The biliary tract orchestrates innate immunity through coordinated interactions between its cellular components, biochemical mediators, and microbial residents(as shown in Figure 2 ).

As the primary defense mechanism, macrophages, dendritic cells, and innate lymphoid cells strategically localize within portal tracts and bile ducts, establishing surveillance networks that detect gastrointestinal-derived pathogens via pattern recognition receptors (30). These immune effectors collaborate with cholangiocytes—transcending their structural role—which actively modulate immune responses through cytokine secretion, antigen presentation, and secretory IgA production to neutralize invading microorganisms (31). Significantly, this cellular interplay is biochemically regulated by Bile Acids(BAs) via TGR5 receptor signaling on cholangiocytes. BA-mediated induction of anti-inflammatory mediators counterbalances pro-inflammatory signals to maintain mucosal homeostasis. The system’s resilience further relies on bidirectional crosstalk with the biliary microbiota: commensal organisms metabolize BAs into immunoregulatory derivatives, while dysbiosis disrupts this equilibrium, predisposing to cholangiopathies such as primary biliary cholangitis through aberrant immune activation (32, 33). Notably, cholangiocyte viability constitutes a critical determinant—their senescence impairs antimicrobial defense, whereas apoptosis initiates fibrotic cascades, thereby delineating how epithelial-immune coordination governs disease progression (18). Consequently, emerging therapeutic strategies target this multifaceted network, aiming to recalibrate BA signaling, restore microbial symbiosis, and preserve cholangiocyte function to intercept pathological cascades.

The innate immune signaling pathways within the biliary tract encompass complex molecular mechanisms regulating host responses to microbial stimuli. While direct investigations of the biliary tract remain limited, insights derived from related tissues and cell types provide valuable insights into these pathways. NF-κB signaling constitutes a pivotal component of innate immune responses across diverse epithelial tissues. NF-κB activation is essential for epithelial defense, with cortactin playing a critical role in facilitating NF-κB-mediated cytokine production, such as IL-8, during bacterial infection (32). This underscores the significance of NF-κB in mediating inflammatory responses, likely relevant to biliary epithelial cells due to their epithelial characteristics. Similarly, microbial components modulate innate immune signaling, as demonstrated in studies of pathogen recognition. Chlamydia trachomatis can induce TLR3 expression while concurrently downregulating the NF-κB and IRF3 pathways in Sertoli cells, resulting in the suppression of pro-inflammatory cytokine production (33). This indicates that certain pathogens can manipulate innate signaling pathways, potentially influencing immune responses in tissues such as the biliary tract that are exposed to microbial stimuli.

Type I and III interferons play critical roles in innate antiviral immunity. Studies demonstrate differential interferon responses in human nasal versus lung tissues following SARS-CoV-2 infection, revealing restricted interferon induction in lung tissue despite productive viral infection (34, 35). These findings indicate tissue-specific regulation of interferon signaling pathways, suggesting parallels to the response mechanisms observed in biliary epithelium upon exposure to pathogens. The role of cytokines, such as Interferon Gamma (IFNγ), in linking immune responses to tissue pathology is underscored (36), who found that chronic IFNγ expression alters hepatic immune microenvironments, potentially contributing to autoimmune conditions like primary biliary cholangitis.

This connection underscores the critical role of cytokine signaling pathways in biliary immune regulation. Furthermore, the involvement of nuclear receptors in modulating immune responses is evident within the context of liver and biliary diseases. Studies indicate that PPARα and FXR may alter the hepatic immune microenvironment in biliary atresia (37, 38), suggesting that nuclear receptor pathways are integral to immune regulation in biliary tissues. Additional insights into innate immune regulation derive from investigations of tissue-specific responses. Bacterial outer membrane proteins activate innate immunity via neural-immune communication pathways, demonstrating that microbial components may influence immune signaling beyond classical receptor pathways (39). Moreover, the multifunctional role of CD14 in innate immunity and tissue homeostasis has highlighted its potential regulatory functions in barrier tissues characterized by rapid cell turnover, such as the biliary epithelium (40).

Typically, Biliary epithelial cells (BECs) are integral to immune response, functioning not only as a physical barrier but also actively participating in immune signaling. The apoptosis of BECs induces the release of auto-antigenic epitopes, which subsequently activate the immune system, driving dysregulation of both innate and adaptive immunity in PBC (41). Mass cytometry analyses demonstrate quantitative alterations in peripheral immune cell subsets in patients, including decreased γδ T cells and memory B cells, alongside increased monocytes and naïve B cells (42). This cellular imbalance underscores the critical role of innate immunity in disease progression (43).

