Secondary lymphedema is a chronic progressive disease characterized by the abnormal accumulation of interstitial fluid and tissue swelling (1). Its core pathological mechanism is due to the structural or functional damage of the lymphatic drainage system. Such damage is often caused by tumor treatments (such as axillary lymph node dissection and radiotherapy for breast cancer), parasitic infections (such as filariasis) or trauma (2). The clinical manifestations include asymmetric swelling of the limbs, fibrosis and recurrent infections. In severe cases, it can progress to lymphangiosarcoma or limb dysfunction, notably impairing the quality of life of patients (3). Among them, breast cancer-related lymphedema (BCRL) accounts for 20-65% of secondary cases (4). Its risk factors include the use of taxane, obesity and radiotherapy to regional lymph nodes at doses exceeding 50 Gy (5-7). A global cancer statistic shows that breast cancer ranks first in the incidence of female malignant tumors (accounting for 24.5% of newly diagnosed cancer cases) (8,9). Reported incidence rates range from 6.7-62.5% depending on surgical and radiotherapy protocols (10,11). However, modern techniques such as sentinel lymph node biopsy and immediate lymphatic reconstruction have reduced the risk to 5-10 and 7.0%, respectively (12,13). BCRL is still a problem that should be solved in the field of cancer rehabilitation.

Currently, the management of BCRL faces a twofold challenge: i) An absence of standardized assessment tools; and ii) limitations of treatment methods. Although the International Society of Lymphology has proposed a staging system based on clinical symptoms (such as the subclinical stage or lymphostatic elephantiasis), it is subjective and unable to quantify the degree of fibrosis (3). While bioimpedance spectroscopy and 3D imaging techniques [such as near-infrared fluorescence lymphatic imaging with 3D reconstruction (14,15), high-resolution volumetric analysis (15) and multiparametric MRI-based radiomics (16,17)] can enhance the sensitivity of early detection, standardized imaging protocols are lacking and are device-dependent, which make it difficult to popularize (3,9). In terms of treatment, conservative therapies (such as compression therapy and manual lymphatic drainage) can relieve symptoms, but their efficacy is limited for advanced fibrosis (18,19). Surgical interventions (such as lymphatic-venous anastomosis and liposuction) can improve the appearance, but they have risks such as damage to residual lymphatic vessels, aesthetic deformities and the formation of unstable scars (20-22). In this context, mesenchymal stem cell (MSC) therapy is a focus of research due to its unique dual mechanisms of tissue repair and immunomodulation (23). MSCs promote lymphangiogenesis by paracrine-secreting factors such as vascular endothelial growth factor C (VEGF-C) and stromal cell-derived factor 1α. Additionally, they inhibit the release of proinflammatory factors such as TNF-α and IL-6, which alleviates fibrosis (24,25).

In the present review, the pathophysiological mechanisms of BCRL, which are the foundation for understanding the disease, were investigated. Subsequently, MSC therapy, with its advantages and disadvantages as a treatment for secondary lymphedema, in the context of BCRL in particular, was evaluated. Finally, the present study summarized and appraised the relevant animal and clinical experiments on various stem cell therapies for secondary lymphedema, including those associated with BCRL. Through this process, the present review aimed to assess the progress made and the problems yet to be solved in this field.

The physiological function of lymphatic vessels is to facilitate the exchange of materials such as proteins, lipids and water between tissue stroma and blood vessels. Its unique structure enables the transportation of macromolecular proteins, lipids and a notable volume of tissue fluid into lymph fluid, which are typically challenging to transfer through the venous system (26). A number of patients with cancer undergoing radiotherapy and chemotherapy may experience lymphatic vascular insufficiency and impaired drainage due to specific therapeutic agents [for example, doxorubicin decreases the lymphatic pumping frequency (27)] and physical factors [for example, radiation-induces axillary fibrosis at doses >50 Gy (28)]. Additionally, to maintain the normal function of lymphatic vessels, the pressure within the vessels should be kept ≤0 mm H₂O, as elevated intraluminal pressure disrupts cytoskeletal dynamics and impairs fluid drainage. This is evidenced by studies on lymphatic biomechanics and pathological conditions such as lymphedema (29-31). Surgical interventions often disrupt axillary lymphatic outflow and cause lymphatic blockage (32), leading to a notable increase in lymphatic pressure. This increased pressure within the lymphatic system affects the transport of proteins and immune cells, resulting in the accumulation of protein-rich fluids in the extracellular matrix and triggering an inflammatory response (Fig. 1).

