Hyperbaric oxygen therapy (HBOT) is a non-pharmacological intervention in which patients inhale near-100% oxygen at pressures exceeding 1 atmosphere absolute (ATA), most commonly 2.0–3.0 ATA, thereby markedly increasing plasma and tissue oxygen partial pressure (1). The biological effects of HBOT extend well beyond the simple correction of hypoxia; accumulating evidence indicates that HBOT can systemically reshape peripheral immune cell composition and indices related to immune tolerance. Accordingly, peripheral immune tolerance (PIT) has emerged as a central conceptual framework for interpreting the immunological effects of HBOT (2, 3).

PIT refers to a series of mechanisms by which lymphocytes, after exiting the thymus and bone marrow, continuously restrain autoreactive immune responses and limit inflammation. These mechanisms include clonal anergy, clonal deletion, inhibitory co-stimulatory signaling, and active suppression mediated by regulatory T cells (Tregs) (4). Deficiency of CD25⁺/FOXP3⁺ Tregs results in fatal multisystem autoimmunity in both humans with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and scurfy mice, whereas ectopic acquisition of FOXP3 expression is sufficient to confer suppressive function on conventional T cells. Together, genetic and functional evidence firmly establishes FOXP3⁺ Tregs as a core cellular determinant of PIT (5). Recent advances, including single-cell suppression profiling, have further delineated microenvironment-specific suppressive programs of human Tregs. In parallel, targeted strategies exemplified by manipulation of the CD2–LFA-3 axis can selectively inhibit high-CD2-expressing effector T cells while relatively sparing Tregs, thereby restoring immune homeostasis across multiple autoimmune models (6, 7). Within this shared regulatory network, T helper 17 (Th17) cells and Tregs display distinct metabolic dependencies: Th17 cells preferentially rely on glycolysis and amino-acid metabolism, whereas Tregs are biased toward fatty-acid oxidation and mitochondrial oxidative phosphorylation (OXPHOS). Mitochondria-derived reactive oxygen species (ROS), mitochondrial dynamics, and processes associated with immune aging and inflammaging jointly shape the Th17/Treg balance and overall T-cell functional states (8, 9). By enabling precise, whole-body modulation of oxygen tension and inducing controlled mitochondrial responses, HBOT can directly engage the oxygen tension–immunometabolism–PIT axis (10).

PIT is often described in terms of the Treg/Th17 axis. However, tolerance induction and maintenance involve multiple immune compartments (4, 11). Innate immune cells, including neutrophils, monocytes/macrophages, and dendritic cells, shape early inflammatory thresholds, regulate antigen presentation, and define cytokine environments that steer subsequent T-cell polarization (12, 13). Natural killer (NK) cells, γδ T cells, and CD8⁺ T cells may also contribute via rapid effector functions and oxygen-sensing or immunometabolic pathways (14). Evidence from acute injury and toxic exposure models can help characterize upstream immune changes reported under HBOT and inform mechanistic links to tolerance-associated alterations described in chronic disease settings.

Despite the growing number of studies reporting immunological effects of HBOT, substantial heterogeneity persists with respect to disease models, treatment protocols, and endpoint selection. Most investigations emphasize anti-inflammatory, anti-infective, or tissue-repair outcomes, and a unifying interpretative perspective centered on PIT remains largely absent. To enhance transparency in evidence retrieval and appraisal, the present study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 reporting framework (15) and adopts PIT as the core analytical lens. We therefore conduct a mechanism-oriented qualitative narrative synthesis and critical analysis of existing evidence, focusing on how HBOT reshapes PIT within a conceptual framework integrating FOXP3⁺ Tregs and oxygen tension–immunometabolic coupling. From a methodological standpoint, this work constitutes a mechanistic narrative review grounded in systematic literature retrieval.

