Diabetes mellitus, especially type 2 diabetes (T2DM), is a complex metabolic disease marked by persistent low-grade inflammation and insulin resistance. In diabetes, adipose tissue macrophages adopt a pro-inflammatory M1 phenotype, secreting cytokines including TNF-α, IL-6, and IL-1β that disrupt insulin signaling and cause metabolic dysfunction. AMP-activated protein kinase (AMPK), a cellular energy sensor, is a key regulator of macrophage polarization. It suppresses M1 responses by inhibiting NF-κB and JNK signaling, activating CREB/SIRT1 pathways, and promoting oxidative metabolism. Therefore, this review investigates the bidirectional interaction between AMPK signaling and macrophage function in diabetes, focusing on how metabolic stress affects AMPK activity, increasing inflammation and insulin resistance, whereas AMPK activation restores immune-metabolic balance. The gut microbiome further influences this axis, with short-chain fatty acids activating AMPK via GPR41/43, promoting M2 polarization and improving metabolic outcomes. Metformin, SGLT2 inhibitors, new direct AMPK activators such as PXL770, and lifestyle changes are also potential therapeutic treatments. However, considerable hurdles remain, including the prevalence of preclinical findings, a lack of macrophage-specific AMPK activators, simplicity of the M1/M2 paradigm, and uncertainty about long-term safety. Future research must focus on macrophage-targeted drug delivery, tissue-specific regulatory networks, biomarker discovery, and rigorous clinical trials with immunological outcomes. In conclusion, the AMPK-macrophage axis is a critical immune-metabolic gatekeeper in diabetes, and targeting this pathway offers a potential technique for restoring immune-metabolic balance, while significant difficulties must be overcome before practical use.
Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy in which inflammatory signaling plays a pivotal role in disease pathogenesis. The dysregulation of the cytokine network leads to an increased abundance of pro-inflammatory mediators, such as IL-1β, TNF-α and IL-6, relative to anti-inflammatory cytokines like TGF-β and CXCL12. This disbalance in cytokine levels is closely associated with tumor development and fosters a pro-tumorigenic microenvironment by facilitating leukemic cell proliferation, reducing survival rates, and promoting drug resistance. In addition, inflammatory cytokines have been shown to preferentially support hematopoietic stem and progenitor cell populations harboring mutations associated with clonal hematopoiesis. This review summarizes the current knowledge on inflammatory cytokines and signaling pathways in AML, focusing on: (i) their mechanisms of action and implications for immune tolerance and clonal hematopoiesis and (ii) the emerging therapeutic strategies targeting these pathways to improve clinical outcomes for patients with AML.
Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder and the most common form of dementia worldwide. Traditionally, its pathology has been defined by the presence of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), primarily composed of hyperphosphorylated tau (pTau), alongside widespread synaptic and neuronal loss. Despite decades of research, AD etiology remains only partially understood. While recent advances in amyloid-targeted therapies mark significant progress, most current approaches have fallen short of expectations. This gap has spurred the re-evaluation of the central mechanisms driving AD, with neuroinflammation emerging as a critical contributor rather than a mere bystander. Among the numerous inflammatory mediators implicated in AD, interleukin-1β (IL-1β) stands out for its dual role, associated with the exacerbation of pathological features but also with neuroprotective effects, including Aβ clearance and neuronal support. This apparent duality highlights the complexity of neuroinflammation in AD, suggesting that IL-1β can act as a context-dependent modulator, its effects shaped by factors such as timing, cellular origin, and disease stage. The purpose of this review is to summarize the evidence on IL-1β's role in AD pathophysiology and clarify its contribution to disease mechanisms and progression.
Death receptors (DRs) are a subset of the tumor necrosis factor receptor (TNFR) superfamily with a protein interaction motif called the death domain. DRs, particularly TNFR1, FAS and TRAIL-Rs, mediate critical cellular outcomes, including apoptosis, necroptosis, inflammation, survival, and proliferation. Phosphorylation is a rapid, reversible post-translational modification, and therefore might alter the downstream fate decisions in signal transduction pathways. Like most cytokines, death ligands activate a wide range of tyrosine kinases. However, our understanding of whether these tyrosine kinases phosphorylate DRs and modulate downstream signaling is limited. Depending on the cell type, several different tyrosine kinases, including Src family members, JAKs and EGFR have been demonstrated to be activated upon death ligand exposure. All three of these kinase families have the potential to phosphorylate DRs, as reviewed here, and these phosphorylation events create a bias towards proinflammatory and proliferative pathways over cell death. Since these kinases are frequently hyperactivated in cancer, this bias may sustain tumor cell survival and resistance to death receptor-targeted therapies, marking the responsible kinases and their opposing phosphatases as candidate therapeutic targets.
