism to emphasize convergent function over homologous mechanism; bracketed numbers cite the primary or review source demonstrating each effector experimentally. Conserved functional outcomes (reduced opsonization, phagocyte neutralization, macrophage reprogramming, biofilm-mediated tolerance) are achieved through largely non-homologous, pathogen-specific effectors. Cells marked “not well characterized” or “preliminary evidence only” indicate a genuine evidence gap in the current literature.

3.1. Checkpoint I. Interference with pattern recognition and complement

As summarized in Table 2, the molecular effectors acting at Checkpoint I differ substantially among ESKAPE pathogens despite converging on a common functional outcome: attenuation of pathogen recognition and complement activation. Lipid A acylation and phosphorylation that reduce TLR4 activation are well characterized in K. pneumoniae and during chronic infection with P. aeruginosa [8]. However, comparable mechanistic evidence remains limited for A. baumannii and Enterobacter species and should not be inferred by analogy [7]. In contrast, S. aureus and E. faecium reduce TLR2 signaling through D-alanylation of lipoteichoic acid and capsular masking, respectively [7, 29]. Capsule-mediated immune evasion provides a clear example of convergent rather than homologous evolution. K. pneumoniae and A. baumannii produce diverse Wzx/Wzy-dependent capsules that sterically limit C3b deposition and antibody access [8, 9]. In E. faecium, the capsule masks surface-bound C3b and lipoteichoic acid without necessarily preventing complement deposition [29]. P. aeruginosa achieves a similar outcome through its structurally distinct alginate, Psl, and Pel extracellular matrix [10]. A similar pattern is observed for complement inhibition. A. baumannii CipA recruits factor H and C4b-binding protein to accelerate C3b and C4b degradation [9]. P. aeruginosa secretes proteases that cleave C1q, C2, and C3, whereas S. aureus expresses complement inhibitors, including SCIN-family proteins, that prevent C3-convertase formation [10, 13]. By contrast, direct evidence for complement-evasion mechanisms in Enterobacter species remains scarce. Despite these mechanistic differences, the common outcome is reduced opsonophagocytic recognition, supporting convergent evolution of immune evasion across ESKAPE pathogens.

3.2. Checkpoint II. Neutralization of neutrophil and phagocyte effector function

Following immune recognition, pathogens must overcome phagocyte effector responses. Across ESKAPE pathogens, immune evasion converges on three major targets: neutrophil extracellular traps (NETs), oxidative killing, and phagosome maturation [30]. However, the strength of the supporting evidence varies considerably among species. S. aureus provides the best-characterized example. It secretes nucleases that degrade NETs and bicomponent leukocidins that directly lyse neutrophils and macrophages [13, 31]. In P. aeruginosa, pyocyanin promotes the generation of reactive oxygen and nitrogen species, leading to host tissue damage and accelerated neutrophil apoptosis. It also impairs macrophage efferocytosis, thereby sustaining local inflammation [32]. In addition, LasB elastase degrades complement proteins, cytokines, and surfactant protein A, weakening host defense before the oxidative burst [10]. For K. pneumoniae and A. baumannii, resistance to oxidative killing mediated by the capsule and lipopolysaccharide is supported by substantial experimental evidence [8, 9]. In contrast, inhibition of phagosome–lysosome fusion remains a plausible but incompletely validated mechanism in both pathogens. Evidence for dedicated NET-evasion mechanisms in E. faecium and Enterobacter species is currently lacking. Therefore, functional convergence in NET evasion cannot yet be extended to all ESKAPE pathogens. This checkpoint highlights a consistent pattern throughout the literature. Mechanistic evidence is strongest for S. aureus and P. aeruginosa, whereas several other ESKAPE pathogens remain comparatively understudied.

3.3. Checkpoint III. Macrophage polarization toward permissive phenotypes

Pathogens that survive neutrophil-mediated killing frequently encounter macrophages. Increasing evidence suggests that several ESKAPE pathogens actively reprogram macrophage function toward a permissive phenotype, although the strength of the evidence varies considerably among species [12, 33]. The strongest support comes from immunometabolic studies. During pulmonary infection, K. pneumoniae induces host metabolic responses that promote bacterial persistence [18]. Likewise, S. aureus drives an itaconate-dependent immunometabolic program that favors biofilm formation rather than bacterial clearance [15]. Together, these studies provide the clearest evidence that ESKAPE pathogens can actively reprogram host immunity rather than simply evade it.