Cytokines and immune mediators orchestrate PBC pathogenesis. Elevated expression of interferon-induced proteins, such as IFIT3, within senescent BECs indicates their involvement in inflammatory processes (44). Furthermore, TIM-3-mediated modulation of chemokine receptors on NK cells contributes to immune dysregulation, suggesting therapeutic potential through targeting this pathway (45). The gut microbiome exhibits significant interaction with innate immunity in PBC. Disease-associated dysbiosis, characterized by reduced microbial diversity and overgrowth of specific bacterial taxa, may influence immune responses via the gut-liver axis (46). Microbial metabolites can modulate both innate and adaptive immunity, thereby linking intestinal homeostasis to biliary inflammation (47).

Identification of disease-associated immune cell subsets and cytokine profiles holds promise for yielding novel biomarkers and therapeutic targets. Promising strategies include modulating the TIM-3 pathway and restoring gut microbiome balance (45, 46). Concurrently, genome-wide association studies identify risk loci predominantly related to immune function, highlighting the contribution of innate immunity to genetic susceptibility in PBC (43).

The innate immune system plays a critical role in the pathogenesis of PBC. NK cells mediate the destruction of BECs through both direct and indirect mechanisms. Specifically, the enhanced frequency and cytotoxicity of NK cells observed in the peripheral blood and liver tissues of PBC patients amplify autoimmune responses via the activation of autoreactive CD4+ T cells and the secretion of inflammatory cytokines (48). Innate Lymphoid Cells (ILCs) exhibit imbalances in subtype distribution among PBC patients, with alterations in cytokine production patterns correlating with disease severity. These ILC dysregulations may promote inflammatory and autoimmune pathways during PBC progression (49). Emerging evidence highlights trained immunity—a persistent functional reprogramming of innate immune cells following initial stimuli—as a contributor to exaggerated inflammatory responses upon secondary challenges (50). This innate immune hyper-reactivity to self-antigens may perpetuate chronic inflammation and tissue injury. The metabolic and epigenetic remodeling underlying trained immunity represents potential therapeutic targets. Reversing these adaptations may attenuate PBC-associated chronic inflammation (51). Pro-inflammatory cytokines secreted by activated innate immune cells establish a destructive microenvironment for BECs. Notably, the Th17/Treg imbalance, characterized by elevated Th17 cell levels and reduced Treg cell levels, reflects the inflammatory shift characteristic of PBC (52).

Gut microbiome dysbiosis in PBC patients correlates with altered microbial diversity and metabolite profiles. Microbiota-derived metabolites (e.g., short-chain fatty acids) modulate innate immunity, suggesting microbiome-targeted therapies could influence disease progression (46). Furthermore, metabolites derived from the gut microbiota reach the liver via the portal venous system, providing persistent low-grade immune stimulation. This continuous gut-derived immunogenic signal is hypothesized to disrupt immune tolerance towards mitochondrial antigens (53). Consequently, this ongoing microbial-driven immune activation provides a mechanistic explanation for the suboptimal efficacy and lack of durability observed with therapeutic strategies solely targeting systemic immune responses (53). Concurrently, the pivotal role of Peroxisome Proliferator-Activated Receptor (PPAR) in regulating the gut-liver immune axis has emerged as a significant finding (23). PPAR agonists to modulate immune responses, Low-dose IL-2 to restore immune balance (52), Trained immunity pathway inhibitors (50, 54). Their involvement in modulating immune and metabolic pathways offers promising novel targets for therapeutic intervention in PBC.

Biliary epithelial cells are primary targets in PBC, where apoptosis releases autoantigen epitopes that trigger immune activation. This process is modulated by genetic predisposition and environmental factors that disrupt immune tolerance, driving disease progression (41). Bile acid accumulation within BECs induces cellular damage through membrane-disrupting detergent effects (55). Concurrently, diminished bicarbonate production compromises the protective “bicarbonate umbrella,” worsening BEC injury and cholestasis (56). Innate immunity critically influences PBC pathogenesis. Inflammatory cytokines released during BEC injury recruit and activate macrophages and NK cells, amplifying bile duct damage. Invariant NK T cells exacerbate liver fibrosis via Interleukin-17A (IL-17A) production, correlating with disease severity in PBC patients (56). Mast cells further contribute by interacting with innate immune cells to promote inflammation and fibrosis in cholestatic liver diseases (57).

