Macrophage-mediated metabolic dysregulation in the pancreas: Insights from obesity

Abstract

Obesity is a major contributor to metabolic dysfunction, and its impact on pancreatic health has garnered increasing attention. Macrophages, as key regulators of inflammation and metabolism, play a central role in mediating obesity-induced pancreatic damage. In obese individuals, excessive lipid accumulation and chronic low-grade inflammation drive the infiltration and polarization of macrophages within the pancreas. These macrophages, particularly the pro-inflammatory Macrophage, pro-inflammatory phenotype (M1) phenotype, secrete cytokines such as C-C motif ligand 2 (CCL2) and transforming growth factor beta (TGF-β), which disrupt pancreatic β-cell function and impair insulin secretion. Conversely, anti-inflammatory Macrophage, anti-inflammatory phenotype (M2) macrophages contribute to tissue repair but may also promote fibrotic changes under prolonged metabolic stress. Pancreatic macrophages are activated under high-fat diet conditions, promoting inflammation and impairing β-cell function through the SUCLA2-HIF-1α axis and mechanistic Target of Rapamycin Complex 1 (mTORC1)/PD-1 pathway, thereby establishing a self-perpetuating "metabolic-immunosuppressive" vicious cycle. Targeted intervention strategies against macrophages—such as SUCLA2 inhibitors can ameliorate metabolic dysregulation. Meanwhile, exosome-mediated interorgan communication [e.g., via microRNA-155 (miR-155) and miR-30a] offers novel insights for multi-system synergistic therapies. Understanding the mechanisms by which macrophages mediate metabolic dysregulation in the pancreas under obese conditions provides critical insights into the pathogenesis of obesity-related pancreatic disorders.

Key Words: Obesity; Pancreas; Macrophages; Metabolic dysfunction; Inflammation response

Core Tip: Obesity contributes to the polarisation of pancreatic macrophages towards pro-inflammatory Macrophage, pro-inflammatory phenotype type through chronic inflammation, releasing factors such as C-C motif ligand 2 and transforming growth factor beta that impair β-cell function and trigger fibrosis. Macrophage metabolites and their interactions with vesicular cells have been identified as key mechanisms of metabolic disorders. Targeted regulation of macrophage polarisation such as the PPAR-γ pathway shows therapeutic potential. Future studies need to focus on macrophage subpopulation heterogeneity to develop precise therapeutic strategies.

INTRODUCTION

Obesity is a chronic metabolic disorder marked by excessive fat accumulation (body mass index ≥ 30 kg/m²), driving a global public health crisis with rising prevalence, severe comorbidities (e.g., diabetes, cardiovascular disease, cancer), and limited effective treatments, projected to affect over half the world’s adult population by 2050[1]. The World Health Organization estimates that obesity-related metabolic disorders have emerged as a significant etiological factor in pancreatic diseases worldwide, with pancreatic islet dysfunction playing a critical role in the pathogenesis of metabolic conditions, including diabetes. This underscores the critical necessity for developing novel therapeutic interventions, given the current absence of clinically available treatments specifically designed to address obesity-associated pancreatic metabolic dysregulation. The imbalance in macrophage phenotypic polarization, particularly the Macrophage, pro-inflammatory phenotype (M1)/Macrophage, anti-inflammatory phenotype (M2) shift, within the pancreatic tissue exacerbates β-cell apoptosis and promotes pancreatic fibrosis. This pathological process is mediated by the excessive secretion of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), as well as the disruption of the pancreatic islet microenvironment. Collectively, these mechanisms contribute to disease progression from simple obesity to pancreatic dysfunction. Obesity drives phenotypic polarization in pancreatic macrophages, thereby exacerbating localized inflammatory responses[2]. Recent years, there has been a marked increase in research focus on the role of pancreatic macrophages in mediating metabolic dysregulation in obesity, as well as their potential therapeutic implications. Moreover, metabolic dysregulation associated with obesity and sustained low-grade systemic inflammation are pivotal contributors to pancreatic injury. Excessive lipid accumulation induces macrophage infiltration and polarization, leading to the secretion of pro-inflammatory cytokines, including C-C motif ligand 2 (CCL2) and TGF-β. This process further exacerbates β-cell dysfunction and pancreatic islet fibrosis via inflammatory signaling pathways[3]. Modulating macrophage polarization and metabolic reprogramming has emerged as a promising therapeutic approach to mitigate obesity-induced pancreatic metabolic dysregulation[4].

