From bench to bedside: advances in cell therapy for tuberculosis treatment

Abstract

Tuberculosis (TB) remains a major global public health challenge, with drug-resistant tuberculosis (DR-TB) presenting a serious threat to TB management. Conventional treatment faces challenges such as significant drug toxicity, frequent emergence of drug resistance, and compromised host immune microenvironment. These limitations, particularly in DR-TB cases, often lead to poor treatment outcomes and heightened recurrence rates, underscoring the need for complementary strategies. Cell-based host-directed therapy (HDT) emerges as a novel therapeutic strategy that may complement conventional drugs by directly modulating pathological immune responses and facilitating the repair of damaged tissue. This narrative review synthesizes preclinical and clinical data on cell therapy for TB. We focus on two distinct strategic approaches: (1) mesenchymal stem cell (MSC)-based therapies, which primarily exert immunomodulatory and tissue-repair functions, and (2) T cell-based adoptive cell therapies (ACTs), which are designed to enhance antimicrobial immunity directly. Current evidence, while promising, predominantly remains in the early exploratory stages or lacks robust evidence-based support. To facilitate successful translation, future research should focus on standardizing cell products, conducting comprehensive safety assessments and implementing more rigorous clinical trials. This review critically assesses the therapeutic potential and translational challenges of cell therapy for TB.

Introduction

Tuberculosis (TB) is a globally endemic disease caused by the aerobic bacterium Mycobacterium tuberculosis (Mtb) [1, 2]. According to the World Health Organization’s Global Tuberculosis Report 2023, there were an estimated 10.8 million new TB cases worldwide, representing an incidence rate of 134 per 100,000 population [3, 4]. China ranks third among the 30 high-burden TB countries, accounting for 6.8% of the global disease burden [3, 4]. The emergence of drug-resistant tuberculosis (DR-TB) poses a major therapeutic challenge. Factors such as prolonged treatment duration, poor adherence, and inappropriate medication practices contribute to the development of drug resistance [5, 6]. Moreover, conventional DR-TB regimens face limitations including drug toxicity, evolving antimicrobial resistance, and compromised host immune microenvironments [7, 8]. These challenges thus necessitate innovative treatment strategies to meet the World Health Organization’s 2035 target for global TB elimination.

Host-directed therapy (HDT) is now regarded as a viable adjunct to conventional antimicrobial regimens. It acts by enhancing pathogen clearance by host cells, mitigating antibiotic resistance, and stimulating innate and adaptive immunity [9]. As a prominent strategy within HDT, cell therapy is capable of delivering functionally optimized autologous or allogeneic cells into patients’ bodies as biological treatment carriers, enabling tissue repair or organ function restoration [10]. A milestone was achieved in 2017 with the regulatory approval of chimeric antigen receptor T-cell therapy (CAR-T), which heralded a new era in cell therapy development [11]. Following prior research demonstrating its safety and efficacy [12], China’s first mesenchymal stem cell (MSC)-based drug, “Amimestrocel Injection,” was approved in 2025 by the National Medical Products Administration (NMPA), paving the way for a new phase in China’s cell therapy industry. Cell therapy is now being investigated in clinical trials across a spectrum of diseases, extending its application beyond oncology to include infectious diseases.

In the context of TB, cell therapy represents a promising adjunctive therapy, which aims to modulate host immune responses to improve treatment outcomes. This review focuses on two strategic approaches: (1) MSC-based therapies, which primarily function to modulate detrimental inflammation and promote tissue repair; (2) T cell-based adoptive cell therapies (ACTs), which aim to directly enhance antimicrobial immunity. It is critical to emphasize that these cell-based strategies are not envisioned as replacements for standard anti-TB chemotherapy. Instead, they are developed as adjunctive therapies with the goal of complementing existing drugs by addressing issues such as excessive immunopathology, bacterial persistence, or drug-induced tissue damage. Critically, these approaches remain in preliminary development, requiring deeper mechanistic investigation and robust clinical validation. This review systematically analyzes current evidence on cell therapy for TB, while identifying key challenges in clinical translation and outlining future directions to advance these therapies from bench to bedside.

Methods

A comprehensive search was conducted to identify relevant preclinical and clinical studies on cell therapy for TB. The following electronic databases were searched from their inception until November 2025: PubMed, Web of Science, ClinicalTrials.gov, as well as the Chinese databases China National Knowledge Infrastructure (CNKI) and Wanfang Data. The search strategy was a combination of Boolean operators, keywords and Medical Subject Headings (MeSH) related to two core concepts: (1) tuberculosis and (2) cell therapy. Key search terms included: “tuberculosis” OR “TB” OR “mycobacterium tuberculosis” AND “cell therapy” OR “cellular therapy” OR “mesenchymal stem cells” OR “MSCs” OR “stromal cells” OR “T cells” OR “NK cells” OR “dendritic cells” OR “adoptive transfer” OR “immunotherapy”. The search was limited to articles published in English and Chinese.