Previous studies demonstrate an increase in the number of CD4⁺ T cells and their differentiation into T helper (Th) type 2 (Th2) cells in lymphedema mouse models (33-35). Inflammation-induced CD4⁺ T cells stimulate the expression of VEGF-C, which drive lymphatic vessel proliferation in tissues (36). After lymphatic damage, M2 macrophages secrete VEGF-C and function as lymphoendothelial progenitor cells. Dendritic cells are activated at the injury site and migrate into lymphatic vessels along the concentration gradient of chemokine C-C motif ligand (CCL)21, which they themselves secrete. Activated dendritic cells then travel to lymph nodes, where they activate Th cells (37). Activated Th cells express surface markers such as cutaneous lymphocyte-associated antigen, C-C chemokine receptor (CCR)4, CCR9 and CCR1. Guided by adhesion molecules and CCLs, activated Th cells infiltrate the injured site and release inflammatory cytokines, including IFN-γ, TNF-α, IL-4 and IL-5, which collectively orchestrate immune responses and tissue remodeling (38-40). A prolonged inflammatory response can lead to tissue remodeling, which is characterized by increased collagen deposition, excessive growth of fat and connective tissue (37). Recruitment of various immune cells, including M2 macrophages, Th2 lymphocytes and neutrophils, promotes fat deposition and fibrosis in lymphedema (41-43). In the chronic phase, there is low-grade inflammation, fibrosis, fat deposition and non-functional lymphangiogenesis, which is characterized by valve defects and systolic dysfunction.

Lymphography-assisted stem cell therapy represents a novel approach for treating secondary lymphedema, offering benefits such as quantifying the severity of lymphedema and enhancing diagnostic accuracy. A study by Peña Quián et al (44) conducts multiple shallow and deep stem cell injections in the lymphatic vessel trace and groin region of 2 patients with chronic lower limb lymphedema, in order to evaluate the anatomical structure and function of the lymphatic system. The study demonstrates that after stem cell implantation, imaging reveals the presence of new lymphatic branches not observed before treatment, along with thicker radioactive columns. Additionally, patients exhibit an increase in dermal reflux and proximal lymph node activity, suggesting improved lymphatic drainage.

The study by Toyserkani et al (45) quantitatively assesses lymphatic drainage by measuring the mean transit time (MTT) in patients with BCRL before and 12 months after injection of adipose-derived regenerative cells. The study notes no notable change in MTT in the lymphedema group before and after treatment, which contradicts the findings of Peña Quián et al (44), the only previous report of lymphography after stem cell therapy. Subsequently, using indocyanine green lymphangiography, the study by Jørgensen et al (46) assesses lymph vessels in real time in 237 patients with BCRL. This approach offers prospective treatment and validates the reliability and safety of this technique for staging BCRL. It provides disease-related information that cannot be obtained by clinical measurements alone (46). Despite facing challenges such as poor spatial resolution and inadequate quantification, lymphatic imaging technology remains the gold standard for assessing the extent of lymphatic dysfunction and is pivotal in determining treatment strategies.

MSCs, as pivotal tools in regenerative medicine, vary in biological traits and therapeutic effects by tissue source. In secondary lymphedema management, bone marrow-derived MSCs (BMSCs) and adipose-derived MSCs (ADSCs) demonstrate distinct clinical profiles. Regarding proliferative capacity, BMSCs show notable donor age-dependent limitations in vitro expansion, whereas ADSCs obtained through minimally invasive lipoaspiration maintain superior passage stability (47). Differentiation analyses reveal that BMSCs possess enhanced osteochondral differentiation potential mediated by constitutive activation of the Wnt/β-catenin pathway within their native bone marrow niche (48). By contrast, ADSCs have adipogenic lineage predisposition while demonstrating unique therapeutic value in ischemic tissue repair through robust secretion of angiogenic factors, such as VEGF (49). Safety evaluations indicate a comparable absence of severe adverse events between both cell types; however, the immunogenic risk is notably reduced for ADSCs in allogeneic transplantation due to their human leukocyte antigen-DR isotype-negative phenotype (50).

