Traditional Chinese Medicine in Chronic Hepatitis B: Integrating Antiviral Effects and Immune Modulation in the Context of T Cell Exhaustion

Abstract

Chronic hepatitis B (CHB) remains a major global health burden because nucleos(t)ide analogues (NAs), although highly effective in suppressing viral replication, rarely achieve functional cure. A central barrier is the exhaustion of HBV-specific T cells, a multilayered state driven by persistent antigen exposure, inhibitory receptor signaling, mitochondrial and metabolic dysfunction, transcriptional and epigenetic fixation, and the tolerogenic hepatic microenvironment. Single-target checkpoint blockade, effective in oncology, is limited in CHB by redundant inhibitory networks, providing a rationale for multi-target strategies. Traditional Chinese medicine (TCM), characterized by multicomponent and multitarget pharmacology, has been widely used as an adjunctive strategy in CHB, but its relationship to antiviral immunity remains incompletely defined. This review synthesizes mechanistic, preclinical, and clinical evidence on TCM-derived phytochemicals and compound formulas in the context of HBV-specific T cell exhaustion. The novelty of this review lies in using T cell exhaustion as the organizing framework to distinguish five mechanistic axes of TCM action: reduction of viral antigen burden, modulation of checkpoint and costimulatory pathways, restoration of metabolic fitness, regulation of transcriptional or epigenetic programs, and remodeling of the hepatic immune microenvironment. Current evidence suggests that many TCM-related benefits are more readily explained by suppression of HBV replication and indirect reduction of antigen-driven T cell dysfunction than by definitive T cell-intrinsic reprogramming. Clinical studies indicate that TCM combined with NAs may improve virological, biochemical, and serological outcomes, including HBeAg seroconversion and HBsAg decline, but functional cure rates remain limited and immunological endpoints are rarely assessed. Key challenges include mechanistic ambiguity, variable formulation quality, pharmacokinetic uncertainty, and region-specific clinical evidence. Future biomarker-driven studies integrating standardized formulations, pharmacokinetic validation, and HBV-specific T cell profiling are needed to establish whether, and under what conditions, TCM can contribute to durable immune control and functional cure in CHB.

Graphical Abstract

Introduction

Chronic hepatitis B virus (HBV) infection remains a formidable global health challenge, affecting an estimated 254 million people worldwide and causing over one million deaths annually as of 2024.1 Despite the availability of potent nucleos(t)ide analogues (NAs) that effectively suppress viral replication, the current therapeutic landscape reveals a critical limitation: functional cure, defined as hepatitis B surface antigen (HBsAg) clearance, occurs in less than 1% of patients annually on NA monotherapy.2 This limitation underscores that viral persistence is not solely a virological issue but is fundamentally a reflection of host immune dysfunction, particularly the exhaustion of HBV specific T cells. This chronic infection is also accompanied by severe complications such as cirrhosis and hepatocellular carcinoma (HCC), which seriously affect the quality of life of patients and increase the medical burden. Thus, it is crucial to find new treatments to alleviate HBV.

Persistent HBV infection is sustained by profound dysfunction of virus specific CD8+ T cells. Unlike classical exhaustion seen in other chronic viral infections, HBV specific T cells display unique features, including cyclic adenosine monophosphate (cAMP) response element modulator (CREM) driven transcriptional reprogramming, metabolic insufficiency with impaired mitochondrial function, and epigenetic barriers that stabilize dysfunction.3–7 Compounding this, the hepatic microenvironment exerts organ specific immunosuppression, with liver sinusoidal endothelial cells (LSECs) activating a cAMP–protein kinase A (PKA) axis that directly restrains antiviral T cell activity.5 Importantly, HBV specific T cells progressively acquire multiple inhibitory receptors, including programmed cell death protein 1 (PD-1), T cell immunoglobulin and mucin domain containing protein 3 (TIM-3), lymphocyte activation gene 3 (LAG-3) and cytotoxic T lymphocyte associated protein 4 (CTLA-4)—that correlate with viral load, inflammation, and disease progression.8–11 Together, these transcriptional, metabolic, and checkpoint mediated mechanisms create a multilayered state of exhaustion that conventional antivirals cannot reverse.

Beyond the limitations of current antiviral monotherapies, the epidemiological burden of CHB has driven sustained clinical interest in complementary strategies, particularly in high-prevalence regions. In China, where an estimated 20–30 million individuals are living with CHB,12 traditional Chinese medicine (TCM) has been used as an adjunct to NAs for decades and is formally endorsed in the national Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 version),13 as well as in the dedicated Expert Consensus on Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Chronic Hepatitis B,14 primarily for anti-fibrotic and hepatoprotective indications. Clinic-based surveys further indicate that approximately one-third of Chinese-speaking CHB patients in Asia have used TCM at least once.15 Its use elsewhere is more limited but growing, reflecting a broader worldwide interest in botanical adjuncts to viral hepatitis care. Despite this widespread clinical use, the immunological mechanisms underlying its effects—particularly on HBV-specific T cell function—remain incompletely understood.

Single target checkpoint blockade has revolutionized oncology but has shown limited efficacy in chronic HBV. The redundancy and hierarchy of inhibitory pathways, coupled with metabolic and epigenetic barriers, mean that targeting PD-1 or TIM-3 alone cannot restore durable T cell function. By contrast, TCM offers a systems level approach with pleiotropic immunomodulatory actions across multiple dysfunctional axes. Pharmacological evidence shows that Astragalus polysaccharides (APS) enhance T cell proliferation and cytotoxic activity via Toll like receptor 4 (TLR4) signaling;10 ginsenosides such as Rg6, Rh4, and Rb3 suppress HBV replication and modulate Janus kinase signal transducer and activator of transcription (JAK-STAT) and Nuclear factor kappa B (NF-κB) pathways;11 glycyrrhizin interferes with HBsAg processing and regulates innate immunity;16 and curcumin enhances T follicular helper (TFH) cell differentiation through NF-κB and JAK-STAT modulation.17 Compound formulas such as FuzhengHuayu further synergistically enhance Natural killer (NK) and T cell function.18 These multi target effects align with the multifactorial nature of T cell exhaustion, offering a unique therapeutic rationale.

Evidence from randomized controlled trials and meta analyses substantiates TCM’s ability to enhance antiviral efficacy and restore immune function in CHB. Meta analysis of 23 studies involving over 3,200 patients demonstrated that TCM combined with NAs significantly improved HBV DNA clearance, Hepatitis B e Antigen (HBeAg) seroconversion, and overall clinical response compared with NA monotherapy, without increasing adverse effects.19 Large scale randomized trials, such as the TiaoganBuXuJiedu (TGBXJD) and YinQiSanHuang (YQSH) studies, confirmed TCM’s ability to reduce relapse risk and improve functional cure outcomes.20,21 While the cumulative HBsAg clearance rate under NA monotherapy remains extremely low, TCM based combination therapy has shown potential to enhance functional cure, though further prospective validation is required.22,23 This review synthesizes mechanistic insights, experimental evidence, and clinical data, systematically analyses the therapeutic potential, safety, and challenges of TCM in ameliorating HBV specific T cell exhaustion, while proposing potential TCM solutions and future research directions to advance precision immunotherapy for CHB. Despite accumulating evidence, it remains unclear whether TCM-mediated immune restoration reflects direct reprogramming of exhausted T cells or is secondary to reduced antigenic burden. Rather than treating TCM-derived compounds merely as nonspecific antiviral agents, this review uses HBV-specific T cell exhaustion as a mechanistic framework to classify their effects into antigen-load reduction, checkpoint/costimulatory modulation, metabolic restoration, transcriptional or epigenetic regulation, and remodeling of the tolerogenic hepatic microenvironment.

Pathophysiological Landscape of HBV Specific T Cell Exhaustion

CHB infection precipitates a profound state of T cell dysfunction known as exhaustion that serves as a primary obstacle to viral clearance and functional cure. This distinct differentiation program is fundamentally driven by persistent antigen stimulation which compels virus specific CD8+ T cells to adopt a hyporesponsive state to preserve tissue integrity.24 The exhausted phenotype is characterized by the sustained upregulation of multiple inhibitory receptors including PD-1 and CTLA-4 that synergistically elevate the threshold for T cell activation.25,26 Mechanistically, this dysfunction is orchestrated by a maladaptive transcriptional network centered on the nuclear factor TOX that establishes stable epigenetic scars on the chromatin landscape to render cells refractory to rejuvenation.27 These transcriptional and epigenetic alterations are intrinsically linked to severe metabolic impairments such as mitochondrial depolarization and defective glycolysis that deprive T cells of the bioenergetic resources necessary for effector function.6,28 Consequently, this cell intrinsic failure is further entrenched by the unique tolerogenic microenvironment of the liver where immunosuppressive cytokines and regulatory T cells (Tregs) actively inhibit antiviral immunity29,30 (Figure 1).