By contrast, evidence linking HIF-1α-dependent metabolic remodeling, IL-10- and TGF-β-dominated cytokine responses, and STAT3 activation to macrophage permissiveness is more limited and heterogeneous. Much of this evidence is derived from chronic infection models or studies of mycobacterial disease [34, 35], and therefore cannot be directly generalized to most ESKAPE pathogens. Similarly, foamy macrophages are well established in tuberculosis but have only limited and indirect support in ESKAPE infections. Direct evidence for pathogen-induced macrophage polarization also remains limited in A. baumannii, P. aeruginosa, E. faecium, and Enterobacter species. This gap reflects the current state of the literature rather than the absence of macrophage-directed immune evasion in these organisms.

3.4. Checkpoint IV. Biofilm-mediated shielding and local immune tolerance

Biofilm formation represents the final checkpoint of immune evasion. Beyond acting as a physical barrier, biofilms create a stable immunological microenvironment that reinforces the effects of the preceding immune-evasion mechanisms. Biofilm matrices differ in composition across ESKAPE pathogens, including polysaccharide intercellular adhesin in S. aureus and E. faecium, capsule-associated exopolysaccharides in K. pneumoniae and A. baumannii, and the alginate, Psl, and Pel matrix of P. aeruginosa [10, 14, 36]. Despite these structural differences, they share similar functions by limiting antibody and complement penetration, restricting phagocyte access, and creating hypoxic, nutrient-limited niches that favor slow-growing, antibiotic-tolerant bacterial populations [10, 14, 36]. Extracellular DNA, derived in part from neutrophil extracellular traps that fail to eliminate bacteria, further stabilizes the biofilm matrix and contributes to persistent local inflammation [14, 36]. Quorum-sensing systems coordinate biofilm maturation and regulate the expression of immune-evasion genes [37]. Although these systems differ mechanistically between Gram-negative acyl-homoserine lactone–based networks and Gram-positive peptide-based signaling, they perform similar regulatory functions [7]. Direct evidence for lymphocyte exclusion from biofilms is strongest for P. aeruginosa [36]. Comparable mechanistic evidence remains limited for the other ESKAPE pathogens, particularly Enterobacter species. Biofilms provide a stable niche that preserves bacterial persistence by reinforcing the cumulative effects of the preceding immune-evasion checkpoints rather than functioning as an isolated defense mechanism.

Taken together (Fig. 2; Table 2), the same pattern recurs: shared functional outcomes achieved through effectors that are rarely homologous and, for three of the six organisms, still poorly characterized. This is best read as a conceptual framework rather than a strict biological sequence, since checkpoints interact and overlap in vivo; its value lies in showing that success at one checkpoint shifts the immunological context of the next, not in claiming strict temporal order. This convergence reflects the innate immune system's finite architecture, which affords only a narrow set of viable evasion solutions, rather than shared ancestry. Clinically, persistent infection despite antimicrobial therapy is best explained by this cumulative interaction rather than any single mechanism. Because biofilm-embedded bacteria also alter antigen presentation and antibody accessibility, this innate cascade connects directly to the adaptive immune dysregulation addressed in Section 4.

4. Adaptive immune evasion: T-cell and humoral dimensions

4.1. Superantigens and interference with antigen presentation and dendritic-cell maturation: T-cell dysfunction

Adaptive immune-evasion mechanisms are less conserved and less well characterized than the innate immune-evasion pathways discussed in Section 3. Mechanistic evidence is concentrated in a few ESKAPE pathogens rather than distributed across all six. The best-characterized mechanism is superantigen-mediated T-cell dysfunction in S. aureus. Toxic shock syndrome toxin-1 and staphylococcal enterotoxins cross-link MHC class II molecules with the Vβ region of the T-cell receptor outside the conventional antigen-binding groove. This interaction triggers widespread polyclonal T-cell activation followed by anergy rather than effective antigen-specific immunity [13, 38]. More recently, clinically derived S. aureus isolates have also been shown to bind PD-1 directly on human T cells, suppressing calcium signaling, proliferation, and IL-2 production independently of PD-L1 [39]. By contrast, comparable evidence for CTLA-4 or TIM-3 engagement, or for checkpoint-mediated T-cell dysfunction in K. pneumoniae, A. baumannii, E. faecium, or Enterobacter species, is currently lacking and should not be inferred from studies of sepsis or other infections. Interference with antigen presentation is better documented in Gram-negative pathogens. In K. pneumoniae, the capsule impairs dendritic-cell maturation and reduces Th1-polarizing cytokine production, an effect reversed in capsule-deficient mutants [40]. Chronic P. aeruginosa infection is likewise associated with impaired dendritic-cell antigen presentation and a shift toward Th2- and Th17-biased responses that fail to eliminate the pathogen [32, 41]. Whether similar mechanisms occur in A. baumannii, E. faecium, or Enterobacter species remains largely unknown.