The studies included in Table 1 were selected based on the following criteria: (1) clinical research (including clinical trials, case series, case reports, and registered protocols with reported results) involving (2) any form of cell therapy (e.g., MSCs, immune cells) for (3) all forms of TB. Studies were excluded if they were purely preclinical, were non-primary research (e.g., reviews), did not focus on therapeutic efficacy, or had unavailable full text/insufficient data.

Table 1.

Relevant clinical research on cell therapy for TB

References	Disease	Subjects (N)	Type	Design	Source	Chemotherapy	Main results
[34]	MDR-TB and XDR-TB	27	BM-MSCs	Single-arm, open-label, observational study	Autologous	Yes	100% clinical improvement rate; 74.1% bacteriological response rate; 40.7% cavity closure rate; 56.3% sustained remission rate
[35]	MDR-TB	36	BM-MSCs	Non-randomized, matched case-control study	Autologous	Yes	81% clinical improvement rate
[33]	MDR-TB and XDR-TB	30	BM-MSCs	Single-arm, open-label, phase I/IIa study	Autologous	Yes	no serious AEs; common AEs: hypercholesterolemia, nausea, lymphopenia, diarrhea
[40]	MDR-TB	8	Vγ9Vδ2 T Cell	Single-arm, open-label, pilot study	Allogeneic	Yes	clinically safe; promotes pulmonary lesion repair, improves host immunity, and reduces TB burden with or without anti-TB drugs
[41]	MDR-TB	1	CIK cell	Case report	Autologous	Yes	significant clinical improvement; no recurrence in 3 years
[42]	MDR-TB	1	CIK cell	Case report	Autologous	Yes	culture conversion achieved with no recurrence in 2 years
[43]	MDR-TB	9	CIK cell	Retrospective cohort study	Autologous	Yes	symptom alleviation, lesion absorption improvement; clinically safe

MDR-TB Multidrug-resistant tuberculosis, XDR-TB Extensively drug-resistant tuberculosis, BM-MSCs Bone marrow mesenchymal stem cells, AEs Adverse Events, CIK cell cytokine-Induced Killer cells

MSC-based therapies

MSC therapy is regarded as a promising therapeutic approach with immunomodulatory, anti-inflammatory, pro-angiogenic, and antioxidant capabilities [13, 14]. These cells can be isolated from diverse biological sources, including bone marrow, adipose tissue, and umbilical cord [15, 16]. Notably, MSCs derived from different tissue origins exhibit distinct functional characteristics, including variations in accessibility, yield, proliferation rate, immunomodulatory potency, and secretion patterns [17–19]. Furthermore, their translational potential has been strongly supported by accumulating evidence from clinical trials across a range of diseases [20–23].

MSCs and TB therapy: therapeutic potential and dual roles

MSCs hold therapeutic potential against infectious diseases through multiple complementary mechanisms. Evidence suggests MSCs may directly eliminate pathogens via the secretion of antimicrobial peptides, modulate immune responses by enhancing the phagocytic activity of macrophages and other immune cells, and facilitate tissue repair by differentiating into functional cell types [24–26]. Moreover, the combination of MSCs with conventional antimicrobial agents could yield synergistic effects and enhanced efficacy [27, 28].

Accumulating preclinical and clinical evidence indicates that MSCs warrant further evaluation as an adjuvant therapy for TB (Fig. 1). In animal models, the administration of MSCs has been shown to reduce inflammatory infiltration, attenuate tissue damage, and accelerate reparative responses such as connective tissue formation [29]. These effects are thought to involve, at least in part, the modulation of macrophage function. Experimental evidence suggests that MSCs may enhance mycobacterial clearance by boosting proinflammatory cytokine secretion, increasing reactive oxygen species (ROS) production, and promoting apoptosis in infected macrophages [30]. However, these mechanisms require further validation in clinical contexts. Beyond their direct antimicrobial and reparative effects, MSCs might mitigate the toxicity of conventional anti-TB drugs. For instance, intravenous administration of bone marrow-derived MSCs (BM-MSCs) significantly ameliorated rifampicin-induced renal injury and attenuated its transgenerational toxicity [31]. However, the generalizability of such protective effects to other drug toxicities and their relevance in patients remain to be determined. Moreover, their therapeutic utility extends beyond TB to other mycobacterial infections. Preliminary evidence from murine models also suggests a potential therapeutic effect of MSCs in nontuberculous mycobacterial infections, showing reduced bacterial load and inflammatory pathology [32]. As this finding is currently reported only in a conference abstract, it necessitates cautious interpretation and further validation.

Fig. 1.