A total of 39 peer-reviewed publications were included in this review. The majority were original research articles (n = 33, 84.6%), comprising 16 animal studies, 5 in vitro or ex vivo studies, 11 clinical studies, and 1 Bayesian modeling study. Six review articles (15.4%) were also included, predominantly narrative reviews, with one systematic review. Among the original studies, animal experiments largely focused on two major contexts: autoimmune and chronic inflammatory conditions, aimed at examining changes in organ-specific and systemic immune responses; and acute injury or toxic exposure models, emphasizing acute tissue damage and secondary inflammatory processes. In vitro and ex vivo studies typically employed peripheral immune cells, pathogen-related systems, or isolated tissues to evaluate the effects of HBOT on antimicrobial efficacy and potential synergistic interactions, while also assessing stress responses and immunogenicity-related endpoints. Clinical studies spanned a wide range of disease settings, including acute severe infections and toxic encephalopathy, as well as chronic autoimmune or inflammatory disorders. These investigations further extended to populations characterized by immune reconstitution or immune activation states, with healthy volunteers and individuals with mild to moderate chronic inflammation serving as reference groups. The Bayesian modeling study integrated existing experimental and clinical data to jointly model and predict HBOT-associated immune parameters, thereby providing a systems-level perspective on the interaction between HBOT and PIT. Collectively, these diverse disease models and experimental approaches provided a relatively comprehensive evidence base for the subsequent narrative synthesis and mechanistic integration.

Across the studies included in this review, HBOT intervention pressures were predominantly in the range of 2.0–2.8 ATA (38/39, 97.4%), with single-session exposure durations of 60–120 min. Treatment frequency was most commonly once daily, and total treatment courses ranged from a single exposure to up to 4 consecutive weeks. Only one study (19) employed a mild HBOT protocol (1.4 ATA, 70 min, single session) to examine peripheral NK cell function in healthy women. As the sole low-pressure intervention included in this review, this study provides an important reference point for exploring pressure thresholds and mechanistic specificity underlying HBOT-induced immune effects. The six review articles primarily summarized the potential roles of conventional clinical HBOT protocols (2.0–2.8 ATA) in sepsis, tumor immunity, and transplant immunology. Detailed data extracted from the included studies are presented in Table 2.

Studies (n = 39) are grouped by study design. The model/subject, hyperbaric oxygen therapy (HBOT) regimen (pressure, session duration, frequency, and total course), the main reported changes in peripheral immune readouts, and associated mechanistic clues are summarized.

Abbreviations: ARDS: Acute respiratory distress syndrome; ASC: Apoptosis-associated speck-like protein containing a CARD (adaptor protein); ATA: Atmospheres absolute; BDNF: Brain-derived neurotrophic factor; BMS: Basso Mouse Scale; CAT: Catalase; CO: Carbon monoxide; CRP: C-reactive protein; CTL: Cytotoxic T lymphocytes; DC: Dendritic cells; DE: Delayed encephalopathy; ESR: Erythrocyte sedimentation rate; G-CSF: Granulocyte-colony stimulating factor; HBOT: Hyperbaric oxygen therapy; HIF-1α: Hypoxia-inducible factor 1-alpha; HIV: Human immunodeficiency virus; HLA-DR: Human Leukocyte Antigen–DR isotype; HO-1: Heme oxygenase-1; IBD: Inflammatory bowel disease; ICAM-1: Intercellular adhesion molecule 1; IgE: Immunoglobulin E; LOOH: Lipid hydroperoxides; MBP: Myelin basic protein; mAb: Monoclonal antibody; MDA: Malondialdehyde; MDSC: Myeloid-derived suppressor cells; MOF: Multiple organ failure; MPO: Myeloperoxidase; NF-κB: Nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; NOx: nitric oxide metabolites; NSTI: Necrotizing soft tissue infection; PaO₂: Partial pressure of arterial oxygen; PBMC: Peripheral blood mononuclear cells; PD-1: Programmed cell death protein 1; SCI: Spinal cord injury; SLE: Systemic lupus erythematosus; SOD: Superoxide dismutase; TBI: Traumatic brain injury; TLR: Toll-like receptor; TME: Tumor microenvironment; Tx: Transplantation; d: day(s); w: week(s); ↑: Increased; ↓: Decreased; =: No significant change.