Figure 1.

The multifaceted pathogenic drivers of T cell exhaustion in chronic hepatitis B.

Persistent Antigen Drive and TCR Overstimulation

The fundamental driver of T cell exhaustion in CHB is the unremitting exposure to high loads of viral antigens, which forces CD8+ T cells into a state of hyporesponsiveness to prevent fatal immunopathology.25,31 Unlike acute resolved infection, where antigen clearance allows for the development of functional memory, the constant presence of HBsAg and HBeAg provides a continuous T cell receptor (TCR) signal (Signal 1) often in the absence of adequate costimulation (Signal 2) and inflammatory cytokines (Signal 3).32,33 This chronic “Signal 1” stimulation triggers a sustained intracellular calcium flux that, distinct from acute activation, leads to the nuclear accumulation of “partnerless” Nuclear factor of activated T cells (NFAT) homodimers which preferentially bind to the regulatory regions of exhaustion associated genes rather than effector cytokine promoters.34 Specifically, HBsAg, often circulating at extremely high concentrations in the form of subviral particles, acts as a “high dose tolerogen” that can physically delete high avidity T cell clones or drive surviving cells into deep exhaustion through receptor over stimulation.35,36 Concurrently, HBeAg functions as a soluble tolerogen that traverses the placenta to induce neonatal tolerance and, in adults, actively suppresses innate signaling pathways such as TLR2, further depriving T cells of the inflammatory context required for functional differentiation.37–39 This persistent antigenic pressure creates a feedback loop where the threshold for T cell activation is progressively raised, rendering the cells inert to the virus they are meant to eliminate.

Collectively, these findings highlight persistent antigen exposure as a dominant driver of T cell exhaustion. However, they also suggest that therapeutic strategies that primarily reduce viral antigen levels may indirectly alleviate exhaustion without necessarily reprogramming T cell intrinsic dysfunction.

Redundancy in Inhibitory Receptor Networks

To restrain the chronic overstimulation driven by persistent antigen, HBV specific T cells progressively upregulate a hierarchy of inhibitory receptors (IRs) that function synergistically to dampen TCR signaling.38 While PD-1 is the hallmark of this state, its expression alone often signifies a reversible stage; however, in CHB, PD-1 is frequently co expressed with T cell Immunoglobulin and TIM-3, LAG-3, CTLA-4, and CD244 (2B4), marking a terminal exhaustion phenotype.38,40,41 These receptors do not operate in isolation but converge on shared intracellular nodes to enforce silence. For instance, PD-1 ligation recruits the phosphatase SHP-2 to dephosphorylate proximal TCR signaling molecules like ZAP70,40,42 while TIM-3 and LAG-3 target distinct downstream pathways, creating a redundant “fail-safe” mechanism that prevents activation.8,43 Consequently, blocking a single receptor (eg, PD-1) is often insufficient to restore function in terminally exhausted cells because the remaining receptors (eg, TIM-3) maintain the inhibitory threshold This synergistic network explains the limited efficacy of monotherapy and necessitates combined checkpoint blockade to release the T cell from this multifaceted brake.

Transcriptional Rewiring and Epigenetic Scarring

The phenotypic and functional defects of exhausted T cells are hardwired by a maladaptive transcriptional program distinct from that of effector or memory cells. Central to this program is the high mobility group box transcription factor TOX, which is induced by chronic TCR stimulation and calcineurin NFAT signaling.44,45 TOX acts as a master regulator that translates persistent antigen stimulation into a stable exhausted fate by repressing genes associated with stemness (such as TCF-1) and sustaining the high expression of inhibitory receptors like PD-1 and TIM-3.45–47 Working in concert with the NR4A family of transcription factors (NR4A1, NR4A2, NR4A3), TOX prevents the apoptosis of chronically stimulated cells, allowing them to persist but at the cost of their effector function.38,44 In the context of HBV, this transcriptional rewiring is further modulated by liver specific signals, such as the LSEC induced cAMP-PKA pathway that activates the transcriptional repressor CREM/ICER, which directly binds to and silences the promoters of key cytokine genes, thereby solidifying a state of transcriptional unresponsiveness that is refractory to standard stimulation.5 These maladaptive transcriptional networks are intimately linked to and cemented by profound alterations at the chromatin level. The barrier to functional cure in CHB is thus reinforced by “epigenetic scarring”, a phenomenon where the exhausted state becomes fixed in the chromatin landscape of the T cell.24,48 Chronic stimulation induces stable changes in chromatin accessibility, where gene loci encoding effector molecules (eg, IFNG, GZMB) become progressively heterochromatized and inaccessible, while regulatory regions for exhaustion factors (TOX, PDCD1) remain constitutively open due to demethylation.45,49 Crucially, studies utilizing ATAC-seq have demonstrated that these epigenetic scars, particularly at super enhancers associated with TOX and HIF1A, persist even after the viral antigen is removed or suppressed by NAs therapy, rendering the cells refractory to rejuvenation.45,50 This epigenetic fixity explains why exhausted T cells often fail to differentiate into functional memory cells even after viral clearance, and why checkpoint blockade alone may yield only transient responses, as the underlying chromatin architecture remains locked in a dysfunctional configuration.

Metabolic Collapse and Mitochondrial Dysfunction

Metabolic failure is a core feature of HBV associated T cell exhaustion, characterized by the inability of T cells to generate the bioenergetic fuel required for antiviral activity. Exhausted HBV specific CD8+ T cells exhibit severe mitochondrial defects, including depolarization of the mitochondrial membrane and accumulating dysfunctional mitochondrial mass that produces excessive reactive oxygen species (ROS) rather than ATP.6,51 This mitochondrial collapse creates a “metabolic lock” mediated by the stabilization of Hypoxia Inducible Factor 1 alpha (HIF-1α); unlike in effector cells where HIF-1α supports glycolysis for proliferation, in exhausted cells, ROS stabilized HIF-1α prevents the utilization of fatty acid oxidation and oxidative phosphorylation, trapping the cells in an inefficient glycolytic state despite the availability of oxygen.6,51,52 Furthermore, the repression of the mitochondrial biogenesis regulator PGC-1α prevents the renewal of healthy mitochondria, leaving the T cells metabolically inflexible and unable to meet the energetic demands of cytotoxicity or cytokine production upon antigen encounter.53,54

The Tolerogenic Hepatic Microenvironment

The hepatic microenvironment imposes a unique layer of suppression on T cells, driven by the liver’s physiological role as a tolerogenic organ designed to prevent reactions against gut derived antigens. This local tolerance is orchestrated by LSECs and Kupffer cells (KCs), which establish an immunosuppressive niche that is co-opted by HBV.55,56 A recently elucidated mechanism, termed the “liver immune rheostat”, reveals that LSECs actively tune down CD8+ T cell responses through a contact dependent activation of the cAMP-PKA-CREM signaling axis within the T cells, which directly represses effector genes like IFNG and IL2 regardless of the antigen load.5 This active suppression is compounded by the accumulation of Tregs and myeloid derived suppressor cells (MDSCs) in the CHB liver, which secrete inhibitory cytokines (IL-10, TGF-β) and express enzymes like Indoleamine 2,3-dioxygenase (IDO) and Arginase-1.57,58 These enzymes deplete the microenvironment of essential amino acids (tryptophan and arginine), creating a “metabolic desert” that triggers stress response pathways in T cells (eg, GCN2 activation), leading to cell cycle arrest and reinforcing the exhausted phenotype dictated by the tissue resident machinery.59,60 Together, these persistent antigenic drivers, inhibitory receptor networks, metabolic and epigenetic derangements, and hepatic microenvironmental cues form an integrated network sustaining HBV-specific T cell exhaustion (Figure 2).

Figure 2.

Integrated signaling networks and microenvironmental cues orchestrating HBV-specific T cell exhaustion.

Notes: Red cross marks (X) denote blocked signaling events: absence of CD28-mediated costimulation (left) and SHP-2–mediated inhibition of TCR proximal signaling downstream of PD-1 (right). Numbered labels 1–5 correspond to the five interconnected mechanisms of HBV-specific CD8⁺ T cell exhaustion described in the text.

Abbreviations: HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; TCR, T cell receptor; PD-1, programmed cell death protein 1; TIM-3, T cell immunoglobulin and mucin domain-containing protein 3; LAG-3, lymphocyte activation gene 3; CTLA-4, cytotoxic T lymphocyte-associated protein 4; TOX, thymocyte selection-associated high mobility group box; HIF-1α, hypoxia-inducible factor 1-alpha; ROS, reactive oxygen species; Tregs, regulatory T cells; MDSCs, myeloid-derived suppressor cells; LSECs, liver sinusoidal endothelial cells.