Main mechanisms of action of MSCs in the treatment of TB. AECⅡ, alveolar typeⅡ; MSCs, mesenchymal stem cells; Mtb, mycobacterium tuberculosis; Mac, macrophage; EVs, extracellular vesicles; ROS, reactive oxygen species.; NLRP3, NLR family pyrin domain containing 3; GSDMD, gasdermin D; NFAT5, nuclear factor of activated T-cells 5; ecto-ADA-1, ecto-adenosine deaminase-1; CR, creatinine; Fi, fibrinogen; Total ADA, total adenosine deaminase. This figure is original and was created by the authors for this publication

Following preclinical studies, early-phase clinical trials are investigating the therapeutic application of MSCs in TB (Table 1). In terms of safety, a clinical trial involving 30 patients with multidrug-resistant or extensively drug-resistant tuberculosis (MDR-/XDR-TB) assessed a single-dose infusion of autologous BM-MSCs administered alongside standard anti-TB therapy. The study reported no serious adverse events, with hypercholesterolemia, nausea, lymphopenia, and diarrhea being the most commonly observed [33]. Regarding therapeutic efficacy, a study of DR-TB patients treated with autologous MSCs reported promising outcomes: 100% showed clinical improvement, 74.1% achieved bacteriological response, 40.7% demonstrated cavity closure, and 56.3% maintained sustained remission over a two-year period [34]. These findings have been further supported by subsequent, larger clinical investigations [35]. While current outcomes are highly encouraging, they originate from studies with limited sample sizes and varying protocols. Future efforts should focus on conducting larger-scale trials to comprehensively assess the long-term safety and efficacy of MSCs in TB treatment regimens.

Despite their potential therapeutic efficacy against TB, MSCs may function as a double-edged sword during infection. Emerging evidence suggests a bidirectional interplay between MSCs and Mtb: dormant Mtb may enhance the long-term survival of MSCs, while in return, MSCs could provide a protective ecological niche that facilitates bacterial persistence—a mechanism implicated in latent TB infection [36–38]. Moreover, Mtb residing within MSCs develops pronounced resistance to multiple anti-TB drugs, mediated in part by drug efflux transporters such as ABCC1 and ABCG2, as well as vacuolar-type H⁺-ATPases [38, 39]. Interestingly, modulation of MSC activity through NOD-2 and TLR-4 signaling has been shown to reduce intracellular Mtb survival, suggesting a potential strategy to disrupt bacterial persistence [39]. Collectively, these findings suggest that targeting the MSC-constructed immune-privileged niche may represent a novel therapeutic avenue for TB control. Future studies should prioritize elucidating how MSC therapy influences these host–pathogen interactions in vivo.

MSC-derived extracellular vesicles (MSC-EVs) and TB therapy

The therapeutic benefits of MSCs are primarily attributed to paracrine activity. EVs, particularly exosomes (Exo), serve as key mediators by transferring bioactive cargo to recipient cells. These nanosized vesicles carry diverse cargo (e.g., mRNAs, miRNAs, proteins, lipids) that can influence essential cellular processes including gene expression, enzymatic reactions, and signal transduction, thereby mimicking the therapeutic effects of MSCs [44, 45]. Compared with whole-cell therapies, MSC-EVs offer potential advantages including enhanced biocompatibility, low immunogenicity, and a reduced risk of tumorigenicity [46, 47]. These attributes have stimulated interest in MSC-EVs as a potential cell-free therapeutic alternative.

Research over the past decade has evaluated the application of MSC-EVs in infectious diseases. MSC-EVs have been shown to modulate immune responses by suppressing pro-inflammatory cytokines and inducing anti-inflammatory mediators, while simultaneously enhancing alveolar epithelial and pulmonary endothelial repair to promote tissue regeneration [48, 49]. Notably, a proposed mechanism involves the delivery of regulatory miRNAs that can reprogram functions in target cells [50, 51].

Preclinical studies have begun to evaluate the potential of MSC-EVs as an adjunct therapy for TB. In a rabbit model of renal TB, the co-administration of MSC-EVs with standard anti-TB drugs was shown to attenuate renal inflammatory lesions, normalize key serum biochemical parameters, and restore pro- and anti-inflammatory cytokine balance [52]. Another study found that MSC-EVs may regulate the immune response of alveolar type II epithelial cells (AECII) by carrying miR-20b, thereby inhibiting inflammation caused by TB infection and alleviating inflammatory damage to AECII [53]. Despite these early findings, the overall evidence for the efficacy of MSC-EVs in TB treatment remains very limited. To advance clinical translation, it will be essential to refine MSC-EVs dosing and delivery strategies for improved tissue-specific targeting, and to evaluate their long-term safety and synergistic potential within existing anti-TB regimens.

MSC-conditioned medium (MSC-CM) and TB therapy

Beyond EVs, MSC-CM has been also investigated as an alternative cell-free approach, offering several distinct advantages. Primarily, this cell-free therapy avoids the risk of host immune rejection associated with whole-cell transplantation [54]. Secondly, MSC-CM demonstrates superior long-term storage stability, which may enhance clinical applicability [55]. Importantly, MSC-CM not only offers considerable cost-effectiveness but also streamlines safety and efficacy evaluations, thereby supporting more straightforward standardization, production, and quality control [56, 57].