Animal and transplantation-related studies provide relatively direct preclinical evidence that HBOT promotes an immune-tolerant phenotype. Across canonical models of autoimmunity and inflammation, HBOT increases the frequency and suppressive function of FOXP3⁺ Tregs while inhibiting Th17 differentiation and reducing Th17-associated cytokines, including IL-17A, IL-22, and IL-23. Together, these effects lower the Th17/Treg ratio. This pattern has been repeatedly observed in autoimmune models. In collagen-induced arthritis in rats, HBOT increased splenic Treg frequencies and decreased Th17 proportions, coinciding with reduced synovial inflammatory infiltration and improved bone destruction scores (20). In non-obese diabetic (NOD) mice, HBOT delayed diabetes onset and preserved residual pancreatic β-cell mass; both peripheral blood and islet microenvironments showed reduced Th17-associated inflammatory mediators and increased Treg markers (21).

Transplantation-oriented evidence further supports a Treg-dependent shift toward tolerance. In murine skin transplantation, HBOT treatment of recipients enabled long-term graft acceptance, whereas selective depletion of CD4⁺CD25⁺ Tregs rapidly abolished immune unresponsiveness (22). This rapid loss of tolerance after Treg depletion highlights the importance of Treg-mediated active suppression in HBOT-associated tolerance induction. Consistently, transplant immunology reviews have proposed that HBOT may facilitate transplant tolerance by modulating lymphatic inflammation and broader immune regulatory processes (23). In addition, human fetal islet allotransplantation studies indicate that HBOT preconditioning downregulates HLA class II expression in donor tissue, attenuates recipient T-cell proliferative responses, and prolongs graft survival (24).

Clinical evidence remains limited but is broadly concordant with preclinical findings. In inflammatory bowel disease, HBOT combined with standard therapy improved mucosal healing and induced clinical remission (25, 26), accompanied by immunoregulatory changes consistent with increased Treg activity and reduced pro-inflammatory cytokine signaling, including IL-6 and IL-17–associated pathways (27). Collectively, these data support the conclusion that a central cellular effect of HBOT in PIT remodeling involves the selective enhancement of FOXP3⁺ Treg abundance and function alongside suppression of Th17 polarization and its downstream pro-inflammatory pathways. This dual modulation reduces the Th17/Treg ratio and favors a tolerance-promoting immune microenvironment. However, most clinical studies prioritize disease outcomes as primary endpoints, and direct immunological readouts of the Treg/Th17 axis remain scarce. For example, in systemic lupus erythematosus (SLE)-associated acute macular neuroretinopathy (AMN) cases, the addition of HBOT to immunosuppressive therapy not only significantly improved tissue oxygenation but also exhibited immunomodulatory effects, consistent with a tolerogenic shift toward increased Treg and reduced Th17 responses (28). Therefore, these mechanistic inferences require confirmation and quantification in prospective clinical studies that prespecify immune tolerance axes as endpoints (Figure 2).

This conceptual schematic summarizes how HBOT may reshape PIT through T-cell centered remodeling in a context dependent manner, contrasting autoimmune and chronic inflammatory settings with tumors and chronic infections.

Symbol legend: Arrows (→) denote directional functional/regulatory relationships within the proposed framework and do not represent physical trafficking of cells, molecules, or signals. Thick blue solid arrows indicate HBOT as the upstream input/overall driver. Green solid arrows indicate positive regulation, and green bidirectional arrows indicate bidirectional shifts/remodeling of immune balance. Red dashed arrows indicate negative regulation, whereas red dashed arrows labeled with “×” indicate pronounced suppression/blockade of the indicated pathway or amplification loop. Small black arrows indicate within-module process flow or stepwise connections; the direction of regulation is defined by the green/red arrows. Context partitions highlight context-dependent immune outcomes.