These interconnected mechanisms provide the conceptual framework for interpreting the therapeutic effects of TCM in CHB. A TCM intervention can be mechanistically linked to T cell exhaustion only when its effects can be positioned on one or more of the exhaustion-related axes identified above, namely the reduction of persistent HBV antigenic load and chronic TCR stimulation, the modulation of inhibitory receptor and costimulatory networks, the restoration of mitochondrial and proteostatic fitness, the attenuation of transcriptional or epigenetic programs that stabilize exhaustion, and the remodeling of the tolerogenic hepatic microenvironment. This distinction is essential because inhibition of HBV replication may indirectly relieve antigen-driven exhaustion, whereas true reprogramming of exhausted HBV-specific T cells requires evidence of restored effector function together with changes in exhaustion markers, transcription factors, or chromatin states. Accordingly, the following sections classify TCM-derived phytochemicals and compound formulas according to these mechanistic axes (Table 1).

Table 1.

Mechanism-Based Mapping of TCM-Derived Phytochemicals to the Five Exhaustion-Related Axes of HBV-Specific T Cell Dysfunction

Exhaustion-Related Axis	Key Molecular Readouts	Representative TCM-Derived Compounds	Reference
Reduction of persistent HBV antigenic load and chronic TCR stimulation	HBsAg↓, HBeAg↓, HBV DNA↓, cccDNA↓; relief of chronic Signal 1	Astragalin; Ginsenoside Rh4; Quercetin; Kaempferol; Chlorogenic acid; Caffeic acid; Myricetin; Swertilactones H–K; Saikosaponins C; Schisandra lignans; Astragaloside IV; EGCG; Oxymatrine; Sophoridine; Matrine; Evodiamine; Berberine	[11,61–80]
Modulation of inhibitory receptor and costimulatory networks	MHC/CD40/CD80/CD86↑ on DCs; IL-10↓, TGF-β↓; restored IFN-γ output	Astragalus polysaccharides (APS); Sophoridine; Radix isatidis polysaccharides (RIP)	[66,67,76,81–87]
Restoration of mitochondrial and proteostatic fitness	Mitochondrial ΔΨm↑, ATP↑, ROS↓; UBXN7-mediated autophagy control	Oleuropein; Resveratrol; Ursolic acid; Astragaloside IV	[71,88–95]
Attenuation of transcriptional or epigenetic programs stabilizing exhaustion	TOX↓, NR4A↓; HNF4α/HNF1α axis suppression; CEBPA-SP2 downregulation; cGAS-STING activation	Resveratrol; EGCG; Luteolin; Baicalin; Myricetin; Schisandrin C	[65,70,74,88,89,91,96–104]
Remodeling of the tolerogenic hepatic microenvironment	Treg↓; M1 macrophage polarization↑; Fas/FasL rebalancing; TBK1/IKKε/IRF3 activation	Astragalus polysaccharides (APS); Polyporus umbellatus polysaccharide (PUPS); Evodiamine; Ginsenoside Rg3; Ginsenoside Rg1; Oxymatrine	[8,10,78,81,105–114]

Notes: ↑, upregulation or activation; ↓, downregulation or suppression.

Abbreviations: TCM, traditional Chinese medicine; EGCG, epigallocatechin gallate; APS, Astragalus polysaccharides; PUPS, Polyporus umbellatus polysaccharide; RIP, Radix isatidis polysaccharides; TOX, thymocyte selection-associated high mobility group box; UBXN7, UBX domain-containing protein 7; cGAS-STING, cyclic GMP-AMP synthase–stimulator of interferon genes.

Molecular Mechanisms: TCM Derived Phytochemicals in Rescuing T Cell Function

Distinct from single target therapeutics, bioactive phytochemicals derived from TCM dismantle the complex network of T cell exhaustion through a pleiotropic, multi target approach. These compounds, ranging from flavonoids and terpenoids to alkaloids and polysaccharides, exert their immunomodulatory effects by directly engaging specific molecular pathways. By systematically targeting the core drivers of exhaustion, including persistent antigen stimulation, inhibitory receptor networks, metabolic collapse, transcriptional dysregulation, and hepatic immunosuppression, these agents collaboratively restore the antiviral efficacy of HBV specific CD8+ T cells. The precise molecular targets and pathways modulated by these phytochemicals are elucidated below and systematically summarized in Table 2.

Table 2.

Pharmacological Mechanisms of Traditional Chinese Medicine Bioactive Phytochemicals Targeting T Cell Exhaustion in Chronic Hepatitis B