Cholangiocytes exhibit injury responses including proliferation, differentiation, and senescence, collectively termed the Ductular Reaction (DR) to repair bile ducts (58). However, maladaptive responses exacerbate fibrosis. Senescent cholangiocytes adopt a Senescence-associated Secretory Phenotype (SASP), releasing pro-inflammatory mediators that sustain fibrogenesis and perpetuate injury cycles (44). Advancements in organoid technology have enabled the modeling of BEC injury, providing insights into cholangiocyte pathophysiology. These model systems facilitate the investigation of cholangiocyte apoptosis and fibrogenic responses critical to the progression of cholangiopathies, including biliary atresia and PBC (59). Such models hold promise for identifying therapeutic targets to mitigate BEC damage in PBC.

UDCA targets enhanced bile flow and reduced cholestatic injury but frequently fails to halt disease progression (60). Emerging therapeutic strategies focus on immunomodulatory agents and anti-fibrotic therapies to improve BEC survival and restore biliary function (55). Targeting cholangiokines—cytokines secreted by cholangiocytes—may also modulate the hepatic microenvironment for therapeutic benefit (61). The complex interplay between BEC injury, immune activation, and cholangiocyte adaptive responses underscores the disease pathogenesis.

Inflammatory factors—ranging from molecular signaling pathways like TGF-β1/Smad and IRF3 phosphorylation, to immune cell subsets such as ILCs, and systemic cytokines—play crucial roles in the innate immune response of the biliary tract in PBC. These factors contribute to inflammation, tissue injury, and fibrosis, shaping the disease course and offering potential targets for therapeutic intervention.

MicroRNA-34a has been identified as a potential marker and regulator of fibrogenesis in PBC which promotes Epithelial-Mesenchymal Transition (EMT) and liver fibrosis by modulating the TGF-β1/Smad pathway, suggesting its pivotal role in inflammatory and fibrotic processes within the biliary system (62). However, the precise role of EMT in the pathogenesis of PBC remains controversial. Although in vitro studies demonstrate that TGF-β1 can induce EMT in cholangiocytes (63, 64), lineage-tracing animal models have failed to provide definitive evidence for EMT occurrence in vivo (65, 66). Cholangiocyte senescence (67, 68), autophagy dysfunction (69), and inflammatory cytokines such as IL-17A (70) are recognized as significant pathogenic mechanisms in PBC. As a matter of fact, whether EMT acts as a primary driver of bile duct injury or a secondary consequence requires further investigation. The extent of concordance between EMT manifestations observed in human PBC and those in experimental animal models also warrants critical evaluation.

Moreover, substantial evidence suggests that interferon regulatory factor 3 (IRF3) phosphorylation serves as a critical mediator of inflammation and tissue injury. Elevated IRF3 phosphorylation levels observed in the livers of patients with PBC and Primary Sclerosing Cholangitis (PSC) reveal that bile acid–induced IRF3 activation mediates cell death, inflammatory responses, and fibrosis, highlighting the pivotal role of innate immune signaling in disease pathology (71). The immune cell landscape also undergoes alterations in PBC. ILC subsets, specifically ILC1s and ILC3s in both patients and murine models, are implicated in the disease process, potentially contributing to inflammatory responses and biliary tract fibrosis (72).

Bile acids themselves function as modulators of inflammation. The roles of bile acids and their cognate receptors underscore their influence on immune responses in autoimmune liver diseases (73). This connection implies that bile acid–mediated signaling pathways may intersect with inflammatory cascades, further modulating innate immunity in PBC. The microbial milieu within the biliary system likewise influences inflammatory responses. Altered biliary microbial patterns correlate with disease progression and reduced transplant-free survival in PSC, suggesting microbial factors modulate innate immune activation and inflammation in cholangiopathies (74).

Additionally, systemic inflammatory cytokines and their mediators have been investigated for causal roles ( Table 1 ). Mendelian randomization analyses demonstrate that circulating inflammatory cytokines mediate the relationship between plasma metabolites and bile duct or gallbladder calculus formation (91), collectively illustrating the integral contribution of inflammatory mediators to disease pathogenesis and progression.