Despite these differences, the available evidence points to a common functional outcome: adaptive immune responses are activated but fail to provide effective protection. This state is achieved through distinct mechanisms, including superantigen activity, checkpoint-receptor engagement, and impaired dendritic-cell function, illustrating functional convergence despite limited mechanistic conservation.

4.2. Capsular and biofilm-mediated interference with opsonizing antibodies and B-cell memory

Humoral immune evasion shows a pattern similar to T-cell dysfunction, with substantial differences in the amount of evidence available for individual ESKAPE pathogens. The most widely documented mechanism is capsular masking of antibody epitopes. In K. pneumoniae and A. baumannii, the capsule limits IgG binding and reduces complement-dependent opsonophagocytosis [8, 9, 42]. E. faecium appears to achieve a similar outcome, although the underlying mechanisms are less well characterized [29]. When antibodies do bind, Gram-positive and Gram-negative pathogens employ distinct strategies to impair antibody function. S. aureus expresses Protein A, which binds the Fc region of IgG, preventing Fc-receptor engagement and reducing both opsonization and productive B-cell receptor activation [13]. In contrast, Gram-negative ESKAPE pathogens primarily rely on capsular shielding and secreted proteases to limit antibody activity through different molecular mechanisms [10]. Biofilms further reduce antibody effectiveness by restricting antibody penetration into the bacterial community. This mechanism is best characterized in P. aeruginosa and is supported by more limited evidence in S. aureus and K. pneumoniae [14, 36]. Comparable data remain scarce for A. baumannii, E. faecium, and Enterobacter species. Antigenic diversity also limits durable humoral protection. In K. pneumoniae, extensive capsular serotype diversity has complicated the development of capsule-based vaccines [42, 43]. During chronic P. aeruginosa infection, antibody responses are often robust but provide limited protection and may contribute to tissue damage through immune-complex formation [41]. Similar constraints on protective immune memory have not yet been demonstrated for E. faecium or Enterobacter species. Structurally distinct humoral-evasion mechanisms converge on a common outcome: antibody responses are generated but remain insufficient to eliminate persistent infection.

These observations support a cautious interpretation of adaptive immune dysfunction. Rather than representing a fully independent immune-evasion program, impaired T-cell and antibody responses may arise, at least in part, from the chronic immunoregulatory environment established during innate immune evasion. Persistent macrophage reprogramming and biofilm-associated antigen sequestration are plausible contributors to defective T-cell priming and reduced antibody accessibility [44]. Although direct evidence for this causal relationship remains limited, current findings are consistent with a model in which adaptive immune dysfunction develops as a downstream consequence of prolonged innate immune dysregulation. This framework provides the conceptual basis for the unified cross-pathogen architecture and therapeutic implications discussed in the following section.

5. Integrative and emerging determinants of persistence

5.1. Biofilm biology and Quorum sensing as immunomodulatory platforms

Biofilm formation and quorum sensing are commonly viewed as structural and regulatory adaptations. However, both also modulate host immune responses and promote bacterial persistence beyond passive physical protection. The functional integration of quorum sensing, biofilm maturation, trained immunity, and immunometabolic reprogramming into a persistence-promoting network is summarized conceptually in Fig. 3. In P. aeruginosa, biofilm-associated infection impairs dendritic-cell antigen presentation and skews T-helper differentiation toward non-protective Th2/Th17 responses. These effects extend the immune dysfunction described in Sections 3 and 4 from innate to adaptive immunity [36]. Quorum-sensing molecules provide an additional layer of immune regulation. The P. aeruginosa autoinducer 3-oxo-C12-homoserine lactone enters host cells, induces macrophage and lymphocyte apoptosis, and suppresses NF-κB signaling. In contrast, the chemically distinct metabolite 2-aminoacetophenone promotes an anti-inflammatory environment that favors bacterial persistence rather than clearance [45]. Together, these findings demonstrate that quorum sensing actively modulates host immunity and that its effects extend beyond biofilm organization. Gram-positive ESKAPE pathogens produce a broadly similar outcome through the agr and fsr peptide-sensing systems [46]. However, whether these systems interact with host signaling as directly as Gram-negative autoinducers remains unknown. Likewise, quorum-sensing-mediated immunomodulation has been largely unexplored in K. pneumoniae, A. baumannii, Enterococcus spp., and Enterobacter spp.

Fig. 3.