MSC-CM has been explored for its potential role in managing infectious diseases through immunomodulatory, anti-inflammatory, and antibacterial effects [58, 59]. Although research on MSC-CM for TB remains limited, a study using a BCG-challenged murine model reported that MSC-CM administration helped restore inflammatory homeostasis. It did so by rebalancing host responses, attenuating lung tissue damage, and establishing an immunologically favorable microenvironment for subsequent adaptive immunity development [60]. Notably, as a cell-free therapy, MSC-CM may mitigate risks associated with MSC-mediated immune evasion during TB infection.

To advance this field, future research needs to focus on several key areas. Firstly, comprehensive studies are required to evaluate the therapeutic potential of MSC-CM against TB, incorporating systematic comparisons with the outcomes of MSC-based therapy, to clarify their relative advantages. Additionally, genetic modification or preconditioning of MSCs could be explored to enhance the therapeutic efficacy of MSC-CM. Ultimately, the clinical translation of MSC-CM will depend on rigorous trials to establish its safety and efficacy in treating TB.

T cell-based ACTs

ACT is a therapeutic strategy that involves isolating, expanding, or modifying immune cells ex vivo and reinfusing them into the body to enhance immune responses [61]. T cells, which play a central role in adaptive immunity, are the most commonly used cell type in ACT. They are being investigated for TB treatment due to their potential to modulate immune responses and enhance anti-TB efficacy. However, most related research remains at a preclinical or early exploratory stage. This section focuses on several T-cell subsets, reviewing their biological characteristics, functional roles in TB infection, and current therapeutic research status.

Central memory T cells (Tcms) and TB therapy

Tcms, a key subset of memory T lymphocytes, are characterized by CCR7 and CD62L expression [62]. They are critical for adaptive immunity due to their robust proliferative capacity and longevity [63, 64]. Crucially, Tcms are thought to execute continuous immune surveillance, enabling preemptive containment and rapid clearance of reinfecting pathogens [65, 66]. Upon antigen re-encounter, they can rapidly differentiate into effector T cells, secreting cytokines and activating memory immune responses.

While Tcm-based therapy is an established strategy in oncology, based on its self-renewing capacity and ability to remodel the tumor microenvironment [67], its application in TB remains largely unexplored. Preliminary evidence comes from a study (reported in a conference abstract) describing the rapid ex vivo expansion of TB-specific Tcms (CD45RO⁺/CD62L⁺) using an optimized cytokine cocktail (IL-2, IL-7, IL-12, IL-15) combined with ESAT-6 antigen stimulation. This approach can generate a sufficient therapeutic cell dose from 100 mL of peripheral blood within three weeks. Thus, it provides a standardized and promising strategy for adoptive T cell therapy against post-transplant TB infection in solid organ transplant recipients [68]. It is critical to emphasize that these findings are preliminary, requiring validation through peer-reviewed publication and independent replication studies.

In summary, current research on Tcms in TB remains largely unexplored. Future studies should prioritize elucidating the functional roles and molecular mechanisms of Tcms during TB infection. Additionally, it is essential to optimize strategies for Tcm therapy, particularly to achieve targeted immune modulation. Notably, systematically evaluating the balance between expansion efficiency, safety, and efficacy in rigorous preclinical models is a necessary step prior to any clinical translation.

γδ T-cells and TB therapy

γδ T cells represent a distinct unconventional T-cell population with intrinsic antigen-presenting capacity [69]. Their antigen activation demonstrates specificity and contact dependency while remaining unrestricted by allogeneic immune rejection [70, 71]. The Vγ9Vδ2 T-cell subset is promising for immunotherapy owing to its reported ability to target tumor cells while sparing normal ones [72, 73]. Multiple clinical studies investigating the cytotoxicity of Vγ9Vδ2 T cells are underway in various solid tumors [74, 75].

Vγ9Vδ2 T cell is thought to contribute to the immune response against TB infection [76, 77]. Expansion of γδ T cells has been observed following BCG vaccination in both neonatal and adult subjects [78]. Mechanistically, BCG-infected dendritic cells (DCs) activate and expand a specific Vγ9Vδ2 T-cell population that can functionally recognize Mtb-infected cells [79]. Notably, the frequency and function of circulating Vγ9Vδ2 T cells are reported to be impaired in patients with active TB [80, 81]. Preclinical in vitro studies suggest potential therapeutic avenues: for instance, the addition of vitamin C to (E)−4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) and IL-2-stimulated peripheral blood mononuclear cells (PBMCs) enhanced the proliferative expansion of Vγ9Vδ2 T cells. These expanded cells subsequently inhibited the growth of the virulent Mtb H37Rv strain, an antimicrobial activity that was likely mediated through the secretion of effector cytokines, specifically TNF-α and IFN-γ [82]. Furthermore, a preliminary clinical study reported that allogeneic Vγ9Vδ2 T cell therapy exhibits dual advantages of safety and therapeutic efficacy in MDR-TB patients, effectively promoting pulmonary lesion resolution, restoring host immune competence, and reducing TB burden [40].

