Diabetes mellitus (DM), encompassing both type I and type II forms with distinct pathogenic mechanisms, is characterized by persistent hyperglycemia; inadequate glycemic control frequently leads to severe complications such as retinopathy, neuropathy, and vasculopathy, all of which profoundly compromise patient health. Type 1 diabetes mellitus (T1DM) is primarily characterized by autoimmune-mediated destruction of pancreatic β-cells, while type 2 diabetes mellitus (T2DM) manifests as a triad of insulin resistance in target organs (skeletal muscle, liver, and adipose tissue), chronic low-grade inflammation driven by pro-inflammatory cytokines (e.g., TNF-α, IL-6) secreted from macrophages and other immune cells, and progressive β-cell dysfunction due to glucolipotoxicity and endoplasmic reticulum stress (11). ADSCs-mediated improvement of hyperglycemia may encompass islet β-cell regeneration via differentiation into insulin-producing cells or promotion of endogenous β-cell proliferation, modulation of hepatic metabolism toward enhanced glucose utilization, attenuation of chronic inflammation through anti-inflammatory cytokine secretion, and amelioration of insulin resistance (IR) in peripheral tissues via regulation of lipid homeostasis and insulin signaling pathways (12–15). ADSCs transplantation facilitates the restoration of islet function through the promotion of β-cell regeneration, attenuation of apoptosis and inflammation, and enhancement of islet vascularization (12, 16). Mechanistically , ADSCs mitigate insulin resistance in T2DM by suppressing chronic inflammation via polarization of pro-inflammatory M1 macrophages to anti-inflammatory M2 phenotypes, a process mediated by interleukin-10 (IL-10) and inhibition of NLRP3 inflammasome activation (17, 18) . In T1DM, ADSCs restore immune homeostasis by downregulating pathogenic Th1/Th17 responses and promoting regulatory T-cell (Treg) expansion, thereby attenuating autoimmune β-cell destruction (19, 20) . Molecularly , ADSC-Exos deliver microRNAs (e.g., miR-146a) that inhibit NF-κB and STAT3 signaling, reducing cytokine storms in pancreatic islets (21) . Additionally, ADSCs enhance β-cell survival and function via paracrine secretion of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) to promote β-cell proliferation and reduce apoptosis (22) . Preclinically , in streptozotocin-induced T1DM rodent models, systemic ADSC administration improves glycemic control by restoring β-cell mass, reducing hyperglycemia (22, 23). In high-fat-diet-induced T2DM mice, ADSCs alleviate insulin resistance via AMPK/SIRT1-mediated enhancement of mitochondrial metabolism in adipose tissue and skeletal muscle (24, 25). Clinically , phase II trials in T2DM patients demonstrate that umbilical cord-derived MSCs (UC-MSCs) reduce HbA1c by 1.5–2.0% and improve insulin sensitivity, correlating with decreased serum TNF-α and increased adiponectin levels (26) . For T1DM, prior case reports have indicated that the infusion of in vitro-differentiated insulin-producing cells derived from ADSCs into patients led to sustained stabilization of blood glucose levels and glycosylated hemoglobin (HbA1c) (27), and a prospective dual-arm clinical trial demonstrated that autologous ADSCs combined with bone marrow-derived hematopoietic stem cells (BM-HSCs) enable sustained glycemic regulation (28). Other clinical trials report transient C-peptide preservation and reduced exogenous insulin requirements, though long-term efficacy remains inconsistent (29) . Challenges include donor-dependent variability in ADSC secretome potency, risks of iPSC-derived β-cell teratoma formation due to residual pluripotency , and fibrotic complications linked to TGF-β overactivation during immunomodulation (30) . Emerging strategies to address these limitations involve biomaterial encapsulation for targeted pancreatic delivery and IFN-γ preconditioning to enhance immunosuppressive capacity (31) .