Macrophages, particularly the pro-inflammatory M1 phenotype, serve as pivotal mediators in the pathogenesis of obesity-induced pancreatic metabolic dysregulation. Aberrant macrophage activation impairs β-cell function and exacerbates islet fibrosis through the secretion of pro-inflammatory mediators, including CCL2 and TGF-β, underscoring the therapeutic potential of targeting macrophage polarization in mitigating obesity-associated pancreatic injury[5]. As pivotal components of the innate immune system, macrophages exert a multifaceted and essential regulatory influence within the pancreatic microenvironment under obese conditions. Under physiological conditions, pancreatic tissue macrophages predominantly display an anti-inflammatory M2-polarized phenotype, playing a crucial role in maintaining tissue homeostasis and facilitating injury repair processes[6]. However, metabolic dysregulation induced by obesity markedly modifies the pancreatic immune microenvironment, resulting in heightened macrophage infiltration and phenotypic alterations. The alterations exert multifaceted impacts on pancreatic function, with three primary mechanisms of action: Firstly, substantial quantities of free fatty acids and pro-inflammatory mediators, liberated during adipose tissue expansion, are systemically transported and subsequently infiltrate pancreatic tissue via circulatory pathways[7]; Secondly, locally produced chemokines within the pancreatic islets facilitate the recruitment of additional monocytes, promoting their infiltration into the pancreas[8]; Finally, the hyperglycemic and lipotoxic microenvironment promotes macrophage polarization toward the pro-inflammatory M1 phenotype. This shift not only directly compromises pancreatic islet β-cell function and survival but may also disrupt the normal pancreatic architecture and function by modulating extracellular matrix composition[9]. Notably, pancreatic macrophages exhibit distinct phenotypic and functional properties compared to their counterparts in other metabolic organs, such as the liver and adipose tissue. These unique characteristics may underlie the pancreas’ specialized response to metabolic stress. A comprehensive elucidation of the biological characteristics of pancreatic macrophages in the context of obesity is crucial for unraveling the pathogenic mechanisms underlying pancreatic dysfunction in metabolic disorders (Figure 1).

Figure 1 Regulatory mechanisms of pancreatic macrophage modulation in obesity pathogenesis. The figure illustrates the pathological mechanisms by which pancreatic macrophages, upon stimulation, undergo various pathological responses that ultimately lead to pancreatic fibrosis. TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor alpha; NF-κB: Nuclear factor-kappaB.

The pancreas serves as a critical dual-function organ, maintaining metabolic homeostasis through coordinated endocrine and exocrine activities[10]. The endocrine compartment, specifically the islets of Langerhans, orchestrates glucose homeostasis through the regulated secretion of key metabolic hormones including insulin and glucagon[10]. The pancreatic endocrine system, principally comprised of the islets of Langerhans, maintains glycemic control through the biphasic secretion of insulin (β-cell-derived) and glucagon (α-cell-sourced), constituting a fundamental glucose-regulatory axis[10]. Under obesogenic conditions, sustained nutrient overload induces cellular metabolic stress, resulting in systemic insulin resistance, persistent hyperglycemia, and subsequent β-cell adaptive hyperplasia that ultimately progresses to secretory dysfunction[11]. This metabolic dysfunction is further aggravated by chronic low-grade inflammation, marked by the recruitment of immune cells—particularly macrophages—into pancreatic islets[11]. Adipocyte-derived pro-inflammatory mediators, including TNF-α, IL-6, and saturated free fatty acids (e.g., palmitate), drive macrophage polarization toward a pro-inflammatory M1 phenotype through TLR4/Nuclear Factor kappa-light-chain-enhancer of activated B cells-dependent signaling[12]. These activated macrophages establish a feed-forward inflammatory loop via increased reactive oxygen species production and secretion of secondary cytokines (notably IL-1β), thereby exacerbating islet inflammation and metabolic dysfunction[13]. These pathological mediators collectively compromise β-cell functional integrity, induce apoptotic cell death, and impair insulin receptor signaling, thereby establishing a self-reinforcing cycle of metabolic deterioration[13]. Furthermore, macrophage-driven dysregulation of extracellular matrix homeostasis and subsequent islet fibrotic remodeling represent key pathological mechanisms through which obesity-induced inflammation promotes progressive pancreatic dysfunction and type 2 diabetes pathogenesis[14].