Collectively, these observations highlight the potential of Vγ9Vδ2 T cells as an adjunctive therapy for TB. However, clinical validation is currently limited to early-phase, non-randomized studies with small sample sizes. Future studies should aim to evaluate efficacy in randomized controlled trials (RCT) using multidimensional endpoints, such as clinical response, immunological biomarkers, and long-term outcomes. Furthermore, the development of standardized protocols for cell expansion and delivery is a prerequisite for translating this approach from preclinical promise to reliable clinical application.

Invariant natural killer T (iNKT) cells and TB therapy

iNKT cells are a unique subset of T lymphocytes that co-express T-cell receptors and NK-cell markers, bridging innate and adaptive immunity [83, 84]. Clinical trials exploring iNKT cell-based therapies have demonstrated promising efficacy in cancer, with investigations extending to infectious diseases [85, 86]. Moreover, CAR-iNKT cell therapy has entered clinical evaluation [87], and gene-editing technologies are being explored to enhance iNKT cell function [88].

iNKT cells interact with macrophages in a context-dependent manner, which can polarize their functions to exert either pathogenic or protective roles across various diseases. During TB infection, macrophage-activated iNKT cells secrete high levels of IFN-γ, which in turn stimulates macrophages to release TNF-α and NO, thereby enhancing phagolysosomal killing of the bacteria [89, 90]. Preclinical evidence from an adoptive transfer model showed that intravenous infusion of purified iNKT cells from healthy donor mice into infected recipients exerted a direct bactericidal effect. It significantly reduced the bacterial burden in the lungs and effectively prolonged the survival time of the Mtb-infected mice [91], providing initial evidence for a protective role of iNKT cells against TB in vivo.

Although these findings suggest that augmenting iNKT cell numbers may improve TB control, their clinical application remains theoretical. Future research should prioritize elucidating therapeutic mechanisms and verifying preliminary efficacy through in vitro and animal models. Concurrently, preclinical infection studies are needed to assess synergistic effects with first-line anti-TB drugs, coupled with comprehensive safety profiling via pharmacokinetic and toxicological evaluations. Ultimately, genetic engineering approaches, including CAR-iNKT or gene editing, may enhance lung homing and bactericidal activity, representing a potential avenue for future immunotherapeutic development.

Cytokine-induced killer (CIK) cells and TB therapy

CIK cell infusion is a form of autologous cellular immunotherapy approach. It involves the sequential incubation of PBMCs with IFN-γ, anti-CD3 monoclonal antibodies, and IL-2, among other cytokines, to obtain ex vivo-expanded and activated T lymphocytes [92, 93]. CIK cells can be easily expanded to clinical-scale doses via standardized culture protocols. Their defined preparation protocols enable enhanced cytotoxic potential under controlled experimental conditions. To date, more than 80 registered clinical trials worldwide have systematically evaluated CIK cell therapy, demonstrating its potential as a therapeutic approach [94, 95].

Current research on CIK cell therapy for TB remains limited, primarily comprising isolated case reports and small-scale pilot studies. A 32-year-old patient with MDR-TB who had failed standard regimens showed marked clinical improvement following three cycles of CIK cell therapy with no recurrence during a 3-year follow-up [41]. Similarly, another study reported a refractory MDR-TB case in which the patient received adjunctive CIK cell therapy, and subsequently showed culture conversion and remained relapse-free during a 2-year follow-up [42]. A recent retrospective analysis further supports these observations. It demonstrated that adding CIK cell therapy to conventional anti-TB drugs was associated with improved outcomes including higher sputum conversion rates, symptom alleviation, lesion absorption, and shorter recovery time [43]. Notably, no significant safety concerns were identified. A potential mechanism involves the secretion of immune mediators (such as cytokines, chemokines, and growth factors) by patient-derived CIK cells, which may contribute to the observed clinical improvements in MDR-TB patients [96].

Collectively, these preliminary reports are suggestive, but the evidence remains at an early stage, requiring further evaluation. Moving forward, well-designed RCTs are warranted to confirm the efficacy and safety of CIK cell therapy in DR-TB patients. Additionally, given the heterogeneity of TB, another important consideration is the development of optimized CIK manufacturing protocols, which will be crucial for devising more patient-specific targeted therapeutic strategies.

Mucosal-associated invariant T (MAIT) cells and TB therapy

MAIT cells serve as a bridge between innate and adaptive immunity, and primarily respond to microbial vitamin B metabolites presented by the nonpolymorphic MHC-related protein 1 (MR1) [97]. They can mount rapid TCR-independent immune responses upon inflammatory stimuli to exert antimicrobial effector functions [98]. Therapeutically, MAIT cells can be genetically modified into CAR-MAIT constructs or expanded and activated via MR1 ligand stimulation [99].