Traditional tumor immunology research has predominantly focused on circulating recruited immune cells. In contrast, tissue-resident immune cells-a unique subset that stably resides in normal tissues and the tumor microenvironment (TME) for extended periods without entering the systemic circulation-exhibit distinct transcriptional, epigenetic and functional profiles, and their roles in tumor initiation, progression and therapeutic response remain incompletely elucidated. Focusing on the representative subsets of resident T cells, natural killer (NK) cells and macrophages, this review defines the origins of tissue-resident immune cells and elucidates the transcriptional regulatory networks (including TGF-β/IL-33 and RUNX3) that control their differentiation, maintenance, and tissue retention. Meanwhile, we systematically compare tissue-resident immune cells with recruited immune cells and summarize the canonical cell surface markers of resident cells such as CD69 and CD49a. We further reveal the bidirectional plasticity between tissue-resident and recruited immune cells: circulating T cells and monocytes can differentiate into resident subsets under the influence of local cytokine signals such as TGF-β and IFN-γ, while a fraction of tissue-resident immune cells retain the capacity to re-enter the circulation and migrate to distant tissues under inflammatory conditions. On this basis, we dissect the molecular mechanisms underlying the dual pro-tumor and anti-tumor effects exerted by the tissue-resident immune cells in the TME, which are mediated through cytokine regulation, direct contact-mediated cytotoxicity, and indirect modulation of recruited immune cells. Finally, we summarize the multifaceted impacts of conventional cancer therapies (radiotherapy, chemotherapy and targeted therapy) on tissue-resident immune cells, propose innovative therapeutic strategies targeting tissue-resident immune cells, and outline the directions for the development of next-generation molecular targeted anticancer agents. Collectively, this comprehensive review clarifies the mechanistic basis of the dual roles of tissue-resident immune cells in tumor immunity, uncovers their functional plasticity and co-evolutionary mechanisms with the TME, and provides a theoretical framework and novel therapeutic targets for overcoming immune escape in cold tumors.
T cells are crucial for defending against viral infection and cancer by eliminating infected or transformed cells and establishing immune memory. However, persistent antigenic stimulation in chronic infections or tumors drives T cells into a dysfunctional state known as exhaustion. This state is characterized by reduced proliferation and effector functions, upregulation of inhibitory receptors like PD-1, LAG-3, and CTLA-4, and alterations in transcriptional, epigenetic, and metabolic programs. T cell exhaustion is driven by both intrinsic factors, including changes in transcription factor networks and metabolic dysfunction, and extrinsic factors, such as continuous antigen exposure and an immunosuppressive microenvironment. Key molecules like PD-1, TOX, and TCF-1 are central to this process, though the complex interactions between intrinsic and extrinsic signals in chronic viral infections and cancers remain poorly understood. This review summarized T cell exhaustion in chronic viral infections, such as HIV, HBV, and SARS-CoV-2, as well as in tumors, emphasizing shared mechanisms and context-specific differences. We focused on the roles of transcriptional networks, metabolic changes, immune checkpoints, and exhaustion-related signaling. Additionally, we discussed emerging therapeutic strategies, such as immune checkpoint inhibitors, CAR-T cell therapies, cytokine supplementation, and metabolic interventions, based on recent high-impact studies. By integrating insights from both chronic infection and cancer, this review aims to identify common principles of T cell exhaustion and propose strategies to improve clinical outcomes in chronic viral diseases and cancer immunotherapy.
While the long-term efficacy of checkpoint inhibition is established, the lack of response in IFN-rich tumors presents a critical challenge. These findings suggest that immune sensitivity depends on variables beyond cytokine levels and should be assessed in a temporal context. We propose the "IFN clock," in which efficacy is determined by the kinetics of interferon signaling rather than its level. The IFN clock is structured into three phases: a fast-on activation phase, a fast-off recovery phase, and a persistent-on resistant phase. In this model, short-lived interferon signaling supports antitumor immunity, whereas prolonged signaling induces therapeutic resistance. In early signaling, Type I interferon drives immune cell coordination through myeloid priming and chemokine-guided T cell recruitment. Effective outcomes require attenuation of signaling; loss of feedback control promotes chronic interferon exposure. Persistent activation results in stable epigenetic remodeling that enforces immune evasion and progressive T cell dysfunction. We introduce the dISG ratio to operationalize this framework. It provides a transcriptomic metric that separates acute from chronic interferon states, enabling patient stratification. Emerging preclinical evidence suggests that modulating interferon kinetics may restore checkpoint blockade sensitivity, though clinical validation remains limited. The IFN clock reframes interferon biology as dynamic and time-dependent. It offers a framework for biomarker refinement and therapeutic design.