METHODOLOGY OF DATA COLLECTION

The data in this review were collected through a comprehensive search of peer-reviewed articles and preclinical studies using PubMed, Scopus, and Web of Science databases. Keywords included “pancreatic macrophages”, “obesity”, “metabolic dysfunction”, and synonyms for these terms, as well as synonyms and related terms for these terms. Only studies published in the last three years were prioritized to ensure up-to-date findings. Inclusion criteria focused on studies examining the role of pancreatic macrophages in obesity-related metabolic dysfunction, including abnormal insulin secretion, inflammatory pathways (e.g., cGAS/STING, Fpr2-mediated chemotaxis), and others. The main study of this review is “Macrophage involvement in the pancreas under obesity and how it helps to free the pancreas from obesity”.

THE ROLE OF MACROPHAGES IN THE PATHOGENESIS OF OBESITY

Chronic low-grade inflammation of adipose tissue, especially visceral fat, is a central component of insulin resistance and metabolic disorders in obese states. Inflammation is an immune response triggered by multiple stimuli involving the coordinated action of different immune cells[15]. The main immune cell type that causes inflammation in the islets of obesity and T2DM is macrophages. Pancreatic resident macrophages are the basis of the inflammatory response in obesity and mechanically participate in the β-cell hyperplasia and dysfunction that characterize this insulin-resistant state[16]. Resident macrophages in lean pancreases maintain tissue homeostasis through an anti-inflammatory phenotype, characterized by the secretion of protective mediators [interleukin-10 (IL-10), TGF-β, insulin-like growth factor-1] to support β-cell function[17]. The PPARγ-KLF4 axis dominates at the transcriptional level and epigenetically suppresses pro-inflammatory genes through H3K27me3[18]. In the obese state, these cells undergo a pathogenic transformation: The secretion profile shifts to IL-1β (which induces β-cell apoptosis through the STING-IFN-I pathway in human islets)[19]. Metabolically, HK1-dependent glycolytic flux activates the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome to maintain the inflammatory state[20]. In conclusion, macrophages drive disease progression in obesity by mediating inflammation, metabolic dysregulation and tissue remodeling, creating a vicious cycle. Intervention strategies targeting their infiltration, polarization and function may provide new directions for the treatment of obesity and related metabolic diseases. However, human macrophage heterogeneity is complex and further studies on its subpopulation-specific mechanisms are needed (Figure 2).

Figure 2 Role of pancreatic macrophages in obesity-associated metabolic dysregulation. This figure delineates the pathway-mediated process by which islet macrophages polarize into M1 and M2 phenotypes under inflammatory conditions, secreting pro-inflammatory cytokines that ultimately lead to β-cell loss. CCL2: Chemokine (C-C Motif) Ligand 2; HIF-1α: Hypoxia-inducible factor-1 alpha; 12-LOX: 12-lipoxygenase; SUCLA2: Succinate-CoA ligase ADP-forming beta subunit; TGF-β: Transforming growth factor-beta; TNF-α: Tumor necrosis factor-alpha; IL-1β: Interleukin-1 beta

TARGETING PANCREATIC MACROPHAGE FUNCTION: A THERAPEUTIC STRATEGY FOR OBESITY

Under conditions of obesity, pancreatic islet macrophages are activated by factors such as excessive free fatty acids, infiltrate pancreatic tissue, and trigger chronic inflammation, thereby driving metabolic dysregulation and insulin resistance associated with obesity and type 2 diabetes[21,22] (Table 1). The construction of the inflammatory microenvironment is also dependent on pancreatic macrophages: A high-fat diet triggers Integrin alpha M (CD11b)+Lymphocyte antigen 6 complex, locus C (Ly6C)+ monocytes to infiltrate into pancreatic islets, creating a pro-inflammatory M1 macrophage dominance that secretes IL-1β and TNF-α to directly inhibit β-cell function[23,24]. Pancreatic macrophages are also involved in immune checkpoint regulation: Obesity induces macrophage programmed death-1 (PD-1) expression through the mTORC1/glycolysis pathway, inhibiting phagocytosis and antigen presentation, forming a vicious cycle of “metabolism-immunosuppression”[16,25]. In terms of intervention, pancreatic macrophages help to “metabolize” the pancreas in a variety of ways Targeting SUCLA2 or PD-1 specifically blocks macrophage pro-inflammatory pathways, and preclinical studies have shown that it improves β-cell function more efficiently than conventional anti-inflammatory drugs, making pancreatic macrophages an important player for metabolic checkpoint inhibitors[23,26]. Meanwhile, probiotics expressing IL-10 or modulating cystine metabolism can remodel the pancreatic macrophage phenotype with both safety and targeting, providing a viable pathway for engineered microbial therapies[27,28]. In addition, activation of the sympathetic nerve-M2 macrophage axis [e.g., nerve growth factor (NGF) delivery] synergistically enhances fat browning and insulin sensitivity, breaking through single-target limitations and serving as a combined multi-system intervention[16,23].