During infection, bacterial invasion is generally accompanied by a reduction in MAIT cell frequency in peripheral blood, with concurrent accumulation in localized infection sites [100]. The absence of MAIT cells increases host susceptibility to bacterial infections and exacerbates pathological damage [101, 102]. In the context of TB, MAIT cells directly delay the priming and activation of CD4⁺ T cells during early infection [103]. During chronic stages, vaccine-driven expansion of MAIT cells has been shown to reduce bacterial burden in affected organs [104]. However, the role of MAIT cells appears inconsistent across studies. Another study demonstrated that MAIT cells effectively controlled M. bovis BCG infection but failed to restrict the progression of chronic TB [105]. These discrepancies may be closely associated with factors such as the route and frequency of administration, dosage, as well as interspecies variations in receptor profiles. Notably, recombinant mycobacteria overexpressing riboflavin biosynthesis genes induce enhanced MAIT cell responses [103], which suggests a potential strategy for TB vaccine development. Another study showed that redifferentiated MAIT-like cells (reMAIT), generated through reprogramming of induced pluripotent stem cells (iPSCs), demonstrate significant protective effects in mycobacterium abscessus infection models, as evidenced by a 40–50% reduction in colony-forming units [106]. These cells achieved maturation and underwent expansion in vivo, acquiring additional T-cell receptors. However, the therapeutic targeting of MAIT cells requires caution. Studies indicate that uncontrolled activation of MAIT cells may carry potential risks, including the induction of hyperinflammatory responses and cellular exhaustion, ultimately leading to host damage [107].

MAIT cells, with their MHC-unrestricted antigen recognition, represent a biologically rational target for immunotherapy against TB. Yet, translating this rationale into a clinically viable treatment paradigm requires addressing several critical knowledge gaps. First, a more comprehensive understanding of the activation and dysfunction mechanisms of MAIT cells during TB infection is essential to advancing this field. Second, although the use of reMAIT cells to replenish depleted MAIT cell populations represents a promising approach, its efficacy and applicability against TB infection require further extensive investigation. Given the paucity of direct preclinical and clinical evidence for adoptive MAIT cell transfer in TB management, future efforts are needed to establish robust expansion protocols and to systematically evaluate both therapeutic outcomes and long-term safety profiles.

Other potential cell-based therapies

Natural Killer (NK) cells contribute to anti-infection defense, antitumor responses, and immune regulation [108]. Strategies for NK cell therapy primarily focus on engineering CAR-NK cells and combining them with immune checkpoint inhibitors or NK cell engagers [109]. Early clinical studies have indicated that these strategies hold promising potential for improving patient outcomes [110, 111]. In TB, NK cells demonstrate complex and stage-dependent characteristics. While some studies report unchanged or decreased peripheral NK cell counts [112, 113], others demonstrate that NK cells undergo phenotypic and functional adaptations during infection that are linked to anti-TB effects [114]. During early infection stages, NK cells can directly recognize Mtb through TLR2, initiating anti-TB immunity [114]. This process involves the activation of surface receptors like NKG2D/NKR and intracellular signaling pathways including ERK and p38 MAPK. These events lead to the production of cytolytic proteins such as perforin and granzymes to achieve direct killing of Mtb [114]. Beyond direct cytotoxicity, NK cell-derived chemokines and cytokines also play essential roles in anti-TB immunity [115]. Notably, NK cells can develop memory-like responses to antigenic or non-antigenic stimuli, a feature observed following BCG vaccination or natural TB infection [116]. In vitro, memory-like CD45RO + NK cells in individuals with latent TB infection exhibit stronger reactivity to Mtb antigens compared to active TB patients [117]. Therapeutically, NK cells serve as key effector cells in early protection. They can control pathogens through mechanisms including ADCC and the production of reactive oxygen and nitrogen species [118, 119], positioning them as candidate targets for future TB vaccine design. However, the activation mechanisms and specific roles of NK cells during early TB infection, particularly in the context of vaccine-induced immune training, remain incompletely elucidated. Therefore, elucidating their functions in TB pathogenesis and immune responses is needed.

DCs are the most potent antigen-presenting cells with essential functions in antigen uptake, processing, presentation, and T-cell activation [120]. Upon TB infection, DCs recognize pathogens via surface pattern recognition receptors and migrate to lymphoid organs to mature [121]. By upregulating MHC and co-stimulatory molecules, mature DCs enhance antigen presentation, thereby enabling T-cell activation and contributing to anti-TB immunity [121]. DC numbers are reduced in TB patients compared to healthy individuals, suggesting a correlation between DC levels and disease progression [122]. Correspondingly, DC depletion delays CD4 + T-cell responses and exacerbates TB infection in experimental models [123]. Beyond antigen presentation, DCs secrete pro-inflammatory cytokines such as TNF-α and IL-6, which promote immune cell recruitment, activation, and inflammatory responses to facilitate bacterial clearance [124]. Additionally, DCs also contribute to granuloma formation, where their localized accumulation may restrict bacterial dissemination [125]. Given their central role in immunity, DC-based therapies offer distinct advantages, including the induction of active immunity, high antigen specificity, and sustained immunological memory [126, 127]. DC-based vaccines are being evaluated in early-phase clinical trials for cancers such as lymphoma and leukemia [128, 129]. Theoretically, DCs can present TB-specific antigens to CD8 + T cells, inducing cytotoxic responses that eliminate intracellular Mtb [130, 131]. Therefore, DC-based therapy represents a promising adjunctive strategy worthy of further study for TB treatment.