In the context where the Treg/Th17 axis has been shifted toward tolerance by HBOT, the reprogramming of effector T cell lineages determines whether peripheral immunity favors immune surveillance or progresses to tissue-damaging inflammation. Preclinical tumor models and systematic reviews focused on tumor immunity jointly indicate that HBOT, by alleviating tumor microenvironment hypoxia, significantly optimizes the metabolic conditions and delivery of effector T cells within the local tumor site (29). In solid tumor mouse models, HBOT at approximately 2.0 ATA increased dendritic cell maturation, enhanced antigen-presenting capacity, boosted CD8⁺ cytotoxic T cell infiltration, and markedly reduced tumor volume (30). Further experiments revealed that HBOT also enhances the delivery of PD-1 monoclonal antibodies within tumor tissues, increasing CD8⁺ T cell numbers while significantly reducing myeloid-derived suppressor cells (MDSC) and M2 macrophages, thereby decreasing tumor immune suppression and increasing the sensitivity to immunotherapy (31). Taken together, these findings suggest that HBOT not only maintains baseline tolerance to self-antigens but also restores effective surveillance and clearance of malignant clones in the tumor setting by relieving hypoxia, improving PD-1 blockade drug delivery, and reshaping the balance between cytotoxic T lymphocytes (CTLs) and myeloid cells.

In autoimmune and organ-specific inflammatory models, by contrast, HBOT preferentially supports FOXP3-mediated regulatory processes. By expanding the Treg pool and improving local cellular stress states, HBOT helps create an environment in which β cells are more likely to be tolerated rather than attacked. In a lupus model, HBOT reduced anti-dsDNA antibody titers, delayed the onset of proteinuria, and ameliorated immune-complex deposition (32). Studies in arthritis rats further suggested that HBOT increases splenic Treg levels, decreases Th17 cell proportions, and reduces serum IL-6, resulting in relief from joint destruction and synovial inflammation (20). In transplant studies, preconditioning with HBOT at approximately 2.5 ATA decreased Human Leukocyte Antigen-DR isotype (HLA-DR) expression in fetal pancreatic tissue, reduced recipient lymphocyte proliferation, and extended graft survival (24). Skin graft experiments further demonstrated that HBOT prolonged graft survival and induced long-term acceptance. However, selective depletion of CD4⁺CD25⁺ Tregs rapidly reversed this tolerant phenotype, underscoring the critical role of Treg-mediated active suppression in HBOT-induced transplant tolerance (22).

Bayesian modeling and clinical reviews provide systemic-level support for these cellular observations. A Bayesian model showed that HBOT significantly reduces the peak intensity of IL-6 during cytokine storms, shortens the duration of high-inflammatory periods, and enhances Treg expansion rates (33). Systematic reviews report that adjunctive HBOT added to standard therapy is associated with improved clinical outcomes in refractory fistulizing perianal and perineal Crohn’s disease, and clinical remission has been observed in some patients (34–36). Human studies further suggest that HBOT reduces pro-inflammatory cytokine production during treatment, including IL-6 (37). These findings suggest that in tumor-associated immunosuppressive states, HBOT enhances the delivery and functionality of effector T cells after PD-1 blockade, enabling compatibility between peripheral tolerance and antitumor immunity. In autoimmune and chronic inflammatory contexts, however, HBOT shifts peripheral immunity back toward a tolerance-driven balance by downregulating pro-inflammatory pathways represented by IL-6 and IL-17 and strengthening the regulatory network mediated by FOXP3. This mechanism sets the stage for the subsequent remodeling of innate immune modules (Figure 2).

Innate-like lymphocytes reside at the intersection of innate and adaptive immunity, and under the influence of HBOT, they are the first to sense changes in oxygen tension, translating metabolic and inflammatory signals into adjustments in early immune rhythms. In a study with healthy female volunteers receiving a single mild HBOT exposure at approximately 1.4 ATA, peripheral NK cell numbers and cytotoxic activity were significantly increased, while systemic inflammation remained stable. This indicates that, under conditions near immune homeostasis, low-dose HBOT preferentially enhances NK cell-mediated tumor and viral surveillance without incurring significant systemic inflammatory costs (19). In another study with healthy participants exposed to standard treatment pressure of approximately 2.4 ATA, a single HBOT exposure induced a transient increase in ROS, while overall antioxidant capacity increased, and plasma cytokine levels remained largely unchanged (38). Additionally, in healthy divers and endurance athletes, a single exposure to approximately 2.8 ATA of HBOT did not cause significant imbalances in oxidative stress or inflammation-related markers, suggesting the immunological safety of short-term exposure in healthy individuals (39). These data highlight that mild HBOT primarily enhances NK cell function with limited systemic oxidative stress effects, making it suitable for mild immune modulation and immune surveillance, while standard treatment pressures establish a new balance between controlled ROS increase and enhanced antioxidant defense, more closely resembling the actual immune resetting seen in pathological conditions. These findings indicate that immune effects may vary with different pressure protocols, but existing evidence is primarily derived from single exposure studies, and more prospective studies with comparable parameters are needed to define clear pressure thresholds or dose-response relationships.