Classification	Compounds	Source	Molecular Formula	Chemical Structure	Dosage of Drugs Used	Cell Lines or Animal Type	Main Indicators	Mechanisms	References
Flavonoids	Astragalin	Astragalus sinicus	C21H20O11		0.5μM, 25μM, 50μM, 100μM, 200μM, 500μM; 20 mg/kg	HepG2.2.15 cells; C57BL/6 mice (HBV carrier model)	HBV DNA ↓, HBsAg ↓	Directly suppresses HBV replication to reduce persistent antigen burden and alleviate T cell exhaustion	[61]
	Quercetin	Hippophae rhamnoides	C15H10O7		10 μg/mL	HepG2.2.15, Huh7 cells	HBeAg ↓, HBsAg ↓	Forms stable complexes with HBV polymerase to halt replication, reducing antigen-driven T cell exhaustion	[63]
					0.1μmol/L, 1μmol/L, 10μmol/L, 25μmol/L, 50μmol/L, 100μmol/L,	HepG2.2.15, HepAD38 cells	HBV DNA ↓, HBeAg↓, HBsAg ↓	Inhibits HBV replication to relieve T cell overstimulation and exhaustion	[62]
	Kaempferol	Hippophae rhamnoides	C15H10O6		10µg/mL	HepG2.2.15 cells	HBeAg↓, HBsAg ↓	Inhibits HBV replication to relieve T cell overstimulation and exhaustion	[63]
	Epigallocatechin gallate (EGCG)	Green tea	C22H18O11		12.5μM, 25μM, 50μM	HepG2.2.15 cells	ERK1/2 MAPK signaling pathway ↑, HNF4α ↓, HBV DNA ↓, HBV core promoter ↓, HBeAg ↓, HBsAg ↓	Modulates the ERK1/2-HNF4α axis to inhibit viral transcription, lowering antigen load to mitigate T cell exhaustion	[74]
					5μM, 10μM, 20μM; 50 mg/kg	HepG2.2.15 cells; HBV transgenic mice	HBV DNA ↓, HBsAg ↓, HBcAg ↓	Inhibits HBV replication to relieve T cell overstimulation and exhaustion	[97]
	Luteolin	Reseda odorata L.	C15H10O6		5μM, 10μM, 20μM, 40μM; 20 mg/kg	HepG2.2.15 cells; C57BL/6 mice (HBV carrier model)	HBV DNA ↓, HBeAg↓, HBsAg ↓, MAPK/ERK signaling pathway ↑, HNF4α ↓	Significantly inhibits HBV replication via ERK-mediated downregulation of HNF4α, reducing antigenic load to alleviate T cell exhaustion	[103]
					5μM, 10μM, 20μM, 40μM, 80μM, 100μM; 5 mg/kg, 10 mg/kg, 20 mg/kg	HepG2.2.15 cells	HBV DNA ↓, HBeAg↓, HBsAg ↓, ERK and JNK signaling pathway ↑, HNF4α ↓	Utilizes ERK-mediated HNF4α downregulation to inhibit transcription, curtailing antigen-induced T cell exhaustion	[98]
	Myricetin	Morella rubra Lour.	C15H10O8		10μM, 20μM, 40μM; 20 mg/kg	HepG2.2.15 cells; HBV transgenic mice	CEBPA ↓, HBV DNA ↓	Suppresses viral promoter activity via targeted downregulation of CEBPA, decreasing antigen load to prevent T cell exhaustion	[65]
	Baicalin	Scutellaria baicalensis Georg	C21H18O11		12.5μM, 25μM, 50μM, 100μM, 200μM, 400μM; 10 mg/kg	pHBV1.2-HepG2 cells; HBV transgenic mice	HNF4α/HNF1α axis ↓, HBV DNA ↓	Downregulates the liver-specific HNF4α-HNF1α axis to directly inhibit viral transcription	[100]
					50μM, 100μM; 10 mg/kg, 20 mg/kg, 40 mg/kg	pHBV1.2-HepG2 cells; HBV transgenic mice	AMPKα ↑, HNF1α ↓	Activates the ERα-AMPKα signaling cascade to reinstate cellular metabolic homeostasis	[99]
					12.5μM, 25μM, 50μM	pHBV1.2-HepG2 cells; pHBV1.3-HepG2 cells	TRIM25 ↑, HBV DNA ↓	Targets TRIM25 to suppress HBV replication and restore functional fitness in exhausted T cells	[91]
Terpenoids	Ginsenoside Rh4	Panax notoginseng	C36H60O8		3.12μM, 6.25μM, 12.5μM, 25μM, 50μM, 100μM	HepG2.2.15 cells, HBV-infected HepG2-NTCPsec+ cells	HBV mRNA ↓, HBsAg ↓	Inhibiting HBx-mediated autophagy, indirectly restoring the metabolic balance of exhausted T cells	[11]
	Ursolic acid	Prunella vulgaris L.	C30H48O3		20μM	HepG2.2.15, Huh7 cells	RhoA ↓, Autophagy ↓	Prevents the degradation of UBXN7 to suppress HBx-mediated autophagy, indirectly reinstating metabolic balance in exhausted T cells	[92]
	Ginsenoside Rg3	Panax ginseng C. A. Mey.	C42H72O13		50μM, 100μM	HepG2.2.15 cells	DDX3 ↑, IFN-β ↑, TBK1/IKKε/IRF3 signaling pathway ↑	Activates the TBK1/IKKε/IRF3 innate immune axis to counteract hepatic tolerance and rejuvenate exhausted T cells	[110]
					10μM, 50μM, 100μM, 200μM	HepG2.2.15 cells	TRAF6/TAK1 signaling pathway ↓, JNK/AP-1 signalling pathway ↓	Promotes the degradation of TRAF6/TAK1 and inhibits JNK/AP-1 signaling to suppress HBV activity, diminishing the antigen load driving T cell exhaustion	[109]
	Ginsenoside Rg1	Panax ginseng C. A. Mey.	C42H72O14		50μg, 100μg	BALB/c mice (HBV-carrier model)	IgG2b ↑, IFN-γ ↑, IgG1 ↑, IL-4 ↑	Acts as an adjuvant to facilitate T cell activation and cytokine secretion, directly reversing the exhausted T cell phenotype	[113]
	Astragaloside IV	Astragalus membranaceus	C41H68O14		60 mg/kg	C57BL/6 mice (HBV-carrier model)	M1 macrophages ↑, HBsAg ↓	Promotes macrophage M1 polarization to support a pro-inflammatory microenvironment essential for exhausted T cell recovery	[93]
					40μg/mL, 100μg/mL, 200μg/mL	HepG2.2.15 cells, DHBV-infected ducks	HBsAg ↓, HBeAg ↓, DHBV DNA ↓	Directly suppresses viral replication and antigen secretion to reduce the antigen load driving T cell exhaustion	[71]
	Swertilactones H-K	Swertia mileensis	N/A	N/A	400μM, 1.53–5.34μM	HepG2.2.15 cells	HBsAg ↓, HBeAg ↓, HBV DNA ↓	Directly lowers the persistent antigen load, mitigating the primary driver of T cell exhaustion	[68]
	Saikosaponins C	Bupleurum spp.	C48H78O17		2.5μg/mL, 5μg/mL, 10μg/mL, 20μg/mL, 40μg/mL	HepG2.2.15 cells	HBsAg ↓, HBeAg ↓, HBV DNA ↓	Directly lowers the persistent antigen load, mitigating the primary driver of T cell exhaustion	[69]
Lignans	Schisandra lignans	Schisandra wilsoniana	N/A	N/A	5 μg/mL	HepG2.2.15 cells	HBsAg ↓, HBeAg ↓	Directly lowers the persistent antigen load, mitigating the primary driver of T cell exhaustion	[70]
	Schisandrin C	Schisandra chinensis	C22H24O6		5μM, 10μM, 20μM; 20mg/kg	HepG2.2.15 cells; C57BL/6 mice (HBV carrier model)	cGAS ↑, STING ↑, IFN-β↑, HBeAg ↓, HBsAg ↓	Synergistically activates the cGAS-STING pathway to enhance antiviral immunity and rescue T cells from exhaustion	[103]
					15mg/kg, 30mg/kg	C57BL/6 mice (HBV carrier model)	cGAS-STING signaling pathway ↑, IFN-β↑	Synergistically activates the cGAS-STING pathway to reverse the tolerogenic niche and T cell exhaustion	[104]
Alkaloids	Oxymatrine	Sophora flavescens	C15H24N2O2		15mg/kg, 30mg/kg, 15mg/kg	C57BL/6 mice (HBV carrier model)	HBsAg ↓, HBeAg ↓, IFN-γ ↑	Promotes IFN-γ production in CD4+ T cells to accelerate viral antigen clearance, relieving chronic T cell overstimulation	[114]
					10μg/mL, 100μg/mL, 1000μg/mL	HepG2.2.15 cells	HBV DNA ↓, HBsAg ↓, HBeAg ↓, p-ERK1/2 ↑, HNF1α ↓, HNF4α ↓	Upregulates p-ERK1/2 and downregulates HNF1α/HNF4α to inhibit viral replication and antigen secretion, thereby relieving chronic T cell overstimulation	[75]
	Matrine	Sophora flavescens	C15H24N2O		20mg/kg	HepG2.2.15 cells, DHBV-infected ducks	DHBV DNA ↓, HBsAg ↓	Indirectly reduces the secretion of viral antigens, thereby alleviating chronic T cell overstimulation	[77]
	Evodiamine	Evodia rutaecarpa	C19H17N3O		5mg/kg, 10mg/kg	HBV transgenic mice	Fas/FasL signaling pathway ↓	Modulates inflammatory stress and Fas/FasL signaling to preserve T cell viability and prevent exhaustion-induced apoptosis	[78]
	Berberine	Coptis rhizome	C20H18NO4		5μM, 10μM, 20μM, 40μM	HepG2.2.15cells	HNF4α ↓	Induces K48-linked polyubiquitination and proteasomal degradation of HNF4α, inhibiting viral transcription to ease T cell exhaustion	[80]
	Sophoridine	Sophora flavescens Alt	C15H24N2O		0.2mM, 0.4mM, 0.8mM, 1.6mM, 3.2mM, 6.4mM	HepG2.2.15 cells	HBV DNA ↓, HBsAg ↓, HBeAg ↓, p38 MAPK ↓, TRAF6 ↓	Downregulates p38 MAPK and TRAF6 to inhibit viral replication and antigen secretion, easing antigen-driven T cell exhaustion	[115]
Polysaccharides	Astragalus polysaccharides (APS)	Astragalus membranaceus	N/A	N/A	500μg	BALB/c mice (HBV-carrier model)	Tregs ↓	Reduces the frequency of abnormally accumulated regulatory T cells, relieving extrinsic suppression on exhausted CD8+ T cells	[10]
					50mg/mL	C57BL/6 mice (HBV carrier model)	MHC I/II ↑, CD40 ↑, CD80 ↑, CD86 ↑, Tregs ↓, IFN-γ ↑, CTL ↑	Stimulates dendritic cell maturation and reduces Treg frequency to enhance HBV-specific T cell proliferation and effector functions, overcoming the tolerogenic niche and T cell exhaustion	[82]
					287.95 mg/kg	HBV transgenic mice	HBV DNA ↓, HBsAg ↓, HBeAg ↓,	Exhibits persistent inhibitory effects on HBV replication and antigen secretion, diminishing the antigen load to mitigate T cell exhaustion	[67]
	Radix isatidis polysaccharides (RIP)	Isatis indigotica Fortune	N/A	N/A	50μg/mL, 100μg/mL, 200μg/mL	HepG2.2.15 cells	IFN-α ↑, JAK/STAT ↑, SOCS-1/3 ↓	Activates IFN-α-dependent JAK/STAT signaling and downregulates SOCS-1/3 to circumvent inhibitory barriers and reverse T cell exhaustion	[87]
	Polyporus umbellatus polysaccharide (PUPS)	Polyporus umbellatus	N/A	N/A	N/A	HepG2.2.15 cells, clinical patients	HBV replication ↓, Phagocytosis ↑, T cell activation ↑	Inhibits HBV replication by enhancing macrophage phagocytic ability and directly activating T lymphocytes, systematically overcoming immune exhaustion	[107]
Phenolic acids	Chlorogenic acid	Lonicera japonica Thunb.	C16H18O9		40μM; 100mg/kg	HepG2.2.15 cells, DHBV-infected ducks	HBV DNA ↓	Directly suppresses HBV replication to reduce the antigen load driving T cell exhaustion	[64]
	Caffeic acid	Salvia miltiorrhiza Bge.	C9H8O4		20μM, 40μM; 100mg/kg	HepG2.2.15 cells, DHBV-infected ducks	HBV DNA ↓	Directly suppresses HBV replication to reduce the antigen load driving T cell exhaustion	[64]
Anthraquinones	Emodin	Rheum palmatumL.	C15H10O5		57.59mg/kg	C57BL/6 mice (HBV carrier model)	HBV DNA ↓, HBsAg ↓, HBeAg ↓,	Exhibits persistent inhibitory effects on HBV replication and antigen secretion, diminishing the antigen load to mitigate T cell exhaustion	[67]
					18.75μM, 37.5μM, 75μM, 150μM, 300μM	HepG2.2.15 cells	HSP90AA1 ↓, MAPK3 ↓	Directly downregulates exhaustion-associated molecules (HSP90AA1, MAPK3) to restore T cell function	[85]
					5mg/kg, 10mg/kg	HepG2.2.15 cells	HBV DNA ↓, HBsAg ↓, HBeAg ↓,	Exhibits persistent inhibitory effects on HBV replication and antigen secretion, diminishing the antigen load to mitigate T cell exhaustion	[66]
Phenylethanoids	Oleuropein	Canarium spp.	C25H32O13		100μM	Exhausted CD8+ T cells	ATP ↑	Directly reverses mitochondrial impairment and depolarization, reinstating metabolic fitness in exhausted T cells	[88]
Stilbenoids	Resveratrol	Veratrum	C14H12O3		12.5μM, 25μM, 50μM, 100μM, 150μM, 200μM,	HepG2.2.15 cells	miR-155 ↓, Autophagy ↑, HBV replication ↓	Inhibits miR-155 and activates autophagy to suppress HBV replication, diminishing the persistent antigen load that drives T cell exhaustion	[102]