Conceptual integration of quorum sensing, biofilm maturation, trained immunity, and immunometabolic reprogramming in persistent ESKAPE infections. Quorum sensing promotes biofilm maturation while directly modulating host immune signaling. Persistent biofilm-associated antigen exposure induces trained immunity through epigenetic and metabolic reprogramming of myeloid cells, whereas immunometabolic pathways, including the itaconate–succinate axis, further shape macrophage polarization and inflammatory tolerance. Together, these interconnected processes establish a self-reinforcing host–pathogen network that promotes persistent infection, immune tolerance, antimicrobial tolerance, and recurrent treatment failure

Despite mechanistic differences, biofilm formation and quorum sensing converge on a common target: myeloid antigen-presenting cells [47]. By altering the function of these cells, they establish a local immune environment that supports the more stable immune reprogramming discussed in the following section. One unresolved possibility arises from this immunomodulatory role. Quorum-sensing inhibition is generally considered an anti-virulence strategy, but it may also restore local pro-inflammatory signaling. This concept has not been evaluated in vivo for ESKAPE infections and should therefore be regarded as a hypothesis rather than an established mechanism.

5.2. Trained immunity: innate epigenetic and metabolic memory

The myeloid cells reprogrammed within the biofilm-associated microenvironment are also capable of acquiring trained immunity. This form of innate immune memory is maintained through epigenetic and metabolic reprogramming and was first described using β-glucan and BCG (Bacillus Calmette–Guérin) [16]. Evidence from S. aureus infection indicates that trained immunity is not uniformly protective. Prior cutaneous S. aureus exposure trains macrophages to provide enhanced heterologous protection against subsequent Gram-negative infection [48]. In contrast, a separate model of recurrent S. aureus infection showed that trained immunity promotes fumarate accumulation and increases antibiotic tolerance during reinfection. This phenotype was reversed by metformin [49]. Because both studies examined the same pathogen, the contrasting outcomes cannot be explained by pathogen identity alone. Instead, they suggest that infection history and host metabolic state can direct trained immunity toward either protection or bacterial persistence. Comparable studies are not available for K. pneumoniae, A. baumannii, P. aeruginosa, Enterococcus spp., or Enterobacter spp. It therefore remains unclear whether this bidirectional behavior is a general feature of ESKAPE pathogens or is largely restricted to S. aureus. The metformin-sensitive fumarate phenotype also provides an early indication that shared host metabolic pathways, rather than pathogen-specific virulence factors, may govern both outcomes of trained immunity.

5.3. Immunometabolic reprogramming (itaconate and related host-metabolite pathways)

The shared metabolic pathway linking these processes is best characterized by the itaconate axis. In this pathway, IRG1 diverts the tricarboxylic acid cycle to produce itaconate, a metabolite with well-established antimicrobial and anti-inflammatory functions during infection [50]. Its role in ESKAPE persistence varies across pathogens. S. aureus induces itaconate production without a parallel increase in succinate, and this response promotes biofilm formation rather than bacterial clearance [15]. K. pneumoniae instead triggers a broader host metabolic stress response that favors pulmonary disease tolerance [18]. Among the organisms examined to date, P. aeruginosa displays the most complex interaction with this pathway. It encounters both host-derived succinate and itaconate, uses succinate as a growth substrate, and senses itaconate to promote metabolic adaptation and biofilm formation [51, 52]. These mechanisms define a common host–pathogen interface. Biofilm formation and quorum sensing establish a locally tolerogenic tissue environment. Trained immunity then determines how infiltrating myeloid cells are reprogrammed within that environment. Immunometabolites such as itaconate and succinate provide the metabolic link between these processes [53, 54]. Together, these interacting processes form the integrated persistence network illustrated in Fig. 3. Itaconate derivatives, including 4-octyl itaconate, are being investigated as anti-inflammatory and anti-infective agents in other disease settings [50]. Whether pharmacological modulation of this pathway can redirect host– P. aeruginosa interactions toward bacterial clearance remains unknown. At present, this possibility should be considered a plausible but untested hypothesis in ESKAPE infections. Current evidence is most complete for P. aeruginosa and S. aureus. In contrast, this immunometabolic interface remains largely unexplored in A. baumannii, Enterococcus spp., and Enterobacter spp. This evidence gap limits the development of a unified cross-pathogen framework, which is discussed further in Section 6.

6. A cross-pathogen immune-evasion architecture: conserved versus pathogen-specific programs

6.1. Conserved (shared) evasion nodes across ESKAPE pathogens

Examining ESKAPE pathogens individually can obscure the common architecture of immune evasion. The evidence summarized in Sections 2–5 identifies six conserved functional nodes, illustrated in Fig. 4 and detailed in Table 3. These nodes represent shared points within the host defense cascade where evolutionarily distinct pathogens have converged on similar functional outcomes despite using different molecular mechanisms.