In models of injury and localized inflammation, HBOT modulates γδ T cells and related inflammatory pathways in a manner that suppresses early pathogenic responses. In acute injury models of the central nervous system, such as spinal cord injury mice, HBOT at 2.0 ATA significantly reduced the proportion of IL-17A⁺ γδ T cells in spinal cord tissue, alleviated neutrophil infiltration, and improved motor function scores. This indicates effective disruption of the IL-17A-dependent γδ T cell amplification loop, thus mitigating secondary tissue damage (40). In studies of traumatic brain injury rats, HBOT not only reduced TNF-α and other inflammatory mediators in the brain but also reshaped the gut microbiome by increasing the abundance of Prevotella copri, transitioning the gut-brain axis from a high-inflammatory state toward a more homeostatic configuration (41). In early acute pancreatitis models, HBOT induced peripheral lymphocyte apoptosis and reduced pancreatic necrosis and disease severity (42). In a skin inflammation model, HBOT at 2.5 ATA transiently increased local ROS levels but significantly reduced IL-4, IL-5, and IgE levels, with a decrease in skin lesion scores, suggesting suppression of Th2-type inflammation in barrier tissues (43). From the central nervous system to peripheral tissues, and from IL-17A-driven γδ T cells to Th2-related cytokines, these findings collectively suggest that HBOT tends to dampen amplification circuits of inflammation in various tissues, promoting a quicker return to a state favorable for tolerance establishment (Figure 3).

In pathogen-associated and antiviral contexts, innate-like lymphocytes and mononuclear cells together form the frontline barrier for HBOT-mediated peripheral tolerance modulation. In an in vitro experiment with HIV-infected peripheral blood mononuclear cells (PBMCs), exposure to approximately 2.4 ATA of HBOT over several days significantly suppressed viral replication and reduced p24 antigen levels, with little effect on cell viability. This indicates that HBOT can reduce viral load without depleting immune cells (44). Combining this with earlier observations of enhanced NK cell cytotoxicity and only transient ROS elevation while maintaining overall stable systemic cytokines, it can be inferred that HBOT’s core feature in pathogen-related contexts is not simply to increase inflammation, but rather to enhance the efficiency of NK cells and mononuclear cells while avoiding a systemic shift to high-inflammatory states (19, 38). In this manner, HBOT may not only improve early control in chronic infections like viruses but also provide an environment with lower inflammatory noise and reduced tissue damage risk, potentially supporting long-term PIT mediated by FOXP3⁺ Tregs and memory T cells. This mechanism aligns with the previously discussed HBOT effects on effector T cell reprogramming in tumor and autoimmune settings.

This schematic summarizes the proposed effects of HBOT on innate immune remodeling across distinct physiological and pathological contexts. It integrates innate-like lymphocyte responses, myeloid network remodeling, and oxygen-sensing and mitochondrial pathways implicated in HBOT-associated immune rebalancing.

Additional symbols in Figure 3: Green dashed arrows indicate supportive/indirect positive associations. “↑/↓” denote upregulation/downregulation. The prohibition mark indicates restricted processes; the “✓” mark denotes beneficial outcomes/functional improvement; circular arrows indicate dynamic turnover or mobilization of repair-associated cells/factors. The balance icon indicates a net rebalancing toward homeostasis/tolerance. Symbols otherwise follow those defined in Figure 2.