Notes: ↑, upregulation or activation; ↓, downregulation or suppression. Bold text indicates phytochemical classification. N/A, not available.

Abbreviations: HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBcAg, hepatitis B core antigen; DHBV, duck hepatitis B virus; EGCG, epigallocatechin gallate; APS, Astragalus polysaccharides; PUPS, Polyporus umbellatus polysaccharide; RIP, Radix Isatidis polysaccharide; HNF1α/HNF4α, hepatocyte nuclear factor 1-alpha/4-alpha; cGAS-STING, cyclic GMP-AMP synthase–stimulator of interferon genes; IFN, interferon; Tregs, regulatory T cells.

Attenuating Persistent Antigenic Load

Persistent antigen load is recognized as a primary driver of T cell exhaustion. Viral replication is directly inhibited by various individual phytochemicals, thereby reducing the antigen burden. Specifically, HBV replication is directly suppressed by astragalin,61 while viral mRNA expression is independently interfered with and viral antigen secretion is suppressed by ginsenoside Rh4.11 The antiviral effect is similarly achieved by quercetin62,63 and kaempferol,63 as well as by chlorogenic acid and caffeic acid.64 HBV DNA is also directly suppressed by myricetin65 and emodin, with the latter concurrently modulating exhaustion markers.66,67 This inhibitory spectrum is further expanded by terpenoids and lignans. For instance, the persistent antigen load is directly lowered by swertilactones H-K,68 saikosaponins C,69 and schisandra lignans.70 Furthermore, viral replication and antigen secretion are markedly suppressed by astragaloside IV, as evidenced in both in vitro and in vivo Duck hepatitis B virus (DHBV) models.71 Viral entry into hepatocytes is distinctly blocked by epigallocatechin gallate (EGCG) through the targeted modulation of the sodium taurocholate cotransporting polypeptide (NTCP) receptor,72,73 while its transcriptional inhibition further lowers antigen levels.74 Furthermore, the secretion of HBsAg and HBeAg is indirectly reduced by alkaloids. Specifically, viral replication and antigen secretion are suppressed by oxymatrine through the upregulation of p-ERK1/2 and the subsequent downregulation of hepatic transcription factors HNF1α and HNF4α.75 Similarly, sophoridine diminishes viral replication and antigen levels by downregulating p38 MAPK and TRAF6 signaling.76 This antigen reduction is also achieved by matrine, whose efficacy is robustly supported by established surrogate models like DHBV.77 Antigenic burden is also mitigated by evodiamine.78 Finally, the core promoter activity of HBV is directly inhibited by berberine through the K48-linked polyubiquitination and subsequent proteasomal degradation of HNF4α, preventing excessive viral transcription.79,80 Through these diverse mechanisms, the chronic overstimulation of T cells is effectively alleviated.116 However, it is important to note that such improvements are likely to be indirect consequences of reduced antigen exposure rather than evidence of direct reversal of intrinsic exhaustion programs. Distinguishing between these possibilities remains a major challenge in current studies.

Modulating Inhibitory Checkpoint Networks

The progressive upregulation of inhibitory receptors marks the terminal phase of T cell exhaustion. T cell function is preserved by modulating these receptor networks. Antigen presentation is indirectly enhanced by APS through the targeted upregulation of MHC molecules and vital costimulatory signals (CD40, CD80, CD86) on dendritic cells, which are essential for robust immune recognition.81–83 Excessive immunosuppressive cytokines, such as IL-10 and TGF-β, are reduced by sophoridine, which indirectly restores T cell activation thresholds.76,84 Moreover, exhaustion associated molecules, including HSP90AA1 and MAPK3, are directly downregulated by emodin, illustrating its multi target capacity alongside its aforementioned direct antiviral properties.66,67,85 Type I interferon production is indirectly promoted by radix isatidis polysaccharides (RIP) via the activation of the IFN-α-dependent JAK/STAT signaling pathway, effectively circumventing inhibitory barriers by downregulating negative regulators such as SOCS-1 and SOCS-3.86,87 Nevertheless, most of these findings are derived from in vitro experiments or non-HBV specific disease models, and their relevance to HBV specific CD8+ T cell exhaustion remains to be fully established. Moreover, changes in systemic or hepatic cytokine profiles may indirectly influence T cell function without directly targeting exhaustion associated pathways. Therefore, while TCM exhibits immunomodulatory potential, current evidence does not clearly delineate whether these effects translate into direct restoration of exhausted T cell function in vivo.

Restoring Metabolic and Mitochondrial Homeostasis

Metabolic failure deprives exhausted T cells of essential bioenergetic resources. Metabolic homeostasis is restored by specific phytochemicals. Mitochondrial impairment and depolarization in exhausted T cells are directly reversed by oleuropein88 and resveratrol,89 reinstating ATP production and metabolic fitness. Autophagy mediated by the HBV X protein is suppressed by ursolic acid, which specifically prevents the degradation of UBXN7 and indirectly reinstates transcriptional and metabolic balance.90–92 Additionally, macrophage M1 polarization is promoted by astragaloside IV.71,93 This effect is driven via the activation of the cGAS-STING pathway,94 indirectly supporting the pro-inflammatory metabolic microenvironment required for antiviral T cell proliferation.95 Given that metabolic insufficiency is a hallmark of exhausted T cells, such effects could theoretically contribute to functional restoration. However, most available data are derived from general immune or cancer models rather than HBV specific T cells. In addition, the extent to which these metabolic changes occur in vivo at pharmacologically achievable concentrations remains unclear.

Remodeling Transcriptional and Epigenetic Landscapes

Stable epigenetic scars and transcriptional dysregulation lock T cells in a dysfunctional state. These maladaptive networks are targeted by multiple compounds. The TOX/NR4A signaling axis is mitigated by resveratrol, reflecting a pleiotropic mechanism that intimately complements its role in metabolic restoration.88,89,96 HBV transcription and associated immune dysregulation are directly inhibited by highly pleiotropic compounds through distinct pathways. Specifically, the ERK1/2-HNF4α axis is modulated by EGCG, further highlighting its multi target profile.74,97 In parallel, ERK-mediated HNF4α downregulation is utilized by luteolin.98 Additionally, antiviral immunity is supported by baicalin, a remarkably versatile flavonoid, which enhances antiviral responses by targeting TRIM25.91 Furthermore, cellular metabolic homeostasis is promoted by baicalin via the ERα-AMPKα signaling cascade,99 while viral transcription is directly repressed through the modulation of the liver specific HNF4α-HNF1α axis.100 Viral promoter activity is suppressed by myricetin via the targeted downregulation of CEBPA, which otherwise binds the SP2 promoter to sustain viral expression.65,101 Furthermore, the cGAS-STING pathway, often suppressed by HBV, is synergistically activated by phytochemicals in macrophages; this activation is independently driven by luteolin, exhibiting dual action efficacy,102,103 and by schisandrin C,70,104 indirectly enhancing antiviral transcriptional responses and type I interferon production.