Obesity induces a decline in ADSC activity, with studies demonstrating a 40% reduction in ADSC activity in obese populations compared to healthy individuals, directly impairing tissue regenerative capacity and potentially triggering metabolic disturbances such as arteriosclerosis and insulin resistance (32). Under obese conditions, ADSCs exhibit a shift toward a pro-inflammatory secretory profile characterized by increased secretion of IL-1β, IL-6, and IL-8 cytokines, accompanied by a concomitant reduction in immunomodulatory, insulin-sensitizing, and weight-regulatory adipokines (e.g., IL-10, TGF-β, and adiponectin), thereby exacerbating metabolic dysfunction (33–35). And Yu Meng et al.’s study demonstrates that obesity impairs the structural integrity and functional capacity of ADSCs’ mitochondria, potentially mediated in part through miRNA-induced regulation of mitochondrial genes, leading to an escalation in oxidative stress (36). Moreover, studies in diet-induced obesity models have established that PD-L1 upregulation contributes to T cell dysfunction, characterized by a marked impairment in cytolytic activity (37). Beyond investigations in animal models, a clinical study involving 47 reproductive-aged African women demonstrated that serum from overweight/obese individuals (with or without metabolic syndrome) significantly impaired ADSCs proliferation and migration, linked to elevated IL6 levels, and induced lipid accumulation during osteogenic differentiation, highlighting systemic inflammatory dysregulation as a key driver of ADSC functional decline in metabolic disorders (38). Although the reciprocal interactions between obesity and ADSCs remain incompletely elucidated, inspired by existing research, ADSCs may hold broad clinical application prospects in obesity and obesity-related diseases. ADSC-derived exosomes ameliorate obesity-associated metabolic dysregulation by promoting M2 macrophage polarization, enhancing white adipose tissue beiging, and improving insulin sensitivity through STAT3-mediated arginase-1 activation (39). Numerous in vivo studies have demonstrated the efficacy of ADSCs in promoting weight loss and ameliorating hyperlipidemia (40–42). Non-alcoholic fatty liver disease (NAFLD), a spectrum ranging from hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma, is closely associated with obesity and metabolic syndrome (43, 44). Studies indicate that ADSCs mitigate NAFLD progression by homing to damaged liver tissue, enhancing hepatocyte regeneration, and exerting anti-inflammatory/antioxidant effects through their self-renewal and multipotent differentiation capabilities (45, 46). Although current studies on the mechanisms and preclinical research of ADSCs in obesity and metabolic disorders suggest their potential therapeutic roles, translating these findings into clinical applications remains a protracted process. This transition necessitates rigorous optimization of multiple procedures, including standardized isolation, purification, expansion, and clinical validation of ADSCs, as well as comprehensive safety and efficacy evaluations in human trials.

ADSCs exhibit a multifaceted and bidirectional relationship with the tumor microenvironment (TME), a heterogeneous ecosystem comprising immune cells, stromal fibroblasts, extracellular matrix (ECM), and metabolic mediators that collectively drive tumor progression and therapeutic resistance (47, 48) . A vitro study demonstrates that bidirectional crosstalk between human adipose-derived stem cells (ADSCs) and malignant melanoma cells (MMCs) in an indirect co-culture model significantly enhances tumor-promoting behaviors, including migration, invasion, and angiogenesis, via upregulation of pro-angiogenic factors (VEGF, IL-8, CCL2), matrix metalloproteinases (e.g., MMP-2), and oncogenic mediators (CXCL12, PTGS2, IL-6, HGF) (49, 50). ADSCs are recruited to the TME via tumor-secreted chemotactic signals, such as CCL2 