Fig. 4.

Conserved immune-evasion architecture across ESKAPE pathogens. Distinct pathogen-specific virulence factors converge on six interconnected functional nodes that collectively impair host immune defense and promote persistent infection, antimicrobial tolerance, recurrence, and treatment failure

Table 3.

Conserved versus pathogen-specific immune-evasion architecture across ESKAPE pathogens

Conserved node	Representative pathogen-specific effectors	Dominant clinical correlate	Strength of evidence
Reduced immune recognition	Capsular masking (Klebsiella pneumoniae, Acinetobacter baumannii); LPS/lipid A modification (Pseudomonas aeruginosa)	Variable; contributes to colonization persistence	Moderate
Complement interference	Capsule-mediated MAC blockade (A. baumannii); complement regulator hijacking (Staphylococcus aureus)	Serum-resistant bacteremia	Strong
Impaired phagocyte killing	Toxin-mediated pore formation, oxidative-burst neutralization (S. aureus)	Toxin-mediated syndromes	Moderate–strong (S. aureus); limited elsewhere
Macrophage/immunometabolic reprogramming	M1-to-permissive shift; trained/tolerant myeloid reprogramming	Chronic, relapsing infection	Moderate, largely extrapolated
Biofilm-mediated immune shielding	Alginate/Psl/Pel (P. aeruginosa); Protein A/ClfA/IsaB-enriched biofilm (S. aureus)	Device- and CF-associated chronic infection	Strong
Persistence-promoting inflammatory remodeling	Genus-heterogeneous; best-defined in P. aeruginosa biofilm context	Non-resolving inflammation, treatment failure	Limited, heterogeneous

Node 1, Reduced immune recognition: Most ESKAPE pathogens reduce activation of pattern-recognition receptors through capsular masking, lipid A modification, or cell-wall remodeling. Although the supporting evidence varies among species, this strategy is broadly conserved across the group [55].

Node 2, Complement interference: Many ESKAPE pathogens limit complement-mediated opsonophagocytosis before phagocyte engagement. They achieve this by recruiting host complement regulators or restricting membrane attack complex deposition [56]. In A. baumannii, capsule locus type correlates with stronger inhibition of the alternative complement pathway, greater resistance to complement-mediated lysis, and increased virulence in invertebrate infection models [57, 58].

Node 3, Impaired phagocyte killing: Several ESKAPE pathogens also interfere with intracellular killing after phagocytosis. They use toxins, oxidative-burst neutralization, or intracellular survival strategies to reduce phagocyte antimicrobial activity. Mechanistic evidence is most extensive for S. aureus and remains limited for several other ESKAPE species [59].

Node 4, Macrophage and immunometabolic reprogramming: Persistent ESKAPE infection shifts macrophages away from a microbicidal M1 phenotype and alters innate immune memory. Depending on the infection context, myeloid cells develop either trained or tolerant responses through shared epigenetic and metabolic pathways rather than pathogen-specific ligands [60, 61]. This node links local macrophage polarization with the systemic trained-immunity and immune-tolerance programs discussed in Section 5.

Node 5, Biofilm-mediated immune shielding: Biofilm formation is the most consistently conserved immune-evasion mechanism across ESKAPE pathogens. The extracellular matrix limits immune-cell access and reduces antimicrobial penetration. This process has been studied most extensively in P. aeruginosa, where exopolysaccharides restrict complement deposition and immune-cell infiltration [36, 62].

Node 6, Persistence-promoting inflammatory remodeling: Some ESKAPE pathogens exploit host inflammation rather than simply avoiding it. They maintain a chronic, non-resolving inflammatory environment that favors bacterial persistence over clearance. Evidence for this mechanism remains more variable than for the other five nodes and should therefore be interpreted cautiously.

Together, these six functional nodes define a conserved framework of immune evasion. As illustrated in Fig. 4, pathogen-specific virulence factors can be mapped onto this shared architecture, which is discussed in the following section.