Overcoming Hepatic Immunosuppression

The tolerogenic hepatic microenvironment enforces T cell suppression. This immunosuppressive niche is remodeled by targeted phytochemical interventions. The frequency of abnormally accumulated Tregs is reduced by APS.10,81 This intervention relieves indirect immunosuppression on CD8+ T cells,105 demonstrating the broad spectrum immunomodulatory nature of APS across different immune subsets.106 Macrophage phagocytic ability and subsequent B cell antibody production are enhanced by polyporus umbellatus polysaccharide (PUPS).107 Inflammatory stress and Fas/FasL signaling, pathways abnormally activated during infection, are modulated by evodiamine (displaying multi target effects alongside antigen reduction), preserving T cell viability.8,78,108 The TBK1/IKKε/IRF3 innate immune axis is activated by ginsenoside Rg3.109,110 This precise activation is achieved via the Akt/p53 pathway111 alongside targeted DDX3 RNA helicase stimulation.112 Additionally, T cell activation and the secretion of critical cytokines such as IFN-γ and IL-2 are facilitated by ginsenoside Rg1, acting as an adjuvant,113 and by oxymatrine, which promotes IFN-γ production specifically in CD4+ T cells.114

In summary, phytochemicals derived from TCM exhibit a wide range of biological activities, which may collectively influence T cell dysfunction associated with the HBV. However, these effects are likely achieved through a combination of antiviral and indirect immunomodulatory mechanisms. The mechanisms of action of various active ingredients inTCM are shown in Figure 3.

Figure 3.

Pleiotropic modulation of T cell exhaustion signaling networks by bioactive TCM components.

Notes: Each colored quadrant represents one class of TCM-derived phytochemicals acting on HBV-specific CD8⁺ T cells; colored arrows indicate the direction of pharmacological action from each class to its target.

Abbreviations: TCM, traditional Chinese medicine; EGCG, epigallocatechin gallate; APS, Astragalus polysaccharides; PUPS, Polyporus umbellatus polysaccharide; RIP, Radix Isatidis polysaccharide; cGAS-STING, cyclic GMP-AMP synthase–stimulator of interferon genes; IFN, interferon; MHC, major histocompatibility complex; JAK/STAT, Janus kinase–signal transducer and activator of transcription; Tregs, regulatory T cells.

Systems Pharmacology: Synergistic Immunomodulation by TCM Compound Formulas

The active components of TCM formulas are proposed to exert anti HBV effects through the combined actions of multiple constituents. These effects may involve the modulation of pathways associated with T cell exhaustion, although whether such improvements reflect direct reprogramming of exhausted T cells or are secondary to reduced antigenic burden remains unclear. The available clinical and preclinical evidence, together with primary outcomes and proposed mechanisms of representative formulations, are summarized in Table 3.

Table 3.

Preclinical Evidence of TCM Compound Formulas and Patent Drugs in Alleviating HBV-Specific T Cell Exhaustion

Formula	Effect	Mechanism	Model	Ref
Baqi Lingmao Formula	Inhibit hepatitis B virus replication, protect the liver, reduce inflammation	Regulate PI3K-Akt pathway, modulate inflammatory cytokines and oxidative stress	Hep G2.2.15 cells	[117,118]
Lingmao Formula	Enhance HBV-related immune responses whilst suppressing the release of pro-inflammatory factors	Reduced expression of TNFα, IL-1β and IL-6 and act upon the PPAR signalling pathway	C57BL/6N-HBV hydrodynamic transfection model	[119,120]
Fuzheng Qudu Decoction	Inhibit HBV replication, protect liver, regulate cellular immunity	Regulate Th1/Th2 balance, modulate related cytokines	HBV-transgenic mice	[121,122]
Bushen Jiedu prescription	Enhance anti-HBV immunity, regulate T lymphocyte function	Block PD-1/PD-L1 pathway, promote IFN-γ secretion	HBV-transgenic mice	[123]
Qingre Lishi Huoxue Formula	Inhibit HBV replication, protect liver tissue, enhance immunity	Activate TLR4-IRF3-IFN signaling pathway, promote IFNα/β secretion	HBV-transgenic mice	[124]
Bushen Qingdu Decoction	Regulate immunity, reduce inflammatory response, assist anti-HBV	Increase IFN-γ level, decrease IL-17A expression	HBV-transgenic mice	[125]
Fuzheng Huayu Capsule	Inhibit HBeAg production, promote HBeAg seroconversion, anti-hepatic fibrosis	Promote TOMM34 gene expression (via quercetin, baicalin, cordycepin)	HBV-transgenic mice	[126]
Yinchenhao decoction	Reduce HBeAg/ALT/AST levels, ameliorate liver injury and lipid deposition	Regulate bile acid, arachidonic acid and retinol metabolism	CHB mouse model induced by rAAV-HBV1.3 hydrodynamic injection + high-fat diet + ANIT	[127]
Xiaochaihu Decoction	Inhibit HBV replication, reduce liver fibrosis, protect liver function	Suppress collagen I synthesis and mRNA expression; inhibit HBsAg secretion; regulate immune response	Hep G2.2.15 cells	[128]
Longchai Formula	Enhance entecavir’s anti-HBV effect, reduce HBV DNA/HBsAg/HBeAg levels	Up-regulate PTEN protein, inhibit PI3K/AKT pathway, down-regulate P-gp expression	Hep G2.2.15 cells	[129]
Le Cao Shi Formula	Inhibit HBsAg/HBeAg secretion, reduce HBV-DNA/AST/ALT levels, ameliorate liver injury	Synergistic action of flavonoids and phenylethanoid glycosides (key active components)	Hep G2.2.15 cells and Duck hepatitis B virus-infected shelduck model	[130]
TCM formula invigorating the spleen and kidney	Promote HBsAg seroclearance, induce intrahepatic macrophage M1 polarization	Regulate gut microbiota (increase Alloprevotella abundance), mediate gut-liver axis to enhance antiviral immunity	Model induced by pAAV-HBV1.2 hydrodynamic injection	[131]
Liuweiwuling Tablet	Inhibit wild-type/entecavir-resistant HBV, suppress HBV antigens/DNA/pgRNA, induce selective apoptosis of HBV-replicating cells	Activate IFN-β/IFN-γ pathways, enhance CD3+CD4+ T cell frequency; Regulate apoptosis-related pathways (PI3K-AKT, CASP8-CASP3, P53) and metabolites; Synergistic action of active components (quercetin, luteolin, wogonin, kaempferol)	HepG2.2.15, HepG2.A64 and HepG2.1403F cells; model induced by pAAV-HBV1.2 hydrodynamic injection	[132,133]
JiGuCao capsule	Inhibit HBV replication, accelerate HBsAg clearance, suppress HBx expression, inhibit HBV-replicating hepatoma cell proliferation	Via metabolites, regulate hepatitis B/PI3K-Akt pathways, HBx-dependent anti-HBV effect	HepG2, HepG2.2.15, and HepAD38 cells; C57BL/6J-HBV hydrodynamic transfection model	[134]

Abbreviations: TCM, traditional Chinese medicine; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; CHB, chronic hepatitis B; PI3K-Akt, phosphoinositide 3-kinase–protein kinase B pathway; PD-1/PD-L1, programmed cell death protein 1/programmed death-ligand 1; IFN, interferon; TNF-α, tumor necrosis factor-alpha.

Yinchenhao Decoction (YCHD) is utilized to clear damp-heat and protect liver function. The inflammatory milieu is directly modulated by YCHD through the downregulation of proinflammatory cytokines, including IL-6 and TNF-α. Lipid and bile acid metabolism are also regulated by this decoction. Consequently, the cytokine environment that sustains T cell dysfunction is indirectly remodeled, leading to an increased HBV DNA clearance rate.127

The Fuzheng Huayu Capsule is composed of multiple herbal ingredients aimed at resolving blood stasis and liver fibrosis. TOMM34 gene expression is promoted by its active compounds.126 Hepatic pathology and fibrosis are directly mitigated by this formula. Therefore, the immunosuppressive environment of the fibrotic liver is indirectly reversed, facilitating immune reconstitution and HBeAg seroconversion.18,135

The Lingmao Formula is designed to invigorate the spleen and kidney. The PPAR signaling pathway is acted upon by this formula, directly suppressing the release of proinflammatory factors. When combined with entecavir (ETV), effective immune surveillance is indirectly restored,119,120 driving significant serological and virological improvements.136,137 Similarly, the PI3K/Akt pathway is regulated by the Baqi Lingmao Formula. Oxidative stress is directly modulated, and HBV replication is inhibited.117,118