and CXCL12, where they undergo functional reprogramming to adopt pro-tumorigenic roles (49, 51). Within the TME, ADSCs contribute to immunosuppression by secreting anti-inflammatory cytokines (e.g., IL-10, TGF-β) and exosomes that dampen cytotoxic T-cell activity, promote regulatory T-cell (Treg) expansion, polarize macrophages toward an immune-tolerant M2 phenotype, inhibit of dendritic cells differentiation, promoting immune escape of tumor cells (18, 19) . The TME reciprocally shapes ADSC behavior through metabolic crosstalk. Hypoxia and nutrient deprivation in the TME drive ADSCs to release fatty acids and lipid metabolites, which tumor cells exploit to fuel oxidative phosphorylation (OXPHOS) and mitigate metabolic stress (52) . This lipid transfer is further amplified by ADSC-derived exosomal miRNAs (e.g., miR-21, miR-155), which activate oncogenic pathways such as PI3K/Akt and Wnt/β-catenin in adjacent tumor cells (53, 54) . Notably, obesity exacerbates this metabolic symbiosis, as high-fat diets enhance lipid availability in the TME, impairing CD8+ T-cell function and accelerating tumor growth—a mechanism conserved across murine and human cancers (55–57) . Furthermore, a vitro study demonstrates MSCs promote reversible metastatic enhancement in breast carcinoma through TME-driven CCL5/RANTES secretion, which activates CCR5-mediated paracrine signaling to potentiate cancer cell motility, invasion, and distant dissemination (58). In contrast to their tumor-promoting effects, MSCs have also been shown to inhibit the progression of malignancies such as leukemia and hepatocellular carcinoma; therefore, as multipotent stromal cells, MSCs can secrete context-dependent factors within the tumor microenvironment that either suppress or exacerbate neoplastic growth through bidirectional modulation of oncogenic signaling pathways (59). Beyond their established roles in promoting tumorigenesis, progression, and metastasis, ADSCs are also closely associated with chemoresistance to antitumor agents.

ADSCs drive chemoresistance in malignancies through multifaceted mechanisms within the TME. Primarily, ADSCs engage in bidirectional crosstalk with tumor cells via paracrine signaling, exemplified by the TSG-6/COX-2 axis: Tumor necrosis factor alpha-stimulated gene/protein 6 (TSG-6) upregulates cyclooxygenase-2 (COX-2) expression, fostering prostaglandin E2 (PGE2)-mediated angiogenesis, immunosuppression, and apoptosis evasion, a mechanism validated by the abrogation of chemoresistance upon TSG-6 silencing in ADSCs (60–63). Furthermore , ADSCs secrete interleukin-6 (IL-6), which activates STAT3 in tumor cells to enhance DNA repair and upregulate multidrug resistance (MDR) transporters such as P-glycoprotein (64, 65). Concurrently , metabolic reprogramming induced by ADSCs—such as the release of platinum-induced polyunsaturated fatty acids (PIFAs) to scavenge reactive oxygen species (ROS)—protects tumor cells from cytotoxic damage, a process reversible through COX-1/thromboxane synthase inhibition (66). Additionally , ADSCs remodel the extracellular matrix (ECM) via matrix metalloproteinase (MMP)-mediated stiffening, creating physical barriers that impede drug penetration while promoting hypoxia-driven angiogenesis through HIF-1α/VEGF activation (67). Critically , ADSCs enhance tumor cell stemness by inducing epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) phenotypes via Wnt/β-catenin and Notch signaling, thereby amplifying self-renewal capacity and therapeutic resistance (68, 69). Notably , targeting these pathways—such as COX-2/PGE2 inhibition, TSG-6 neutralization, or metabolic disruption of PIFA synthesis—holds therapeutic potential to restore chemosensitivity. In summary , ADSCs orchestrate a pro-survival TME through integrated paracrine, metabolic, and structural adaptations, highlighting the urgency of developing stroma-targeted adjuvants to overcome multidrug resistance in oncology.