6.2. Pathogen-specific adaptations and their clinical correlates

Table 3 illustrates how each conserved immune-evasion node is implemented through pathogen-specific effectors and the clinical phenotypes they produce. S. aureus primarily exploits Nodes 2 and 3 through Protein A-mediated immunoglobulin neutralization and a diverse repertoire of superantigens. These factors induce non-specific polyclonal T-cell activation followed by immune anergy instead of effective adaptive immunity [63]. Clinically, this profile is associated with toxin-mediated diseases, including toxic shock syndrome and exfoliative disease, as well as persistent device-associated biofilm infections. Immune-evasion proteins such as Protein A, ClfA, and IsaB are strongly enriched in mature biofilms and correlate with enhanced intracellular survival in monocytes and macrophages [64]. P. aeruginosa exemplifies Node 5 through the production of alginate, Psl, and Pel exopolysaccharides under quorum-sensing control. These polymers generate the characteristic mucoid phenotype associated with chronic cystic fibrosis lung infection and ventilator-associated pneumonia rather than acute bloodstream infection [36, 62]. K. pneumoniae primarily engages Nodes 1 and 2 through capsular hypermucoviscosity. This phenotype is especially prominent in K1 and K2 serotypes carrying rmpA and is linked to hypervirulent community-acquired liver abscess with metastatic spread to the eye, lung, or central nervous system, even in otherwise healthy individuals [65]. A. baumannii relies mainly on capsule-mediated resistance to complement rather than toxin production. This strategy corresponds to Node 2 and is associated with serum-resistant bacteremia and pneumonia, particularly in intensive care units and immunocompromised patients [43, 66]. Compared with the other ESKAPE pathogens, Enterococcus spp. and Enterobacter spp. remain less well characterized mechanistically. Current evidence primarily links Enterococcus spp. to biofilm-mediated device colonization and Enterobacter spp. to genomic plasticity and antimicrobial resistance [67, 68]. These traits are associated with catheter-related recurrent infection and opportunistic healthcare-associated disease, respectively. The limited definition of their clinical phenotypes likely reflects gaps in mechanistic evidence rather than reduced immune-evasion capacity.

6.3. Proposed conceptual model

Figure 4 summarizes the conceptual framework proposed in this review. We suggest that coordinated host immune pressures, including complement activation, phagocyte activity, and epithelial pattern recognition, drive the evolution of a limited set of conserved immune-evasion strategies. Although the underlying effectors differ, these mechanisms converge on the same functional nodes because they target common features of host defense. Around this shared framework, each pathogen has evolved lineage-specific effectors shaped by its ecological niche and evolutionary history, including horizontal gene transfer (Table 3). Persistent infection, antimicrobial tolerance, recurrent disease, and treatment failure therefore arise from the interaction between conserved immune-evasion nodes, pathogen-specific effectors, and the host environment rather than from any single virulence factor. Several important knowledge gaps remain. Few studies have compared immune-evasion nodes across multiple ESKAPE pathogens using standardized experimental models. As a result, most mechanistic evidence is derived from single-pathogen studies and cannot be directly generalized across genera. The contribution of trained immunity and immune tolerance to recurrent ESKAPE infections in humans also remains uncertain. Current evidence is largely indirect and is based on findings from heterologous experimental systems. In addition, mechanistic studies of Enterobacter spp. and, to a lesser extent, Enterococcus spp. remain limited compared with those of the other ESKAPE pathogens. Addressing these gaps will be essential for refining and validating the cross-pathogen framework proposed in this review.

7. Translational and therapeutic implications

The six conserved immune-evasion mechanisms discussed in this review, reduced immune recognition, complement inhibition, impaired phagocyte-mediated killing, macrophage and immunometabolic reprogramming, biofilm-associated immune protection, and persistence-driven inflammatory remodeling, represent more than a descriptive framework for bacterial pathogenesis. Their conservation across phylogenetically distinct ESKAPE pathogens suggests the existence of a limited set of shared host-directed therapeutic targets that may be exploited independently of the infecting species. Accordingly, this section examines host-directed therapies, immunotherapeutic approaches, and vaccine strategies within the context of these conserved mechanisms. It also clearly distinguishes findings supported by clinical evidence from those based on preclinical studies or proposed as mechanistic hypotheses.

7.1. Host-directed therapeutics targeting shared evasion nodes

Host-directed therapy (HDT) shifts the therapeutic focus from direct bacterial eradication to restoration of host immune function. Unlike conventional antibiotics, HDTs target evolutionarily conserved host pathways rather than rapidly evolving bacterial components, thereby theoretically increasing the genetic barrier to antimicrobial resistance [69]. When considered within the framework of the conserved immune-evasion nodes, the current evidence varies substantially across mechanisms.