The Liuweiwuling Tablet is applied to alleviate liver injury and inhibit viral replication. Both wild type and ETV resistant HBV strains are directly inhibited by this patent drug. The IFN-β and IFN-γ pathways are activated, which indirectly enhances the frequency of CD3+CD4+ T cells. Selective apoptosis of HBV infected cells is also induced.132,133

The PD-1/PD-L1 pathway is blocked by the Bushen Jiedu Prescription. IFN-γ secretion is promoted, which indirectly enhances dendritic cell vaccine efficacy.123 Inflammatory responses are further reduced by the Bushen Qingdu Decoction. IFN-γ levels are increased while IL-17A expression is decreased.125

The JiGuCao Capsule is utilized to treat HBV infection by targeting multiple metabolic and inflammatory pathways. HBx expression is directly suppressed by this formula. The PI3K/Akt pathway is regulated via its metabolites, accelerating HBsAg clearance.134

Tiaogan-Buxu-Jiedu Granule (TGBXJD) and YinQiSanHuang Decoction (YQSH) are employed in consolidation therapy to prevent virological relapse. Sustained immune control is indirectly established by TGBXJD after nucleoside analogue withdrawal.21,116 The incidence of liver fibrosis is directly reduced by YQSH, further preventing the formation of an immunosuppressive niche.20

Liver fibrosis is reduced and liver function is protected by the Xiaochaihu Decoction. Collagen I synthesis is suppressed and HBsAg secretion is directly inhibited.128 Furthermore, the anti HBV effect of ETV is enhanced by the Longchai Formula. The PI3K/AKT pathway is inhibited via the upregulation of PTEN protein.129

HBV replication is inhibited and immunity is enhanced by the Qingre Lishi Huoxue Formula. The TLR4-IRF3-IFN signaling pathway is activated, promoting IFNα/β secretion.124 Cellular immunity is additionally regulated by the Fuzheng Qudu Decoction. The Th1/Th2 balance is modulated, facilitating a robust immune response.121,122

HBsAg and HBeAg secretion is inhibited by the Le Cao Shi Formula through the synergistic action of flavonoids and phenylethanoid glycosides.130 Lastly, HBsAg seroclearance is promoted and intrahepatic macrophage M1 polarization is induced by the TCM Spleen Invigorating Formula. Gut microbiota is regulated, mediating the gut liver axis to enhance antiviral immunity.131

In summary, TCM formulations represent a systems level therapeutic approach with the potential to target multiple aspects of CHB pathogenesis. However, current evidence suggests that their beneficial effects are more readily explained by combined antiviral and indirect immunomodulatory actions, rather than direct reprogramming of exhausted T cells.

Translational Insights: Clinical Efficacy, Safety, and the Pursuit of Functional Cure

Distinct from the “one drug, one target” paradigm, TCM composite formulae function through a systemic network regulation, making them particularly suitable for addressing the complex heterogeneity of T cell exhaustion in CHB. By modulating multiple signaling pathways involved in T cell dysfunction, TCM treatment has been shown to not only invigorate antiviral immunity but also improve patient tolerance to long term antiviral regimens. Clinical data support the hypothesis that integrating TCM with NAs can amplify immune surveillance and promote functional cure rates.138 Detailed evidence regarding the impact of these TCM interventions on T cell phenotype and function is synthesized in Table 4.

Table 4.

Summary of Randomized Controlled Trials Investigating the Immunomodulatory Potential and Clinical Efficacy of TCM in CBH

Population	Intervention	Comparison	Outcome	Design	Ref
640 HBeAg-negative CHB patients with mildly elevated ALT	Lingmao Formula (oral intake, 15mg/time, 30mg twice a day, for 96 weeks) + ETV	ETV treatment	HBsAg loss rate, quantitative HBsAg decline, intrahepatic cccDNA reduction, and histological improvement	RCT	[136]
271 HBeAg-positive CHB patients with mildly elevated ALT	Lingmao Formula (oral intake, 4.5g/time, 9g twice a day, for 52 weeks) + ETV	ETV treatment	Reduction of serum HBV DNA level, HBeAg loss, HBeAg seroconversion, ALT normalization, and histological improvement	RCT	[137]
96 patients with compensated hepatitis B cirrhosis diagnosed by pathology (Ishak ≥ F5)	Fuzheng Huayu tablet (oral intake, 1.6 g/time, 4.8g three times a day, for 48 weeks) + ETV	ETV treatment	HBV DNA load, rate of virological response, HBeAg seroconversion, biochemical response (ALT/AST normalization), and liver stiffness measurement	RCT	[135]
114 patients with CHB diagnosed with damp-heat syndrome	Yinchenhao Decoction (oral intake, 34g, 78g twice a day, for 4 weeks) + NAs (ETV, TDF, or TAF)	NAs treatment	Liver function (ALT, AST), HBV-DNA negative conversion rate, inflammatory factors (IL-1β, IL-6, TNF-α), liver fibrosis indicators (LSM, HA, LN, CIV, PIIIP), lipid metabolism profiles, and TCM syndrome scores	RCT	[127]
802 patients with (CHB) manifesting as “liver stagnation and spleen deficiency and dampness” syndrome	YinQiSanHuang decoction (oral intake, 5g/time, 10g twice a day, for 52 weeks) + ETV	ETV treatment	Annual incidence of cirrhosis (primary outcome); HBV DNA negative rate, HBsAg negative rate, HBeAg seroconversion rate, liver function indices (ALT, AST, etc), spleen thickness, and clinical symptom evaluation scores	RCT	[20]
596 HBeAg-positive CHB patients, naive to nucleoside analogues (NAs), with high serum HBV-DNA (≥ 20,000 IU/mL) and elevated ALT or biopsy-proven inflammation/fibrosis	Tiao-Gan-Yi-Pi granule (TGYP)/Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) (oral intake, one dose/time, twice a day, for 108 weeks) + ETV	ETV treatment	HBeAg loss rate (primary endpoint), quantitative HBsAg level, proportion of undetectable HBV-DNA, and liver enzyme (ALT, AST, GGT) normalization	RCT	[21]
490 HBeAg-positive CHB patients who have achieved HBeAg loss or seroconversion	Tiaogan-Buxu-Jiedu granule (oral intake, 30 g/time, once daily, for 96 weeks) + ETV	ETV treatment	Cumulative rate of clinical recurrence (CR) after drug withdrawal, virological relapse, histological changes (liver biopsy), and serological/viral markers including cccDNA, HBcrAg, pgRNA, and HBsAg levels	RCT	[116]

Abbreviations: TCM, traditional Chinese medicine; RCT, randomized controlled trial; CHB, chronic hepatitis B; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; cccDNA, covalently closed circular DNA; NAs, nucleos(t)ide analogues; ETV, entecavir; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Building on this mechanistic rationale, emerging RCTs provide clinical validation that the addition of specific TCM formulations to NAs significantly potentiates the restoration of antiviral immunity. Regarding functional cure—the ultimate indicator of reversed T cell exhaustion—Lingmao Formula combined with ETV significantly elevated the HBsAg loss rate (5.5% vs 1.8%; p=0.031) and promoted substantial HBsAg decline (≥1lg·IU/mL) in 11.1% HBeAg negative patients, which is better than 5.9% of patients in the control group (p=0.043),136 suggesting a restoration of effective immune surveillance. In HBeAg positive patients, similar formulas like Tiao-Gan-Yi-Pi (TGYP) or Tiao-Gan-Jian-Pi-Jie-Du (TGJPJD) granules, combined with ETV, demonstrated superior efficacy in inducing HBeAg loss (37.54% vs 27.21%; p=0.008) at week 108, indicating a successful shift toward an active immune clearance phase.116 Crucially, the TGBXJD was specifically designed for consolidation therapy and demonstrated a superior reduction in the off therapy virological recurrence rate when compared to placebo (p< 0.05), as finding directly supporting the establishment of sustained immune control after NA withdrawal.21

Furthermore, modulating the inflammatory milieu is crucial for reversing exhaustion. Yinchenhao Decoction (YCHD) combined with NAs was found to significantly downregulate pro inflammatory cytokines such as IL-6 and TNF-α (p<0.05) while increasing the HBV DNA negative conversion rate (33.9% vs 13.8%; p=0.021), thereby remodeling the cytokine environment that sustains T cell dysfunction.127 Similarly, YinQiSanHuang-antiviral decoction (YQSH) demonstrated a reduction in the annual incidence of liver fibrosis, a histological outcome critical for reversing the immunosuppressive environment of the fibrotic liver.20 Additionally, Fuzheng Huayu (FZHY) tablet combined with ETV showed a trend toward improved HBeAg seroconversion (21.05% vs 4.76%) and significantly higher biochemical response rates (86.96% vs 65.96%; p=0.017), suggesting that mitigating hepatic pathology may concurrently facilitate immune reconstitution.135 Collectively, these clinical outcomes substantiate the therapeutic value of TCM as an immunomodulatory adjuvant that sensitizes the host immune system to antiviral therapy, thereby overcoming the exhaustion associated refractoriness to viral clearance.