Although ADSCs may exhibit pro-tumorigenic effects, including tumor initiation, progression, and metastatic dissemination through crosstalk with the tumor microenvironment, emerging evidence paradoxically highlights their significant clinical potential as anti-neoplastic agents through immunomodulatory mechanisms and targeted therapeutic delivery. Preclinical studies demonstrate their capacity to suppress tumor growth in glioblastoma (70), hepatocellular carcinoma (71, 72), colon cancer (73, 74) and other tumor models (75). Meanwhile, the homing capacity of ADSCs to tumor niches positions them as ideal cellular vectors for targeted drug delivery. Engineered ADSCs overexpressing TNF-α or TRAIL via CRISPR/Cas9 have shown enhanced tumor-specific cytotoxicity in murine models, selectively localizing to metastatic sites while minimizing off-target effects (76, 77). Additionally, ADSC-derived exosomes loaded with chemotherapeutic agents (e.g., doxorubicin) or oncolytic viruses achieve precise intratumoral delivery, overcoming biological barriers and reducing systemic toxicity (78, 79). Recent advances highlight their utility in photodynamic therapy, where photoactivated ADSCs release reactive oxygen species (ROS) to induce localized tumor cell death, synergizing with checkpoint inhibitors to amplify anti-PD-1/PD-L1 efficacy (80). ADSCs, in addition to their direct/indirect antitumor effects, have also demonstrated positive clinical effects in managing toxic side effects associated with chemoradiotherapy, including cisplatin-induced fertility impairment (81), salivary gland dysfunction following radiotherapy for head and neck tumors (resulting in xerostomia) (80, 82), and chemotherapy-induced granulocytopenia through secreting Granulocyte Colony-Stimulating Factor (G-CSF (83, 84). Ongoing research focuses on bioengineering strategies to “lock” ADSCs in anti-tumor states through metabolic priming (e.g., mTOR inhibition) or epigenetic modulation to suppress pro-metastatic gene networks . These innovations underscore ADSCs’ versatility as modular therapeutic platforms, though rigorous characterization of their spatiotemporal dynamics within the TME remains critical to mitigate context-dependent risks.

Autoimmune disorders, encompassing various chronic organ-specific and systemic diseases caused by immune system malfunction that mistakenly attacks the body’s own cells and tissues, affect approximately 8-10% of the population, resulting in significant health impairments, elevated mortality rates, and substantial medical burdens (87, 88). As summarized in Table 1 , numerous preclinical and clinical studies have investigated the therapeutic potential of adipose-derived mesenchymal stem cells (ADSCs) in managing various autoimmune disorders. Rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), and type 1 diabetes mellitus (T1DM) represent the most prevalent systemic autoimmune conditions globally. These chronic disorders share a common pathogenesis characterized by dysregulated immune responses leading to persistent organ inflammation and progressive tissue damage. Current standard treatments, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, and chemotherapeutic agents such as methotrexate (MTX), often present significant limitations. Given their demonstrated anti-inflammatory properties and immunomodulatory capabilities, ADSCs have emerged as a promising therapeutic alternative for autoimmune diseases, offering the potential to restore immune homeostasis while avoiding the detrimental side effects of conventional pharmacotherapies. This unique biological profile positions ADSC-based therapy as a novel paradigm in the evolving landscape of autoimmune disease management.

Acute and chronic graft-versus-host disease (GVHD) are common yet challenging clinical complications following allogeneic hematopoietic stem cell transplantation and solid organ transplantation (such as ocular grafts, kidneys, etc.). Given the immunomodulatory and anti-inflammatory properties of adipose-derived mesenchymal stem cells, they hold potential for combating GVHD (97–99). Animal model studies have clarified the effectiveness of ADSCs against bone marrow aplasia in GVHD (100), while another animal study demonstrated that subconjunctival injection of ADSCs significantly improved post-transplant corneal integrity and promoted wound healing, highlighting their clinical potential in this context (101). Beyond animal research, clinical data on ADSCs for GVHD management have also been reported. A single-arm clinical study involving pediatric patients with refractory bronchiolitis obliterans syndrome (BoS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed that ADSCs could be safely administered (102). Additionally, a phase I/II study indicated that combining ADSCs with immunosuppressive therapy is feasible and safe for chronic GVHD post allo-HSCT, with potential positive impacts on disease progression (103). More studies are warranted to understand the potential benefits of ADSCs in GVHD.