This study explores the interaction between HBOT and PIT, systematically integrating 39 peer-reviewed studies. It incorporates evidence on how oxygen tension, immune metabolism, and the regulatory axis of PIT interact to modulate immune responses. The study aims to elucidate how HBOT, through oxygen tension-driven immune metabolic reprogramming, alters the thresholds of PIT, thereby recalibrating the balance between immune effector functions and immune tolerance in different disease contexts. It is important to note that the included studies show considerable heterogeneity in exposure protocols and endpoint assessments, meaning that related inferences should be interpreted in the context of specific study conditions and observed indicators. Animal studies often involve prolonged treatment courses (multiple days or weeks), allowing for the observation of immune lineage and functional state remodeling over multiple time points. Human studies, however, typically involve single exposures, primarily capturing short-term ROS dynamics and transient fluctuations in peripheral cell subsets. In vitro studies, by eliminating the regulatory background of the organism, primarily reflect the direct effects of acute hyperoxic stress on cellular effector functions and stress markers. Based on this structure of evidence, the more robust conclusions regarding Treg/Th17 shifts rely on multiple treatment course studies, while the threshold of different pressure protocols and dose-response relationships remain exploratory and need further verification in prospective studies with comparable parameters.

In high-inflammatory, glycolysis-biased contexts, such as autoimmune diseases and chronic inflammatory conditions, HBOT typically results in a reduction of pro-inflammatory cytokine levels, an increase in FOXP3⁺ Treg proportions, and a shift of the Treg/Th17 ratio back toward physiological levels. This suggests a partial recalibration of PIT thresholds, which have been disrupted due to inflammation load (63, 64). From the perspective of cellular metabolism and subcellular structures, HBOT alleviates tissue hypoxia and excessive oxidative stress, weakens the glycolysis bias driven by HIF-1α, and reduces the dependency of effector T cells and Th17 cells on high glycolysis. At the same time, HBOT improves mitochondrial function and ROS homeostasis, facilitating a metabolic profile in Tregs that is dominated by fatty acid oxidation and OXPHOS (65). These changes in the metabolic environment further impact transcriptional regulatory programs sensitive to metabolism, enhancing Treg-related gene expression while limiting the expansion of pro-inflammatory lineages, thereby strengthening key components of regulatory suppression and functional unresponsiveness within the PIT network (66, 67). Thus, in high-inflammatory settings, HBOT does not merely suppress immune responses but instead lowers the metabolic thresholds for pathological effector responses and upregulates the activity of tolerance-related modules, pushing PIT back toward a more homeostatic set point.

In addition to these direct immunometabolic effects, a gut-mediated component may also contribute to immune rebalancing in high-inflammatory states. Intestinal oxygen and redox tone are established ecological constraints that can reshape microbial niches and metabolite availability and thereby influence dysbiosis-linked inflammatory outputs (68, 69). Against this backdrop, HBOT-induced shifts in tissue oxygenation under inflammatory conditions could plausibly propagate to the gut microenvironment, with secondary effects on microbiota-derived immunoregulatory cues that interface with the Treg and Th17 axis discussed above. Early evidence from distinct indications is compatible with this possibility. In Crohn’s disease, HBOT was accompanied by clinical improvement together with coordinated changes in microbial community features, and stool transfer from post-HBOT donors mitigated inflammation in recipient mice, supporting a contributory microbial component (70). Similarly, in a traumatic brain injury rat model, HBOT increased Prevotella copri and coincided with reduced TNF-α and attenuated neuroinflammatory readouts (41). Nevertheless, current evidence remains limited in scope and heterogeneous across indications, and establishing definitive causality in humans will require well-designed longitudinal studies.

In deeply hypoxic and metabolically suppressed lesions, such as malignant tumors and certain chronic infections, this regulatory axis exhibits opposing effects depending on the immune and metabolic background. These lesions are typically characterized by a significant drop in local tissue oxygen tension, the accumulation of lactate and other metabolic inhibitors, impaired antigen-presenting cell function, and the development of exhausted phenotypes in CD8⁺ T cells and NK cells. This local immune environment essentially represents a pathological “over-tolerant” state (71). In such contexts, HBOT increases local oxygenation levels, alleviates the lactate load, and improves mitochondrial metabolism, which helps restore the ability of antigen-presenting cells to process and present antigens. Additionally, it increases the infiltration and effector functions of CD8⁺ T cells and NK cells (72). Under conditions of improved ROS signaling and mitochondrial quality control, effector T cells are more likely to transition from a state of deep exhaustion to partial functional recovery or memory lineage differentiation (73). At the nuclear level, the transcriptional programs associated with co-inhibitory receptor-driven exhaustion are partially downregulated, accompanied by a moderate lowering of local PIT thresholds, thus alleviating the pathological tolerance in the lesions (74). However, the current research lacks sufficient evaluation of the systemic costs of self-tolerance, and due to limitations in sample size and follow-up duration, safety-related inferences must be made cautiously. This group of findings suggests that in tumor and chronic infection contexts, HBOT is more aligned with relieving metabolic suppression, selectively weakening the excessively high tolerance barriers within the lesions, thereby enhancing effective immune responses against tumors or pathogens (75).