Regulatory T (Treg) cells contribute to immune homeostasis by exerting immunosuppressive functions through diverse mechanisms, such as inhibitory cytokines, granzyme- or perforin-mediated cytolysis, metabolic disruption, and DC suppression [132]. Their immunosuppressive function has led to their investigation as a therapeutic approach in autoimmune diseases such as type 1 Diabetes and Systemic Lupus Erythematosus [133, 134]. This has further prompted interest in exploring their utility in other contexts, such as infectious diseases [135]. Treg cells exert dual effects in the immune response to TB infection. Firstly, Treg cells mediate immunosuppression by impairing macrophage bactericidal activity and inhibiting CD4 + T cell proliferation, thereby promoting mycobacterial immune evasion [136, 137]. Secondly, by restraining excessive CD8 + T cell activation, Treg cells may help control immunopathology, thereby limiting pulmonary cavity formation and tissue fibrosis [138, 139]. Therefore, modulating Treg cell activity has been proposed as a potential strategy to ameliorate TB-associated immunopathology. To this end, translating this concept into a viable therapy would require careful determination of optimized dosing and timing to achieve a balance between bacterial control and mitigation of tissue damage.

In summary, immune cells including NK cells, DCs, and Treg cells represent potential candidates for developing novel immunotherapeutic strategies against TB. Their value may lie not only in direct antimicrobial activity but also in their capacity to modulate immune responses, which could address some limitations of conventional antibiotic regimens. However, translating these findings into clinical applications will require deeper mechanistic insights into cell-specific functions, intercellular interactions, and pathogen evasion strategies. Future research must therefore resolve these mechanistic questions and translate insights into safe and effective therapeutic protocols.

Challenges and future directions for clinical translation

In summary, the preceding sections have systematically synthesized and appraised the existing evidence and application potential of MSC-based therapies, T cell-based ACTs, and other potential cell therapies in the treatment of TB. Although these cell-based therapies have demonstrated potential as adjunctive therapeutic modalities for TB, their translation is still impeded by a host of intertwined core challenges. This chapter will focus on dissecting the key translational bottlenecks of two representative strategies and critically exploring targeted future directions to overcome these hurdles.

MSC-based therapies

Further clinical applications of MSC therapy for TB face practical challenges including treatment safety, inherent complexity and variability in the manufacturing process, large-scale production under Good Manufacturing Practice (GMP) standards, cost, and regulatory classification. Firstly, the safety profile of MSC therapy remains incompletely understood. While MSCs can modulate excessive inflammation, they also carry the potential risk of TB reactivation or disseminated infection. Moreover, MSCs may create a protective niche that promotes bacterial persistence. Furthermore, their capacities for self-renewal and differentiation introduce theoretical long-term concerns, such as ectopic tissue formation or tumorigenesis. Secondly, source heterogeneity presents another significant barrier. MSCs derived from different tissues exhibit inherent donor- and tissue-specific variations, which are further compounded by differences in isolation techniques [140]. During the expansion phase, MSCs’ heterogeneity and potency are shaped by multiple factors including donor traits, passage number, source material quality, and variations in isolation and cultivation methods [141, 142]. Furthermore, the administration route and recipient’s health status introduce additional layers of variability. Thirdly, manufacturing scalability and cost present another major barrier. The high consumption of culture reagents, particularly fetal bovine serum (FBS), poses a major cost barrier, limiting accessibility in resource-limited, high-TB-burden regions. The use of FBS may also trigger adverse immune reactions in recipients. Its batch-to-batch variability compromises product consistency and safety, potentially leading to significant quality issues [141, 143]. Lastly, significant obstacles remain in translating MSCs from research platforms into GMP-compliant medicinal products. Current standardization and regulation are characterized by a lack of unified cell characterization guidelines and a fragmented global regulatory landscape, with many countries still lacking specific frameworks [144].