BACKGROUND:Despite advances in emerging therapies, colorectal cancer (CRC) incidence continues to rise and clinical outcomes remain suboptimal, highlighting the need for improved management strategies. One potential therapeutic target is osteoprotegerin (OPG), a glycoprotein which exhibits context-dependent functions by interacting with both Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) to produce anti-resorption effects and TNF-related apoptosis inducing ligand (TRAIL) to promote cell survival, potentially modulating key hallmarks of CRC progression. However, its translational potential remains underexplored. AIMS AND SCOPE:This review summarizes OPG's structure, expression, and physiological roles, followed by a comprehensive analysis of its mechanistic contributions to CRC progression. We then examine therapeutic strategies targeting OPG and its potential as a diagnostic biomarker, before concluding with perspectives on future research. KEY FINDINGS:Present evidence suggests that circulating OPG levels are associated with prognostic factors in CRC such as overall survival and metastasis rates. However, unresolved mechanistic questions remain, particularly regarding dominant cellular sources of OPG and whether circulating OPG levels directly reflect inflammatory and/or tumor dysfunction. Clinically, OPG holds promise as a biomarker for CRC, though it may be more effectively utilized within multi-marker panels rather than as a standalone biomarker. Current research has predominantly focused on the RANKL signaling pathway, leading to development of anti-RANKL therapeutics such as Denosumab, while OPG-specific therapeutics remain underdeveloped. Collectively, future research could investigate whether compartment-specific OPG levels could serve as a biomarker for CRC and predict responses to immunotherapeutics, alongside drug repurposing of existing anti-RANKL therapeutics, and non-pharmacological strategies targeting OPG.
Interleukins (ILs) are powerful regulators of anti-tumor immunity, yet their clinical impact in cancer has remained limited despite decades of therapeutic development. Although first-generation cytokines such as IL-2 established proof-of-principle for cytokine-driven cancer immunotherapy, their broader clinical translation was constrained not by insufficient immunostimulatory potency, but by imprecise deployment, including poor receptor selectivity, systemic exposure, and inadequate alignment with tumor immune context. Despite major advances in cytokine engineering, clinical benefit has continued to lag because cytokine deployment remains insufficiently matched to receptor biology, spatial pharmacology, and immune-state architecture. In this Review, we examine how next-generation interleukins, particularly IL-15, IL-21, and IL-10, are redefining cytokine therapy through functionally specialized roles in sustaining cytotoxic persistence, preserving effector competence, and rewiring suppressive immune states. We synthesize emerging strategies in receptor-biased engineering, spatially restricted delivery, and context-matched combination design, and propose a cytokine-guided framework that integrates receptor logic, delivery geometry, immune-state matching, and biomarker-informed deployment. We further argue that the principal barriers to clinical translation are no longer primarily molecular, but translational, including biomarker insufficiency, trial misalignment, tissue-level resistance, and patient heterogeneity. Overall, next-generation interleukins are best understood not as stronger cytokines, but as more precisely deployable immunotherapeutic modules for durable and rational cancer immunotherapy.
Adoptive T cell therapy has transformed the treatment of hematologic malignancies but fails to control solid tumors, where T cell dysfunction and an immunosuppressive tumor microenvironment (TME) remain the central barriers. Cytokines are essential regulators of both T cell fate and the TME, making cytokine engineering a key lever for overcoming these limitations. Here we review recent advances in intrinsic strategies that embed cytokine support directly into the engineered T cell product and extrinsic strategies that deliver cytokines to the tumor site to remodel the TME, providing a comprehensive analysis to guide rational strategy selection and combination. We further highlight synthetic cytokine and receptor designs that induce novel T cell states beyond the boundaries of natural T cell biology. Finally, we propose virtual cytokine networks as a framework for predicting patient-specific immune cascades triggered by any designed cytokine intervention, providing a path toward personalized cytokine-guided adoptive T cell therapy.