In populations close to immune homeostasis or with non-inflammatory indications, existing limited follow-up data have not suggested that HBOT induces sustained peripheral immune dysregulation or tolerance disruption (76). This observation resonates with the two previously discussed disease contexts, suggesting that the effect of HBOT on PIT can be uniformly explained within the same regulatory axis. When baseline inflammation load is low and tissue oxygenation is close to physiological levels, the immune cell metabolism and PIT network are already near a steady state. In such cases, the changes in oxygen tension induced by HBOT cause only limited recalibration at the immune metabolic level, and consequently, the impact on PIT thresholds is relatively small. Combining the three scenarios discussed above, a unified explanatory framework can be developed (Figure 4). HBOT influences PIT through regulating upstream oxygen tension, inducing immune metabolic remodeling at the cytoplasmic and mitochondrial levels, and altering gene expression and regulatory programs related to PIT at the nuclear transcriptional level. In autoimmune and chronic inflammatory diseases, HBOT primarily enhances tolerance-related pathways, while in tumors and chronic infections, it reduces excessive tolerance in the lesion sites. In populations with immune states close to homeostasis, the overall impact of HBOT is limited. This differential pattern of immune modulation is mainly related to baseline inflammation load, tissue hypoxia, and metabolic status.

This schematic outlines a conceptual framework linking HBOT associated shifts in oxygen tension to immunometabolic remodeling and PIT. It integrates the oxygen tension to metabolism axis with context dependent recalibration of PIT across autoimmune or chronic inflammatory conditions and hypoxic tumor microenvironments.

Additional symbols in Figure 4: “+” indicates an increase or improvement of the indicated process/outcome. The shield icon denotes context-dependent adjustment of the PIT threshold. Bidirectional arrows indicate reciprocal interactions between connected modules; green vs red denotes the dominant direction of the net effect (enhancement vs suppression). This differs from Figure 2, where the green bidirectional arrow is used specifically to denote immune-balance remodeling. Other symbols follow those defined in Figure 2 and 3.

Based on this unified framework, the effect of HBOT on PIT can be clearly summarized as a continuous regulatory process that involves upstream oxygen tension sensing, intermediate immune metabolic remodeling, and downstream immune cell lineage and functional state adjustments. Oxygen tension changes mainly regulate ROS generation and antioxidant defense systems through HIFs and related oxygen-dependent pathways (77, 78). These pathways shape the metabolic environment of immune cells, subsequently affecting the balance between glycolysis and OXPHOS in the cytoplasm and mitochondria, the redistribution of fatty acid oxidation and glutamine metabolism, and mitochondrial dynamics and autophagy processes. Collectively, these metabolic and lineage changes dictate the plasticity of T cells and myeloid cells in differentiating toward effector, regulatory, memory, and exhausted functional states (79). These metabolic and lineage shifts are then integrated through nuclear transcription programs, resulting in coordinated changes in key immune mechanisms, such as the Treg/Th17 balance, effector T cell exhaustion, memory lineage switching, and polarization of key myeloid subpopulations. Ultimately, these changes manifest as an upward or downward shift in the PIT threshold (80, 81). In this sense, HBOT is better understood as an intervention tool that modulates oxygen tension, immune metabolism, and PIT, rather than a simple immune stimulator or immunosuppressant.