Table 1 Therapeutic strategies targeting pancreatic macrophages in obesity: Molecular mechanisms and clinical implications[22].

	Mechanism of action	Biological consequences	Therapeutic implications	Ref.
Obesity-associated pancreatic macrophage activation	Excessive free fatty acids → activation of islet macrophages → induction of metabolic reprogramming → triggering of a pro-inflammatory phenotype (Integrin alpha X (CD11c)+/major histocompatibility complex class II (MHC-II)+, secretion of IL-1β/TNF-α) → recruitment of T cell infiltration	Pancreatic inflammation and tissue destruction contribute to insulin resistance and the progression of type 2 diabetes mellitus	Caloric restriction and bariatric surgery reduce macrophage infiltration
PD-1/mTORC1 pathway	A high-fat diet activates the mTORC1 pathway in macrophages, leading to increased expression of PD-1. Elevated PD-1 suppresses macrophage phagocytic capacity and antigen presentation, creating a "metabolic-immunosuppressive" vicious cycle. PD-1/programmed cell death ligand 1 interactions further promote immune tolerance, impairing metabolic regulation and perpetuating obesity-associated pancreatic dysfunction	Creates "metabolic-immune suppression" vicious cycle	PD-1 blockade (e.g., immune checkpoint inhibitors) could restore macrophage surveillance	[22,27]
IL-1β/TNF-α secretion	Obesity triggers the infiltration of CD11b+Ly6C+ monocytes into pancreatic islets, where they differentiate into M1-polarized macrophages. These macrophages excessively secrete IL-1β and TNF-α, which directly damage β-cells by inhibiting insulin secretion, disrupting calcium homeostasis, and inducing apoptosis. These cytokines also activate NF-κB and c-Jun N-terminal Kinase pathways, amplifying islet inflammation and fibrosis	Direct β-cell toxicity and insulin secretion inhibition	Engineered probiotics expressing IL-10 may counteract inflammation	[23,28]
Microbial DNA sensing	Gut dysbiosis in obesity releases microbial DNA (e.g., bacterial CpG motifs) into circulation, which activates pancreatic macrophages via toll-like receptor 9. TLR9 signaling triggers inflammasome assembly (e.g., NLRP3), leading to IL-18 and IL-1β maturation. This sterile inflammatory response exacerbates islet damage and promotes fibrotic remodeling	Promotes islet inflammation and fibrosis	DNase I treatment or TLR9 antagonists might mitigate sterile inflammation	[23]
Sympathetic-NGF axis	Sympathetic nerve-derived NGF binds to Tropomyosin Receptor Kinase A receptors on macrophages, driving their polarization toward the anti-inflammatory M2 phenotype. M2 macrophages secrete IL-10 and TGF-β, which enhance insulin sensitivity and promote adipose tissue browning. Concurrently, NGF suppresses M1-associated genes [e.g., inducible nitric oxide synthase], mitigating inflammatory responses	Improves insulin sensitivity and induces adipose browning	Targeted NGF delivery systems (e.g., hydrogel-based) could enhance precision therapy	[23,25]
Exosomal miR-155	Adipose tissue macrophages release exosomes containing miR-155, which are taken up by pancreatic macrophages. miR-155 suppresses suppressor of cytokine signaling 1 (suppressor of cytokine signaling 1), leading to hyperactivation of signal transducer and activator of transcription 1 signaling and amplifying pro-inflammatory responses. Additionally, miR-155 inhibits β-cell proliferation by downregulating key genes (e.g., pancreatic and duodenal homeobox 1, contributing to diabetic progression	Amplifies pro-inflammatory microenvironment	Anti-miR-155 oligonucleotides (exosome-loaded) may achieve tissue-specific inhibition	[26,29]

CD11c: Integrin alpha X; MHC-II: Major histocompatibility complex class II; IL-1β: Interleukin-1 beta; TNF-α: Tumor necrosis factor-alpha; mTORC1: Mechanistic target of rapamycin complex 1; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death-ligand 1; CD11b: Integrin alpha M; Ly6C: Lymphocyte antigen 6C; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; JNK: C-Jun N-terminal kinase; TLR9: Toll-like receptor 9; NLRP3: NLR family pyrin domain containing 3; IL-18: Interleukin-18; TrkA: Tropomyosin receptor kinase A; TGF-β: Transforming growth factor-beta; NGF: Nerve growth factor; iNOS: Inducible nitric oxide synthase; miR-155: MicroRNA-155; SOCS1: Suppressor of cytokine signaling 1; STAT1: Signal transducer and activator of transcription 1; PDX1: Pancreatic and duodenal homeobox 1.