The safety profile of TCM formulas in combination with NAs has been rigorously evaluated across multiple RCTs, demonstrating high tolerability without compromising the safety of standard antiviral regimens. In the large scale trial of Lingmao Formula, the incidence of adverse events (AEs) was similar between the combination and control groups, with the treatment group showing a statistically lower incidence of abnormal kidney function (0.0% vs 2.2%; p=0.028), indicating a potential renal protective effect.136 Similarly, the TGYP/TGJPJD trial reported no severe AEs, with the overall incidence of AEs being comparable to the placebo group (9.82% vs 8.13%; p>0.05).116 Studies involving FZHY and YCHD also reported no serious drug related adverse reactions, with no significant differences observed in renal function, blood glucose, or lipid profiles between treatment arms.127,135 These data collectively support the clinical safety of integrating these TCM formulas into long term CHB management strategies.

Despite these promising findings, several limitations constrain their interpretation. Most studies are conducted in region specific populations, often with relatively small sample sizes and variable study designs. In addition, clinical endpoints are predominantly virological or biochemical, with limited assessment of HBV specific T cell function or other immunological parameters. Moreover, potential publication bias and heterogeneity in formulation composition further complicate cross study comparisons. As a result, while TCM formulations may contribute to improved clinical outcomes, their role in achieving durable immune restoration or functional cure remains uncertain.

Discussion

This review critically evaluates the role of TCM in modulating T cell exhaustion in CHB by integrating mechanistic insights and clinical evidence. The available data indicate that TCM derived phytochemicals and compound formulations influence multiple aspects of CHB pathogenesis, including viral replication, immune signaling, cellular metabolism, and the hepatic microenvironment. These pleiotropic effects are conceptually aligned with the multifactorial nature of T cell exhaustion. However, a central conclusion of this analysis is that the observed benefits are more convincingly explained by combined antiviral activity and indirect immunomodulation, rather than by direct reprogramming of exhausted HBV specific T cells. Clarifying this distinction is essential for accurately defining the therapeutic role of TCM.

A major challenge lies in disentangling the relationship between antigen reduction and immune restoration. Persistent antigen exposure is a primary driver of T cell exhaustion in CHB. Therefore, interventions that reduce viral replication or antigen load may secondarily improve T cell function. Many TCM derived compounds exhibit antiviral properties, including inhibition of HBV replication and suppression of antigen expression, which can alleviate chronic TCR stimulation. Under these conditions, partial recovery of T cell activity may occur without fundamentally reversing the underlying transcriptional and epigenetic programs that define exhaustion. Importantly, current studies rarely distinguish between indirect functional improvement and true cell intrinsic restoration, which would require evidence of sustained changes in exhaustion associated transcription factors, chromatin accessibility, and memory differentiation. Consequently, claims that TCM reverses T cell exhaustion should be interpreted with caution unless supported by antigen specific and mechanistically rigorous data.

At the mechanistic level, the specificity of reported immunomodulatory effects remains uncertain. A substantial proportion of studies rely on in vitro systems, non-HBV disease models, or generalized immune assays. These approaches do not fully recapitulate the immunological context of CHB, which is characterized by persistent antigen stimulation, liver specific tolerance, and complex cellular interactions. In addition, many reported effects involve modulation of cytokine production, macrophage polarization, or dendritic cell activation. These processes influence the immune environment but do not directly target T cell intrinsic exhaustion pathways. While such systemic effects may contribute to improved immune function, they do not constitute definitive evidence of exhaustion reversal. Future studies should prioritize HBV specific CD8⁺ T cell models and incorporate functional assays alongside analysis of key transcriptional and epigenetic regulators.

Another important limitation concerns the gap between experimental findings and clinical applicability. Many TCM derived compounds demonstrate biological activity under experimental conditions, yet in vivo relevance is constrained by pharmacokinetic factors such as low bioavailability, rapid metabolism, and uncertain hepatic exposure. Without clear pharmacokinetic and pharmacodynamic relationships, it is difficult to determine whether the concentrations required to modulate immune pathways are achievable in patients. This issue is particularly relevant for polyphenolic compounds that exhibit strong in vitro effects but limited systemic exposure. Addressing this gap will require integrated pharmacokinetic studies, tissue distribution analysis, and validation of target engagement in vivo.

Clinical evidence suggests that TCM, especially when combined with NAs, may improve virological and biochemical outcomes in CHB. However, the strength of this evidence is limited by several factors. Most studies are conducted in region specific populations and vary in design, sample size, and formulation composition. Clinical endpoints are predominantly surrogate markers, including HBV DNA suppression, HBeAg seroconversion, and HBsAg decline, whereas direct assessment of immune restoration is largely lacking. Given that durable immune control is essential for achieving functional cure, the absence of data on HBV specific T cell responses represents a significant limitation. In addition, variability in TCM formulations complicates reproducibility and cross study comparison, highlighting the need for standardization.139

The complexity of TCM formulations presents both opportunities and challenges. Multi component systems may theoretically target multiple pathogenic pathways simultaneously, but their mechanisms of action remain insufficiently defined. Current approaches often rely on network pharmacology predictions without adequate experimental validation, limiting interpretability. Identification of key bioactive components, clarification of their interactions, and establishment of quality control standards will be essential for advancing TCM toward evidence-based application. Without these efforts, mechanistic understanding will remain incomplete.

From a future therapeutic perspective, TCM is unlikely to replace potent NAs or emerging HBV-targeting agents, but may serve as an adjunctive component in rational combination regimens aimed at functional cure. Current cure-oriented strategies increasingly emphasize the need to combine sustained viral suppression, reduction of viral antigen burden, and restoration of antiviral immune competence. Within this framework, standardized TCM formulations or well-characterized bioactive compounds could be explored as immune-metabolic or microenvironmental modulators added to established NA therapy, finite pegylated interferon-based regimens, or emerging antigen-lowering approaches such as RNA-silencing or capsid-targeting agents. The most plausible role of TCM may therefore lie in reducing hepatic inflammation and fibrosis, improving tolerability during long-term antiviral treatment, and creating a more permissive immune environment for HBV-specific T cell recovery. However, such combinations should be regarded as testable hypotheses rather than clinical recommendations until validated in biomarker-driven randomized trials using HBsAg loss, off-treatment durability, and HBV-specific T cell function as predefined endpoints.

Future research should adopt a more integrated and rigorous framework. Mechanistic studies should focus on HBV specific T cell models and employ advanced technologies such as single cell transcriptomics, epigenetic profiling, and spatial analysis to determine whether TCM interventions can directly modulate exhaustion associated cellular states. Translational studies should incorporate pharmacokinetic and pharmacodynamic analyses to establish exposure–response relationships and confirm target engagement. At the clinical level, well designed randomized trials with standardized formulations and inclusion of immunological endpoints will be necessary to validate therapeutic efficacy and define clinical relevance.

In conclusion, TCM represents a promising adjunctive strategy for CHB management due to its multi target pharmacological properties. However, current evidence indicates that its therapeutic effects are primarily mediated through antiviral activity and indirect modulation of the immune environment, rather than through definitive reversal of T cell exhaustion. Bridging the gap between mechanistic plausibility and clinical validation will be essential for determining whether TCM can contribute meaningfully to achieving durable immune control and functional cure in CHB.

Funding Statement

This work was supported by the Science, Technology and Innovation Specialization 2023 (Grant No.DZMKJCX-2023-014), National Natural Science Foundation of China (Grant No.82405314) and Clinical Collaboration Project for Major and Difficult Diseases with Integrated Traditional Chinese and Western Medicine (ZDYN-2024-1-017).

Abbreviations

ALT, alanine aminotransferase; APS, Astragalus polysaccharides; AST, aspartate aminotransferase; cAMP, cyclic adenosine monophosphate; cccDNA, covalently closed circular DNA; CHB, chronic hepatitis B; CREM, cAMP response element modulator; CTLA-4, cytotoxic T lymphocyte-associated protein 4; EGCG, epigallocatechin-3-gallate; ETV, entecavir; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HIF-1α, hypoxia-inducible factor 1-alpha; LAG-3, lymphocyte activation gene 3; LSECs, liver sinusoidal endothelial cells; NAs, nucleos(t)ide analogues; PD-1, programmed cell death protein 1; TCM, Traditional Chinese Medicine; TIM-3, T cell immunoglobulin and mucin domain-containing protein 3; TOX, thymocyte selection-associated high mobility group box.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report there are no competing interests to declare in this work.