The biliary microbiome constitutes a complex microbial community inhabiting the biliary tract. Dysbiosis—an imbalance within this ecosystem. Specifically, patients with PBC exhibit compositional alterations in their biliary microbiota, which may drive immune dysregulation and disease progression (92, 93). Certain bacterial genera, including Enterococcus and Fusobacteria, demonstrate significant correlations with PBC severity. The detection of Enterococcus in bile samples is associated with heightened risks of disease advancement, suggesting that specific microbial populations exacerbate inflammatory cascades within the biliary tract (41, 94).

Biliary epithelial cells regulate local immune responses through secretory IgA expression and chemokine receptor modulation, while bile acids confer cytoprotection via TGR5 receptor activation (95). Conversely, secondary bile acids generated by microbial metabolism exhibit concentration-dependent and microbiota-contextual effects on cholangiocytes, ranging from protective to detrimental outcomes (41, 96). The interplay between biliary microbiota and inflammation involves multifactorial mechanisms. Dysbiosis may promote intestinal barrier dysfunction, facilitating bacterial translocation and metabolite influx into the biliary system. This process can incite aberrant immune activation and cholangiocyte injury (93, 97). Distinct microbial signatures within the bile of PBC patients correlate with disease duration and severity. Elevated microbial richness and enrichment of specific taxa are linked to advanced fibrotic stages (98).

Given the emerging role of biliary dysbiosis in PBC, microbiome-targeted interventions represent a promising therapeutic strategy. Approaches including probiotics, prebiotics, and fecal microbiota transplantation aim to restore microbial homeostasis and enhance biliary immune function (99, 100). Pharmacological agents modulating bile acid metabolism and cholangiocyte signaling pathways also hold therapeutic potential as PPAR agonists (23, 32).

UDCA persists as the cornerstone of PBC management, attenuating cholestatic injury through pleiotropic mechanisms (32, 100). Although its cytoprotective effects on cholangiocytes against bile acid toxicity are well-established, the precise molecular pathways—particularly its interactions with bile acid transporters and nuclear receptors—require further elucidation. This knowledge gap holds clinical significance: approximately 40% of patients exhibit suboptimal biochemical responses to UDCA, necessitating second-line therapies (41). OCA, a potent FXR agonist, targets this therapeutic gap by reprogramming bile acid homeostasis. Its efficacy derives from the transcriptional upregulation of efflux transporters (BSEP, MRP2/3, MDR3), thereby reducing hepatocellular bile acid retention and apoptosis (43, 101). However, the dose-dependent pruritus of OCA and heterogeneous treatment responses underscore the necessity for personalized FXR agonist selection based on patient genetics and disease phenotype. The autoimmune pathogenesis of PBC positions innate immunity regulators as promising therapeutic targets, as illustrated in Figure 3 .

Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) functions as a critical signaling hub within the NOD-mediated inflammatory cascade (102). Pharmacological inhibition of RIPK2 may disrupt the self-perpetuating cycle of biliary epithelial cell damage and cytokine release- a strategy potentially synergistic with bile acid-directed therapies. Similarly, interleukin-1 blockade (Canakinumab) represents a rational therapeutic approach to attenuate inflammasome activation in patients refractory to UDCA/OCA (103). Its established efficacy in autoinflammatory disorders such as Still’s disease suggests applicability in PBC patients exhibiting prominent serological inflammation (elevated CRP/SAA). Nevertheless, strategic stratification of patients is essential: IL-1 antagonists may benefit individuals with dominant innate immune activation, whereas RIPK2 inhibitors might target those with NOD pathway dysregulation. Non-immunosuppressive adjuncts play vital roles in symptom control and mucosal protection. Hymecromone exemplifies this approach—its triple mechanisms of action (choleretic, cholekinetic, spasmolytic) alleviate biliary pain without inducing gallbladder contraction, rendering it uniquely suited for biliary dyskinesia (104, 105). Concurrently, the gut-liver axis emerges as a therapeutic target. Host defense peptides (HDPs), induced by dietary components, enhance mucosal barrier integrity and exert selective antimicrobial effects without exacerbating inflammation (105). This host-directed strategy could counteract dysbiosis-associated disease progression, particularly given evidence that UDCA modulates gut microbiota composition- a potential biomarker for treatment response (106).