Currently, there are no clinically approved therapies specifically targeting pancreatic macrophages, but several promising preclinical approaches are under investigation. These include metabolic pathway interventions (e.g., SUCLA2-HIF-1α axis inhibitors and PD-1/mTORC1 pathway blockers), macrophage phenotype modulation (e.g., PPAR-γ agonists and IL-10 delivery systems), neuro-immune regulation (e.g., NGF-mediated M2 polarization), and exosome-based technologies (e.g., miR-155 inhibitors). However, significant challenges remain, such as achieving pancreatic-specific drug delivery due to the organ's fibrotic barrier and low vascularity, addressing macrophage heterogeneity revealed by single-cell sequencing, and mitigating safety risks like autoimmune pancreatitis from systemic immunomodulation. Future directions focus on developing pancreas-targeted nanocarriers, CRISPR-based gene editing of macrophage-specific inflammatory genes, and human organoid models for drug testing. While metabolic interventions and exosome therapies show the most near-term translational potential, overcoming delivery efficiency and specificity hurdles will be critical, with clinical candidates likely requiring another 5-10 years of development before reaching human trials.

IMPLICATIONS FOR THE TREATMENT OF OBESITY

As a multifactorial-driven metabolic disease, the pathogenesis of obesity is closely related to metabolic disorders and chronic low-grade inflammation. As one of the important components of the innate immune system, pancreatic macrophages play a dual role in the local microenvironment of the pancreas and systemic metabolic regulation[29]. Targeted inhibition of their M1-type polarization can down-regulate the release of pro-inflammatory mediators, and at the same time, promote the M2-type anti-inflammatory phenotypes - the secretion of IL-10 and TGF-β, which can remodel the pancreatic immune homeostasis, and improve glucose-lipid metabolic disorders[30-32]. The targeted regulation of its functional phenotype M1, M2 polarization provides a mechanistic target for therapeutic intervention and helps to develop effective drugs for the treatment of obesity and its complications[32]. Its functional plasticity makes it a pivotal node in the treatment of obesity (Concluding statement). Modulation of its phenotypic transformation by small molecule agonists such as: PPARγ agonists and nanocarrier-targeted delivery or gene editing techniques can synchronize anti-inflammatory, pro-catabolic and organ-protective effects[29]. It provides ideas for future research focusing on the functional analysis of its heterogeneous subpopulations, as well as the development of precise regulatory strategies based on single-cell sequencing technology[29,30]. In addition, M2 macrophage-derived exosomes carrying miR-155, miR-30a and other non-coding RNAs can repair pancreatic islet β-cell function through paracrine mechanisms, enhance skeletal muscle GLUT4 membrane translocation and hepatic glycogen synthesis, and this trans-organ communication network provides a molecular basis for systemic metabolic regulation, addressing multiple disease mechanisms and providing comprehensive therapeutic approaches[27,29,33].

FUTURE DIRECTIONS

In the study of pathological mechanisms of obesity-associated pancreatic islet inflammation, macrophage polarisation regulation is emerging as a key entry point for reversing the inflammatory microenvironment (Concluding statement). EP4 receptor agonists provide a novel strategy for intervening in pancreatic islet inflammation through the mechanism of epigenetic remodelling of M2-type macrophage polarisation, which can significantly improve pancreatic islet β-cell function in an obesity model through remodelling of immune cell phenotypes, with precise modulation of macrophage polarisation status at the core[6]. In addition to this, Nrf2 activators such as eugenol reveal the importance of mitochondrial dynamics regulation through maintenance of mitochondrial dynamics[34]. In addition, the anti-inflammatory mechanism of action of Nrf2 activators such as eugenol reveals the importance of the regulation of mitochondrial dynamics, which not only enhances the anti-inflammatory phenotype of macrophages by maintaining the dynamic balance between mitochondrial fusion and fission, but also builds a new dimension of immune regulation at the level of cellular energy metabolism, suggesting that synergistic targeting of multiple pathways may be a key pathway to break through the existing therapeutic barrier[34]. These findings provide a theoretical basis for therapeutic strategies targeting macrophages at the molecular and organelle levels (Concluding statement).