Reduced immune recognition and complement interference. At present, no HDT in clinical development specifically restores complement-mediated opsonization during ESKAPE infections. Existing complement-targeting agents, including eculizumab, avacopan, and iptacopan, are approved for disorders associated with excessive complement activation [70]. However, these agents inhibit key components of the complement cascade, such as C5a and the membrane attack complex, and may increase susceptibility to encapsulated bacterial pathogens. This highlights the complexity of therapeutic modulation of the complement system and emphasizes that complement restoration remains an unresolved translational challenge rather than an established therapeutic strategy [69, 70].

Macrophage and immunometabolic reprogramming. Among the conserved immune-evasion mechanisms, this node is supported by the strongest preclinical evidence. Induction of trained immunity through β-glucan or BCG vaccination reprograms myeloid cell metabolism via the itaconate–succinate and mevalonate pathways, enhancing nonspecific protection against lethal bacterial infections in animal models. These effects depend on IL-1 signaling and monocyte/macrophage activity, but the evidence remains preclinical and has not been validated as a therapeutic intervention for ESKAPE infections [71, 72]. Modulation of these metabolic pathways using approved drugs, including statins, metformin, and rapamycin, has also been proposed as a strategy to attenuate maladaptive immune responses [73]. Nevertheless, this concept remains mechanistic and has not yet been evaluated in clinical trials targeting bacterial infections.

Biofilm-mediated immune shielding and quorum sensing (QS), inhibition is of translational interest because it can restore innate immune signaling suppressed within bacterial biofilms, rather than functioning solely as an anti-virulence strategy. Experimental studies have shown that QS-deficient P. aeruginosa strains are eliminated more efficiently from biofilms than wild-type strains [74, 75]. In addition, small-molecule LasR/RhlR antagonists, such as meta-bromo-thiolactone, reduce virulence factor production and improve survival in preclinical infection models [76]. Despite these promising findings, QS inhibitors have not yet advanced to clinical trials specifically targeting ESKAPE pathogens.

Altogether, HDTs offer a common translational advantage across these immune-evasion mechanisms by preserving the commensal microbiota to a greater extent than broad-spectrum antibiotics [69, 77]. However, clinical translation remains limited. With the partial exception of trained-immunity concepts adapted from tuberculosis and fungal infection research, most HDT strategies have not been evaluated in ESKAPE-specific clinical populations.

7.2. Immunotherapeutic strategies

Monoclonal antibodies targeting bacterial surface polysaccharides can restore immune recognition by enhancing opsonization, complement activation, and phagocytic clearance. A human monoclonal antibody against the KL64 capsular polysaccharide protected mice from bloodstream infection caused by pandrug-resistant ST147 K. pneumoniae, whereas only capsule-specific antibodies showed in vivo efficacy despite similar in vitro bactericidal activity among candidates, emphasizing that laboratory potency does not necessarily predict therapeutic benefit [78]. Likewise, the humanized monoclonal antibody MAb5, targeting the O-antigen capsular carbohydrate of A. baumannii, demonstrated broad cross-strain binding and protective activity in animal models [79]. Further studies showed that its efficacy depended on concurrent host immune modulation, suggesting that passive antibody therapy and host-directed approaches may act synergistically rather than independently [80]. Neutralization of bacterial toxins represents another immunotherapeutic strategy. Suvratoxumab, an anti-S. aureus α-toxin monoclonal antibody, showed an acceptable safety profile in a phase II trial but failed to improve the primary clinical outcome, indicating that targeting a single virulence factor is insufficient against pathogens with redundant immune-evasion mechanisms [81].

Checkpoint-associated immunomodulation is an emerging concept. S. aureus can suppress T-cell activation through PD-1 signaling, while PD-1 blockade restores T-cell function in vitro [82]. Although immune checkpoint pathways are considered promising therapeutic targets [83], their clinical application in ESKAPE infections remains unproven because of pathogen heterogeneity, uncertainty regarding treatment timing, the risk of excessive inflammation, and the lack of validated predictive biomarkers.

7.3. Next-generation vaccine strategies and translational perspectives

Conventional single-antigen vaccines against ESKAPE pathogens have shown limited clinical success. The best-characterized example is the IsdB vaccine against S. aureus. Although it demonstrated strong protection in preclinical studies, it failed in a phase III clinical trial. Subsequent investigations revealed that previous exposure to S. aureus, which is common in humans, induces non-protective hyper-sialylated antibodies against IsdB [84]. Vaccination preferentially recalls these antibodies, reducing the generation of protective immune responses [85]. Similar immune imprinting has also been reported for other S. aureus antigens, including MntC and FhuD2, suggesting that this limitation reflects a broader challenge of single-antigen vaccines rather than failure of a single candidate [84]. In addition, the absence of validated correlates of protection for most ESKAPE pathogens complicates vaccine evaluation and clinical trial design.