The therapeutic landscape of PBC is poised for transformation through innovative strategies extending beyond conventional approaches. Drug repurposing spearheads this evolution, with network pharmacology identifying promising candidates—including IL-1, EGFR, and TNF-α inhibitors, branched-chain amino acids, and curcumin—tailored to distinct PBC endotypes (107). These agents offer accelerated translational potential due to established safety profiles, enabling rapid deployment for phenotype-specific interventions. Building on cross-disciplinary insights, oncology-inspired therapeutic synergies present compelling paradigms. The efficacy of CDK4/6 inhibitors combined with cytotoxic chemotherapy in biliary tract cancers demonstrates how autophagy blockade overcomes treatment resistance (108). While direct applicability to PBC requires validation, this mechanistic approach—particularly triple therapy regimens targeting autophagic flux—could inform combinational strategies for advanced, treatment-refractory PBC.

Furthermore, advanced delivery systems are redefining precision targeting. Engineered exosomes exemplify this frontier, functioning as modular platforms for cholangiocyte-directed immunomodulation (109). Their capacity to deliver bespoke cargo (e.g., miRNA silencing RIPK2 or anti-inflammatory cytokines) could overcome limitations inherent to systemic drug administration, enabling site-specific pathway modulation with reduced off-target effects. Additionally, immunogenic microenvironment reprogramming—inspired by oncology’s “cold-to-hot” tumor conversion strategies—holds untapped potential. Activating Double-stranded RNA (dsRNA) sensors within fibrotic hepatic niches may reverse immunological anergy, priming PBC microenvironments for enhanced responsiveness to checkpoint inhibitors (110). This approach could synergize with existing immunomodulators to interrupt cycles of autoimmune-driven fibrosis.

Mesenchymal stem cells (MSCs) represent a promising therapeutic strategy for PBC owing to their immunomodulatory properties, capacity for multilineage differentiation, and potential to promote tissue repair (111, 112). MSCs modulate immune responses by suppressing pro-inflammatory cytokine production and augmenting anti-inflammatory pathways, thereby potentially restoring immune homeostasis in PBC patients (41, 111). MSC therapy may mitigate the effects of trained immunity—a phenomenon wherein innate immune cells exhibit hyperresponsiveness to secondary stimuli that may otherwise exacerbate pathologies such as stroke (41, 112).

However, the clinical translation of MSC therapy for PBC remains nascent, with ongoing research focused on optimizing therapeutic protocols. Clinical trials have demonstrated promising efficacy, indicating MSC administration improves hepatic function and attenuates inflammation in autoimmune liver diseases (112–114). Nevertheless, clinical trials in autoimmune liver diseases are ongoing, with results awaited (NCT02997878). The challenges persist, including the necessity for standardized methodologies for MSC isolation, expansion, and delivery, alongside concerns regarding long-term therapeutic safety and efficacy (113, 114).

Furthermore, integrating MSC therapy with established treatments may enhance clinical outcomes. Combining MSC therapy with immunomodulatory agents could yield synergistic effects, advancing overall PBC management (115, 116). Recent advances in stem cell membrane-camouflaged nanoparticles demonstrate potential for targeted delivery to inflamed tissues, offering a particularly advantageous approach for PBC treatment (117).

Neutrophil-to-Lymphocyte Ratio (NLR) and Monocyte-to-Lymphocyte Ratio (MLR) are readily available and cost-effective markers of systemic inflammation (118–120). The potential utility of NLR and MLR as predictors of treatment response to novel therapies for PBC. However, these biomarkers have not yet been validated for routine clinical application and are not incorporated into current international management guidelines. NLR reflects the balance between innate (neutrophils) and adaptive (lymphocytes) immune responses (121). Elevated NLR indicates a heightened inflammatory state, often associated with poorer outcomes in various diseases (120). Similarly, MLR reflects the proportion of monocytes relative to lymphocytes, providing another dimension of immune system activity (121, 122).

Several studies have demonstrated the prognostic value of NLR and MLR in various diseases, including autoimmune conditions and cancers (119–130). In seropositive autoimmune encephalitis, a high NLR was associated with a higher likelihood of first-line treatment failure (129). In advanced gastric and colorectal cancers, lower MLR was associated with prolonged progression-free survival and overall survival (120). Higher NLR has been correlated with poor prognosis in several cancers, as well as being a reliable marker of inflammation, infection and sepsis (121, 129). High NLR levels independently associated with poor prognosis in heart failure (129). Therefore, NLR and MLR can serve as indicators of disease severity and predictors of treatment response and survival. A study found the maximal NLR had the best predictive value for in-hospital and 30-day mortality in ICU patients with CAD and CKD (128). Meanwhile, the total cholesterol, ALP, and NLR were the three independent risk factors associated with early biochemical nonresponse to UDCA treatment (129).