The dual pathogenic role of the 12-lipoxygenase (12-LOX) pathway in the metabolic-immune interface has attracted much attention: Its aberrant activation not only exacerbates pancreatic islet inflammation by driving a pro-inflammatory cytokine cascade, but also directly impairs β-cell function through lipotoxicity, resulting in a vicious cycle of metabolic disorders and immune dysregulation[35]. The Nargis et al's studies in mice have demonstrated that inhibition of 12-LOX simultaneously improves glucose-lipid metabolic parameters and reduces pancreatic macrophage infiltration[35]. Nargis et al[35] demonstrated in a mouse model that inhibition of 12-LOX can simultaneously improve glucose-lipid metabolism parameters and reduce pancreatic macrophage infiltration, which functionally verifies the feasibility of this pathway as a therapeutic target. In the regulatory system of the gut-pancreas axis, the mitigating effect of the flagellin-TLR5 signaling pathway on pancreatic islet inflammation is blocked, which reveals the mechanism of the trans-organ dialogue between the microbial metabolites of the intestine and pancreatic immune microenvironment[36]. Li et al[37] showed that inulin inhibits histone deacetylase (HDAC) activity by generating butyrate through intestinal flora, and constructed a three-level regulatory network of ‘diet-flora-epigenetic’, which provides empirical evidence for the remodelling of macrophage phenotypes through dietary interventions[36,37]. These cross-systemic regulatory mechanisms suggest that macrophage dysfunction is a key factor linking metabolic disorders and immune microenvironments. dysfunction is a central hub linking metabolic disorders and immune injury.

Challenges and innovations at the clinical translational level are driving the field towards interdisciplinary integration. While drug candidates such as EP4 agonists have demonstrated clear efficacy in preclinical studies, their lack of pancreas-specific delivery efficiency remains a constraint to clinical application, and the rise of vagus neuromodulation has opened a new track for non-invasive therapies, providing a physiological basis for the development of novel therapeutic devices through the neuromodulation of metabolic homeostasis via cholinergic pathways[38]. Breakthroughs in engineered exosome technology have also heralded an iterative upgrade of drug delivery systems: MiR-155 exosomes of adipose macrophage origin can be used to remodel the metabolic homeostatic system through remodelling of adipose macrophages[27]. The breakthroughs in engineered exosome technology herald the iterative upgrading of drug delivery systems: MiR-155 exosomes derived from adipose macrophages can exert therapeutic effects by remodelling the pancreatic islet microenvironment, while the modified exosomes developed by Gao et al[23] have laid the technological framework for the construction of the third-generation nano-drug carriers by improving the drug loading efficiency[22,23,27]. These advances have highlighted the need for innovation in the whole chain, from the analysis of the molecular mechanism to the translation of the technology, and have also confirmed the need for immunology to develop new therapeutic devices. These advances not only highlight the need for innovation in the whole chain from molecular mechanism analysis to technology translation, but also confirm the irreplaceability of the cross-fertilisation of immunology, metabolomics and materials science in tackling complex diseases. When the molecular targets of basic research resonate with the delivery innovations of engineering technologies, therapeutic strategies targeting pancreatic macrophages are gradually transforming from laboratory hypotheses to solutions with clinical potentials.

CONCLUSION

Pancreatic metabolic dysregulation associated with obesity serves as a pathological basis for multiple systemic diseases, and macrophages play a pivotal role in this process. This review elaborates on how, within an obese environment, the polarization imbalance (M1/M2) of pancreatic macrophages disrupts β-cell function and impairs normal pancreatic metabolism by secreting pro - inflammatory factors (such as TNF-α, IL-1β) and metabolites (such as lactate). Mechanistically, lipotoxicity, gut microbiota dysbiosis, and abnormal activation of immune checkpoints (such as PD-1) jointly drive this vicious cycle. Current intervention strategies mainly focus on regulating macrophage phenotypes (such as PPAR-γ agonists), blocking metabolic pathways (such as the SUCLA2 - HIF-1α axis), and modulating the sympathetic nerve - M2 macrophage axis (such as NGF). However, there are still unknown challenges in clinical translation. Future research needs to integrate emerging approaches such as polarization regulation and metabolic reprogramming to achieve precision treatment. In summary, the multi-dimensional regulation targeting macrophages provides a novel pathway for reversing obesity-related pancreatic injury, and its translational potential urgently awaits further exploration by researchers.