Fibroblast growth factor homologous factors (FHFs) are the intracellular, non-secretory branch of the fibroblast growth factor (FGF) superfamily. They regulate a range of biological processes, including embryonic development, cell proliferation, and differentiation. Unlike canonical FGFs that primarily signal through fibroblast growth factor receptors (FGFRs), FHFs function predominantly through intracellular mechanisms and exhibit marked enrichment in the nervous system. Emerging evidence identifies FHFs as multifunctional regulators of neuronal excitability, axonal organization, cytoskeletal dynamics, intracellular signaling, and neural circuit stability. Mechanistically, FHFs regulate voltage-gated ion channels, interact with kinase signaling complexes, stabilize microtubules, and participate in nuclear and organelle-associated processes. Notably, mutations in FHF genes have been implicated in various neurological diseases. Therefore, further research on the broad functional roles and distinct mechanisms of these intracellular FGFs in neurophysiological processes and neuropathological conditions present significant promise. In this review, we summarize current understanding of the expression patterns, molecular mechanisms, and neurological disease associations of FHFs, with emphasis on how their intracellular regulatory functions contribute to neural development, excitability, and neuropathology. Based on these insights, we additionally discuss emerging therapeutic strategies targeting FHF-associated signaling and protein interaction networks.
Chronic Obstructive Pulmonary Disease (COPD) is characterised by upregulation of inflammatory mechanisms in the lungs, influenced by a variety of environmental and genetic factors. Tobacco smoke (TS) is the most prominent risk factor and one of the most potent sources of oxidative stress. It is accompanied by two conditions, chronic bronchitis and emphysema, which lead to airflow obstruction. The hallmarks of COPD are breathlessness (dyspnea), a persistent cough, and sputum production. Toxins in TS trigger the release of damage-associated molecular patterns (DAMPs), inducing oxidative stress in cells. Various studies show that mtROS elevation following TS exposure is mainly due to dysregulation of mitochondrial antioxidant systems. A significant increase in intracellular ROS further activates redox-sensitive inflammatory pathways and induces the production of pro-inflammatory cytokines. So, mitochondrial damage induced by TS in immune cells intensifies oxidative stress, causing inflammation, structural remodelling, and cellular senescence in COPD. Significantly increased levels of freely circulating mitochondrial DNA (mtDNA) in the plasma and bronchoalveolar lavage fluid of COPD patients have been observed, indicating mitochondrial damage. The released mtDNA is sensed by Cyclic GMP-AMP synthase (cGAS), activating the cGAS-STING signalling pathway, with functional effects on tissue repair and inflammatory responses, as well as cytokine induction. The involvement of cGAS in human COPD samples emphasises its pathogenic relevance in persistent airway inflammation. The NLRP3 inflammasome pathway also serves as a key regulator of innate immune-mediated inflammation by activating caspase-1 and further maturing pro-inflammatory cytokines, interleukin-1β (IL-1β) and interleukin-18 (IL-18). Various studies have implicated cGAS-STING in regulating NLRP3 inflammasome activation, suggesting that crosstalk occurs between the pathways, which play central roles in sterile inflammation and airway injury in COPD. This review aims to understand the mechanisms by which mtDNA-mediated stimulation of the cGAS-STING pathway contributes to COPD pathogenesis and its interaction with the NLRP3 inflammasome, which amplifies inflammation and tissue injury.
Pulmonary fibrosis is the common end-stage pathological outcome of diverse interstitial lung diseases (ILDs), defined by progressive alveolar structural destruction, aberrant extracellular matrix (ECM) deposition, and ultimately fatal respiratory failure. For decades, idiopathic pulmonary fibrosis (IPF), the most lethal form of fibrotic ILD, was framed as a primarily epithelial-fibrotic disorder with minimal immune involvement, a paradigm supported by the failure of broad immunosuppressive therapies in clinical trials. However, advances in single-cell and spatial transcriptomics have redefined the role of the immune system in fibrosis, revealing that dynamic, context-dependent immune cell interactions—collectively termed immunodynamics—are central drivers of pathological lung remodeling across all fibrosing ILDs. In this review, we synthesize the spatiotemporal dynamics of innate and adaptive immune populations across disease stages, delineate the core molecular circuits that sustain immune-epithelial-mesenchymal crosstalk, and provide a critical evaluation of the successes and failures of immune-targeted therapeutic translation. We argue that the immunodynamics framework not only unifies the pathogenesis of IPF and secondary fibrotic ILDs, but also identifies actionable therapeutic windows and patient stratification strategies to advance precision treatment for these devastating diseases.