Over the past decade, there have been a number of reports on MSC-based treatments for lymphedema in both animal studies and clinical trials (Fig. 2; Tables I and II). In the animal studies, lymphedema models are predominantly established using mouse posterior limbs and tails (51-53). Evaluating the treatment outcomes involves immunohistochemical staining methods such as perimeter measurements, depth of skin edema, imaging techniques, anti-CD31 staining for angiogenesis, anti-lymphatic vessel endothelial receptor-1 (LYVE-1) staining for lymphangiogenesis and staining for VEGF receptor expression levels. Additionally, no notable adverse events associated with MSC transplantation were observed in the clinical trials analyzed in the present review.

BCRL is predominantly induced by radical surgery, radiotherapy and cytotoxic chemotherapy, and manifests in 20% of patients with upper extremity, thoracic or breast involvement (87). The emerging therapeutic potential of MSCs in degenerative, autoimmune and genetic disorders has extended to lymphedema management. BMSCs demonstrate therapeutic efficacy through paracrine-mediated lymphangiogenic properties that facilitate damaged network reconstruction. However, their clinical implementation is constrained by invasive harvesting procedures and age-dependent proliferative decline (88-90). By contrast, ADSCs exhibit superior proangiogenic capabilities via elevated VEGF secretion, coupled with minimally invasive harvesting procedures, demonstrating enhanced ischemic tissue revascularization and lymphatic remodeling in preclinical models. However, the adipogenic tendency of ADSCs may increase the risk of post-transplant fat deposition (91). The present review suggests that the selection of the MSCs source is optimized according to BCRL heterogeneity and pathological stage (acute edema/chronic fibrosis), and that the synergistic effects of multi-source MSCs combination therapies is investigated.

While MSCs exhibit therapeutic potential in autoimmune diseases and chronic inflammation through their immunomodulatory properties and paracrine effects, their clinical application presents a complex duality of advantages and risks that requires examination. A prominent limitation is their unpredictable differentiation behavior (92). As a study by Yoon et al (93) demonstrates, transplanting MSCs may form ectopic tissues due to microenvironmental cues, where BMSCs without immunophenotypic purification (for example, those that lack CD105⁺, CD90⁺ or CD73⁺) cause myocardial calcification instead of functional repair. Furthermore, their dual role in oncology is also concerning. While MSCs can inhibit tumors via immune modulation (94), they may paradoxically promote tumor progression by suppressing natural killer/CD8⁺ T cell activity, polarizing Th2 responses and stimulating angiogenesis (95). Such contradictions highlight the need for further mechanistic studies to reconcile the regenerative benefits of MSCs with their pathological risks.

Current animal models for BCRL successfully mimic localized swelling but fail to recapitulate the inflammatory tumor microenvironment, which obscures the risks associated with MSC therapies. Cancer exerts an influence on the immune response through the release of various factors, such as cytokines and chemokines, and these factors have the capacity to modify the capability of the immune system to recognize and eliminate cancer cells (96). Limitations in animal lifespans and experimental durations restrict long-term safety evaluations, especially for delayed tumorigenic effects. By contrast, clinical trials observe no MSC-triggered cancer recurrence or metastasis in cases with BCRL. ADSCs, prioritized for their availability, ethical compliance and trophic factor release, show clinical potential. However, their inherent tumor tropism and unaddressed chronic safety issues emphasize the necessity to balance regenerative benefits against oncological hazards during therapeutic development.

Although MSCs demonstrate therapeutic efficacy in clinical trials through tissue regeneration and immunomodulation, their clinical translation remains hindered by unresolved biological risks such as uncontrolled differentiation and unclear long-term safety (97,98). While MSC-derived exosomes show reduced oncogenic concerns compared with whole-cell therapies, several trials have yielded favorable clinical outcomes, showcasing both safety and efficacy (99-101). Previous studies highlight MSCs transplantation safety in short-term applications, yet gaps in the understanding of chronic inflammatory responses, genomic instability and tumor microenvironment interactions remain. To advance MSC-based therapies, further studies are imperative, in which direct comparisons of their regenerative benefits against latent pathological risks should be prioritized.

MSC therapies exhibit promise in ameliorating BCRL by addressing edema, fostering lymphangiogenesis and mitigating fibrosis. However, due to the absence of a universally recognized or standardized treatment regimen for BCRL, additional clinical studies with larger sample sizes and extended follow-up periods are required to further investigate this prospective therapeutic modality.