While specific studies focusing on NLR and MLR as prognostic markers in PBC are still emerging, the existing literature provides a strong rationale for their potential utility. Combining NLR and MLR with other inflammatory markers, such as the Systemic Immune-inflammation Index (SII) (122, 123, 125, 126), to improve prognostic accuracy (38).

Dysbiosis, or an imbalance in the gut microbiota, has been implicated in the pathogenesis of PBC. For instance, alterations in the gut microbiome have been associated with the severity of liver disease and the response to treatment. Research indicates that specific microbial taxa may influence the immune response and contribute to the autoimmune processes observed in PBC patients (131). Furthermore, the salivary microbiota of PBC patients exhibited significant differences, suggesting that oral microbiota may play a role in the disease’s pathogenesis (132).

Consequently, given the emerging evidence of the gut-liver axis’s role in PBC, several therapeutic strategies are being explored to manipulate the biliary microbiota. One promising approach involves the use of bile acid sequestrants, such as cholestyramine, which have been shown to alter the gut microbiome and improve cholestatic symptoms in PBC patients (133). Additionally, the use of fenofibrate as a second-line therapy for patients with inadequate responses to UDCA has shown promise. Studies have demonstrated that fenofibrate can improve liver biochemistry and histological features in PBC patients, suggesting that it may also exert beneficial effects on the gut microbiota (134). The combination of UDCA and fenofibrate has been associated with improved biochemical responses, indicating a synergistic effect that may be mediated by changes in the gut microbiome (135). The exploration of biliary microbiota therapy in PBC is still in its infancy. Moreover, clinical trials investigating the efficacy of probiotics, prebiotics, and other microbiota-targeted therapies in PBC patients are warranted (136). Beyond cholestatic pathologies, Hypoxia-inducible Factors (HIFs) exhibit immunosuppressive properties in hepatic malignancies by fostering pro-tumorigenic microenvironments, positioning them as therapeutic targets in liver cancer management (137).

Originally developed for hematological malignancies, Chimeric Antigen Receptor (CAR)-T cell therapy has recently demonstrated sustained, profound depletion of autoreactive B cells in autoimmune diseases, exhibiting promising safety and efficacy profiles (138). This transition from oncology to autoimmunity represents a transformative advancement in therapeutic strategy (139). Currently, CAR-T therapy is under investigation across 372 institutions in 40 countries/regions for various autoimmune conditions, including Systemic Lupus Erythematosus (SLE) and multiple sclerosis (140). The development of novel CAR architectures, such as fourth-generation constructs, continues to enhance therapeutic potential (141, 142).

However, CAR-T therapy entails significant risks, including Cytokine Release Syndrome (CRS), neurotoxicity, and organ-specific toxicities. These adverse events are influenced by inflammatory microenvironments, limitations inherent in CAR design, and systemic immune disruption (143). Safety optimization may be achievable through innovative strategies—e.g., logic-gated CAR systems or alternative cellular carriers—coupled with rigorous clinical monitoring. Future efforts should prioritize generating disease-specific clinical evidence and developing adaptable CAR designs to facilitate broader, safer application.

Although CAR-T expansion into autoimmunity offers new therapeutic potential for refractory cases (144–147), its adverse effects present distinctive challenges within autoimmune pathological contexts (138, 139). For instance, inflammatory microenvironments can impair CAR-T persistence and exacerbate toxicity (140). Disease-specific toxicities, such as renal dysfunction or cutaneous manifestations, have also been reported, particularly with CD19-directed CAR-T therapy in SLE (146). Research characterizing toxicity profiles is evolving rapidly. Critical future directions include developing allogeneic CAR-T products to circumvent limitations associated with autologous approaches and extending CAR technology to alternative effector cells (e.g., CAR-macrophages or CAR-Natural Killer (NK) cells) to improve safety and efficacy (148, 149). Integration of precision medicine methodologies may facilitate enhanced risk stratification and personalized monitoring protocols (150). Therefore, Refined CAR designs and systematic real-world evidence are essential for safe, effective translation from oncology to autoimmunity. It must be emphasized that the application of CAR-T therapy in PBC remains speculative, there is no clinical evidence currently supports its potential efficacy in this condition.