Thyroid cancer, the most prevalent endocrine malignancy, exhibits a diverse range of clinical behaviors, from indolent to highly aggressive phenotypes. Growing evidence indicates that chemokines, cytokines involved in the trafficking of leukocytes and other cell types, significantly influence the tumor microenvironment by facilitating immune evasion, promoting angiogenesis, and driving metastatic progression in thyroid malignancies. This review comprehensively explores the roles of chemokine signaling pathways in the pathophysiology of thyroid cancer, with a particular emphasis on their impact on tumor-immune system interactions, epithelial-mesenchymal transition (EMT), and stromal remodeling. We underscore the chemokine-mediated processes that characterize the various histological subtypes of thyroid cancer, including papillary, follicular, medullary, and anaplastic thyroid carcinoma. Additionally, we investigate the diagnostic and prognostic potential of specific chemokines, assessing their value as biomarkers and their emerging roles as therapeutic targets for immunomodulatory and anti-metastatic strategies. By synthesizing data from both in vitro and in vivo studies, this review highlights the translational significance of chemokine biology and suggests future directions for utilizing chemokine pathways in personalized treatment approaches for thyroid cancer.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that bridges innate immunity, cellular senescence and age‑related pathology. In this review, we describe the unique secretion mechanisms, compartment‑specific signaling, and redox‑dependent conformational states that MIF has in different contexts. We detail how extracellular MIF amplifies chronic inflammation through CD74, CXCR2/4 and NF‑κB, while intracellular MIF sustains proliferation, DNA repair, and autophagy by antagonizing p53. We also highlight oxidized MIF as an emerging marker with unique relevance in age-related diseases. Through systematic comparison of evidence from cardiovascular, neurodegenerative, musculoskeletal and pulmonary disease studies, this review reveals context‑dependent protective versus deleterious outcomes of MIF signaling. The nature of MIF and its involvement in age-related diseases makes it a challenging yet intriguing therapeutic target.
Glioblastoma (GBM) remains highly resistant to immunotherapy due to limited T-cell infiltration and a profound immunosuppressive tumor microenvironment (TME). A recent first-in-human clinical trial of the oncolytic herpes simplex virus rQNestin34.5 v.2 (NCT03152318) shows that a single intratumoral dose can trigger durable T-cell activation and sustained cytotoxic engagement within tumor tissue. Spatial profiling reveals persistent immune-tumor interactions after viral clearance that correlate with clinical outcome. These findings indicate that oncolytic virotherapy can remodel tumor-immune architecture and establish lasting spatial immune surveillance. This correspondence discusses the mechanistic and translational implications of persistent spatial T-cell immunity in GBM.
The human immune system is a complex defense mechanism that protects the body against external and internal threats. Disruption of an effective immune response can lead to detrimental effects, such as autoimmune diseases or cancer. To ensure an adequate response, a complex network of immunoregulatory pathways exists. Cytokines and galectins represent two immunoregulatory protein families that, for long, were considered to act independently. Current research shows that the expression and secretion of galectins and cytokines is reciprocally controlled. More recently, cytokines and galectins were found to form heterodimers, affecting protein functionality. All these findings suggest a cooperative activity of cytokines and galectins during immune regulation. To fully understand their combined immunoregulatory capacities, it is essential to investigate this reciprocal relationship between cytokines and galectins. Here, we summarize our current knowledge regarding the regulatory and functional relationship between galectins and cytokines in the context of the immune response.
Tumor-associated macrophages (TAMs) are central regulators of the tumor microenvironment (TME), shaping immune suppression, tumor progression, and therapeutic resistance. Toll-like receptors (TLRs) orchestrate innate immune activation and represent a compelling axis for reprogramming TAMs toward antitumor states. However, the context-dependent nature of TLR signaling, combined with metabolic and tolerogenic constraints in the TME, presents substantial translational barriers. Nevertheless, recent advances including chimeric antigen receptor macrophage (CAR-M) and antibody-TLR agonist conjugates offer new pathways to harness TLR signaling with improved precision and safety. This review summarizes the molecular foundations of TLR signaling in macrophages, dissects the bidirectional consequences of TLR activation within tumors, evaluates current therapeutic platforms, and outlines a translational roadmap to guide the clinical development of TLR-based TAM modulation.