Reverse vaccinology provides a promising alternative. Instead of focusing on individual surface proteins, this strategy uses comparative genomic analysis to identify conserved antigens shared across multiple strains [86]. Computational studies have identified proteins such as OprD and TolC as conserved vaccine candidates across several ESKAPE pathogens. However, these findings remain limited to in silico analyses and early preclinical studies. A recent National Institute of Allergy and Infectious Diseases (NIAID) workshop emphasized that systems immunology, genome-wide interaction studies, machine learning, and host-response profiling remain underutilized in ESKAPE vaccine research [87]. Likewise, artificial intelligence-based epitope prediction has successfully identified conserved immunogenic epitopes in other pathogens and may improve antigen discovery for ESKAPE organisms in the future [88].

Targeting conserved immune-evasion components may also reduce antigenic variation because these proteins are under stronger structural constraints than highly variable surface antigens. Nevertheless, several obstacles remain. Capsular polysaccharides and O-antigens can mask conserved targets, while biofilms further limit antigen accessibility. Vaccine efficacy is also reduced in immunocompromised patients, who account for a large proportion of ESKAPE infections. Moreover, reliable correlates of protection are still lacking. Therefore, the most realistic strategy is the development of multivalent vaccines containing several conserved antigens combined with adjuvants that stimulate trained immunity and macrophage reprogramming, thereby integrating vaccination with host-directed immunomodulation. Successful clinical translation is also likely to require combination therapies rather than single interventions. Current evidence suggests that monoclonal antibodies may be more effective when combined with host-directed immune modulation, as demonstrated for A. baumannii [80]. Likewise, suvratoxumab was evaluated as an adjunct to standard antimicrobial therapy rather than as a replacement [81]. Future strategies may combine antibiotics, host-directed therapies, immunotherapies, and vaccines to achieve complementary immune protection.

A precision-medicine approach offers an important framework for future clinical trials. Evidence from the ImmunoSep trial demonstrated that biomarker-guided immunotherapy, based on ferritin levels and monocyte HLA-DR expression, improved resolution of organ dysfunction despite no significant reduction in 28-day mortality [89]. Similar strategies could be adapted for ESKAPE infections by stratifying patients according to immune endotypes, considering immunocompromised status, selecting interventions based on the stage of infection, and using organ function and bacterial clearance as primary outcomes. Monitoring microbiome preservation should also be included because maintaining the normal microbiota represents a major theoretical advantage of host-directed therapies over conventional antibiotics [69, 77].

8. Conclusion, limitations and future research directions

This review synthesizes current evidence into a unified conceptual framework for cross-pathogen immune evasion. Despite their phylogenetic diversity, ESKAPE pathogens employ distinct molecular effectors to achieve remarkably similar immunological outcomes. These shared strategies define an integrated persistence network rather than isolated virulence mechanisms. Immune evasion extends beyond impaired recognition, complement interference, and defective phagocyte killing. It is tightly linked to biofilm formation, quorum sensing, trained immunity, and immunometabolic reprogramming. Together, these interconnected processes sustain bacterial persistence within the host. This framework identifies conserved host–pathogen interaction nodes as candidate shared therapeutic targets. Targeting these common mechanisms may provide a more durable therapeutic strategy than approaches directed at individual pathogens. This conceptual framework remains constrained by important limitations. Mechanistic evidence is heavily weighted toward S. aureus and P. aeruginosa, whereas Enterococcus and Enterobacter remain comparatively understudied. Most available data originate from isolated, non-standardized single-pathogen models that differ substantially in infection site and host context. In addition, causal evidence from human studies remains limited. Although experimental models consistently associate immune reprogramming with persistent infection, these relationships have not been established conclusively in patients. Likewise, host-directed and immunometabolic therapies remain largely at the preclinical stage.

Future research should prioritize direct experimental validation of conserved immune-evasion nodes across multiple ESKAPE pathogens under harmonized conditions. Such studies will determine whether these pathways represent broadly applicable therapeutic targets. Progress will also require systems immunology, integrated multi-omics analyses, and longitudinal human studies capable of defining causal mechanisms. Biomarker-guided precision immunotherapy and artificial intelligence (AI)-assisted target discovery offer additional opportunities, provided computational predictions undergo rigorous experimental validation. Ultimately, overcoming antimicrobial resistance will likely depend less on targeting individual pathogens than on disrupting the conserved host–pathogen interactions that enable persistent infection across the ESKAPE group.

Funding Statement

Funding sources: No financial support was received for this study.