The findings of this study have significant theoretical implications and potential translational value. HBOT can be viewed not only as a traditional physical adjuvant therapy but also as an immune-metabolic intervention that modulates PIT thresholds. Future research should shift from an overall evaluation of therapeutic efficacy to defining appropriate patient populations and conditions of action. Specifically, future studies should clarify which oxygen tension trajectories and exposure models can regulate PIT thresholds to more favorable ranges for disease control under different immune and metabolic backgrounds. Existing evidence suggests that future research should avoid focusing solely on individual inflammatory markers or specific cell ratios and instead adopt PIT as the central framework. This framework should incorporate composite endpoints, including the Treg/Th17 axis, effector T cell exhaustion and memory lineage, myeloid cell subsets, ROS levels, and mitochondrial function, while employing multi-timepoint evaluation strategies to assess the dynamic time characteristics of the transition from innate to adaptive immune remodeling. Current results indicate that patients with significant Treg/Th17 imbalance and local hypoxia in autoimmune and inflammatory diseases may be better suited for HBOT intervention. In the field of cancer immunotherapy, HBOT could be prioritized as a potential adjunct to immune checkpoint inhibitors, adoptive cell therapy, or vaccines, particularly in tumor types where hypoxia drives immune evasion, and should be evaluated in related clinical studies.

However, translating the regulatory axis proposed in this study from a conceptual framework to evidence-based conclusions still faces multiple limitations. The existing studies exhibit high heterogeneity in terms of disease spectra, HBOT pressure and treatment parameters, immune endpoint selection, and other factors. Furthermore, many studies have small sample sizes, and key information related to randomization, blinding, and loss to follow-up is often inadequately reported, making bias risks better suited for qualitative rather than quantitative assessment. Given these realities, this study did not apply a unified bias risk evaluation scale to all included studies, nor was it pre-registered on platforms like PROSPERO. Instead, we relied on predefined inclusion and exclusion criteria and conducted a narrative analysis of core methodological elements and their limitations in each mechanism section, thus delimiting the evidence base and applicability of the mechanistic inferences made in this study. To capture mild HBOT-related evidence as comprehensively as possible, this study lowered the pressure threshold to 1.4 ATA; however, only one study using approximately 1.4 ATA met the criteria (19). The increase in tissue oxygen tension and cumulative oxygen load in this study is difficult to directly compare with conventional protocols using ≥ 2.0 ATA, and it is more appropriate as an exploratory observation for mild hyperbaric exposure rather than a reliable basis for dose-response relationships. Moreover, most studies employed limited time points for measurements, which are insufficient to support rigorous time-series analysis of the presumed causal pathways. Prospective randomized controlled trials focused on PIT restoration or immunosenescence reversal as primary outcomes remain scarce in several key disease areas, and high-level evidence to support these conclusions is lacking.

Given these limitations, future research needs to adopt more targeted designs at the basic, translational, and clinical levels. At the basic and translational levels, studies using representative autoimmune diseases, inflammatory storms, and tumor models, with consistent or comparable HBOT parameters, could integrate multi-timepoint single-cell omics and metabolomics techniques. Such studies should focus on the hypothesized regulatory sequence driven by oxygen tension changes, which alters ROS dynamics, reprograms metabolic pathways, and ultimately affects the Treg/Th17 axis and effector T cell lineage remodeling. This approach could identify key nodes with potential regulatory significance. At the clinical level, it is recommended that cohort studies and randomized controlled trials predefine relatively uniform PIT endpoints and integrate oxygen tension change curves, dose and exposure parameters, and clinical outcomes into the same multivariable analysis models to define potential immune modulation treatment windows in different disease types and immune baseline states. Furthermore, the combined application of HBOT with other immune-metabolic or tolerance-regulating approaches should be further evaluated to explore whether the concept of oxygen tension, immune metabolism, and PIT can be translated into a feasible, individualized intervention strategy.

Overall, the regulatory axis centered around oxygen tension, immune metabolism, and PIT proposed in this study provides a relatively structured and testable theoretical framework for integrating the complex immunological effects of HBOT in various disease contexts. Despite existing limitations in the scope and quality of evidence, the conclusions drawn still need further validation through more rigorous basic and clinical studies. However, systematically researching the concept of PIT remodeling through immune-metabolic regulation holds promise for clarifying the immunomodulatory effects of HBOT in autoimmune diseases, inflammatory storms, cancer immunotherapy, transplantation, and other fields, and evaluating its potential clinical translation value.