To overcome the heterogeneity of MSCs, improve therapeutic efficacy, and accelerate the development of GMP-compliant products, several strategies are being explored, including pretreatment, genetic modification, the use of iPSC-derived MSCs (iMSCs), and cell-free therapies. Pretreatment and genetic modification strategies aim to directionally optimize MSC functions such as paracrine signaling, homing, and immunomodulation [145, 146]. Another promising approach involves iMSCs, which offer a more homogeneous, stable, and renewable cell source. This strategy may effectively overcome key bottlenecks such as donor variability, expansion limitations, and sample accessibility [147, 148]. Lastly, cell-free therapies, including MSC-EVs and MSC-CM, represent another approach, which may help address issues such as the low survival rates, high heterogeneity, and short lifespan of MSCs. A unique challenge lies in the variability of the secretome across different MSC sources and culture conditions, complicating standardization and reproducibility [149]. Future translational efforts should prioritize elucidating the secretome’s mechanisms of action, establishing robust quality control standards, and developing safer and more controllable cell-based therapies. Concurrently, global harmonization of regulatory standards and mutual recognition pathways for cell-based products will be essential to accelerate the worldwide accessibility of MSC-based therapies.

ACTs

The clinical translation of ACT is impeded by interconnected challenges spanning clinical safety and industrial manufacturing. Firstly, managing treatment-related toxicities—such as cytokine release syndrome (CRS), neurotoxicity, and graft-versus-host disease (GVHD)—remains a paramount concern [150]. These adverse effects necessitate the development and standardization of more refined real-time monitoring systems and precise intervention protocols to ensure patient safety. Concurrently, ACT faces profound scalability and manufacturing hurdles. Autologous therapies are burdened by complex, variable, and costly manufacturing processes, coupled with demanding cold-chain logistics [151]. These factors collectively limit production capacity, hinder scalability for large-scale trials, and ultimately restrict patient access due to high costs and logistical barriers [61].

Product innovation aims to enhance safety and broaden therapeutic applicability. Key strategies include developing “off-the-shelf” allogeneic products, employing combination therapies with immune checkpoint inhibitors, and integrating gene editing along with targeted delivery technologies to achieve greater precision [152–154]. In parallel, manufacturing innovation is equally essential. The adoption of automated closed systems, advanced bioreactors, and data-driven processes is critical for modernizing ACT manufacturing. Incorporating real-time analytics and machine learning into these systems is essential to standardize production, improve control, and ultimately achieve cost-effective scalability [155]. Ultimately, overcoming the translational barriers of ACT requires sustained interdisciplinary and cross-sector collaboration. By synergizing advances in cellular engineering, manufacturing technology, and clinical management, the field can advance towards more reliable and affordable therapies.

Conclusion

Cell therapy represents a unique innovative frontier in TB treatment, offering potential to address critical limitations of conventional antimicrobial therapy. The evidence from studies on MSCs and T cell-based ACTs demonstrates their potential as adjunctive therapies for TB. However, research on both remains at a preliminary stage, facing considerable obstacles in clinical translation. The successful integration of cell therapy into TB management hinges on several critical advances: (1) elucidating the bidirectional interactions between therapeutic cells and TB; (2) optimizing delivery strategies and dosing regimens; (3) combining cell-based interventions with standard anti-TB drugs to achieve synergistic efficacy; (4) developing predictive biomarkers for precise patient selection; and (5) establishing scalable, cost-effective biomanufacturing platforms. While significant work remains, the progress achieved to date provides a foundation for optimism that cell therapy may become a valuable addition to the TB treatment regimen, especially for patients with drug-resistant disease who have exhausted conventional therapeutic options. It has the potential to transform TB treatment and contribute to global TB elimination goals.

Abbreviations

TB

Tuberculosis

DR-TB

Drug-resistant tuberculosis

MDR-/XDR-TB

Multidrug-resistant or extensively drug-resistant tuberculosis

M.tb

Mycobacterium tuberculosis

HDT

Host-directed therapy

MSC

Mesenchymal stem cell

ACT

Adoptive cell therapy

CAR-T

Chimeric antigen receptor T-cell therapy

MSC-EVs

MSC-derived extracellular vesicles

Exo

Exosomes

AECII

Alveolar type II epithelial cells

MSC-CM

MSC-conditioned medium

Tcms

Central memory T cells

PBMCs

Peripheral blood mononuclear cells

RCT

Randomized controlled trials

iNKT

Invariant natural killer T cells

CIK

Cytokine-induced killer cells

MAIT

Mucosal-associated invariant T cells

iPSCs

Induced pluripotent stem cells

Treg

Regulatory T cells

NK

Natural killer cells

DC

Dendritic cells

GMP

Good manufacturing practice

FBS

Fetal bovine serum

CRS

Cytokine release syndrome

GVHD

Graft-versus-host disease

Author contributions

LC: writing–original draft, writing–review and editing, conceptualization, and visualization. FJ: writing–review and editing. CX: writing–review and editing. WX: funding acquisition, writing–review and editing. LS: funding acquisition, project administration, supervision, and writing– review and editing.

Funding

The authors declare that financial support was received for the research and/or publication of this article. This work was supported by the Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project (2025ZD01907900), National Nature Science Foundation of China (Grant Numbers 32394014), Shenzhen Medical Research Fund (No. D250403009) from the Shenzhen Medical Academy of Research and Translation (SMART) and Shenzhen High-level Hospital Construction Fund (No. 25260G1002).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.