搜索结果：Cytokine & growth factor reviews

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.

High-intensity intermittent exercise can acutely alter circulating cytokines, but findings are heterogeneous. The aim was to systematically synthesize acute blood cytokine responses after a single high-intensity intermittent exercise session in humans. PubMed, Scopus, and Web of Science Core Collection, plus reference screening. Eligibility criteria included original human studies measuring serum or plasma cytokines pre-exercise and at least one post-exercise time point after high-intensity intermittent exercise. Sampling was mapped to prespecified recovery windows. Risk of bias was assessed using RoB 2 (randomized trials) and the Joanna Briggs Institute quasi-experimental tool. Narrative synthesis was used. From 2077 records, 45 studies were included. Most protocols used cycling or treadmill modalities, and sampling clustered in the immediate and early recovery windows. Interleukin 6 most consistently increased after exercise, whereas tumor necrosis factor alpha, interleukin 10, and other mediators showed mixed or context-dependent changes. Risk of bias was commonly rated as some concerns, with frequent limitations in pre-analytical control and reporting. Across included studies, high-intensity intermittent exercise tended to elicit a short-lived myokine-dominant inflammatory signal, characterized primarily by an increase in circulating interleukin 6, most often detected in the immediate and early recovery windows. Conflicting findings for tumor necrosis factor alpha, interleukin 10, redox-related outcomes, and less frequently measured mediators were best explained by a small set of dominant moderators: post-exercise sampling window, exercise dose/internal load, participant metabolic and training phenotype, and pre-analytical or assay-related heterogeneity. Registration: Open Science Framework (osf.io/wspr6; 17 February 2026).

Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is a well-characterized myokine with pleiotropic regulatory effects on skeletal muscle. LIF modulates several fundamental cellular processes, including myoblast proliferation, apoptosis, angiogenesis, and energy metabolism. Exercise upregulates LIF expression in skeletal muscle, thereby promoting satellite cell activation, proliferation, myoblast differentiation, and angiogenesis, facilitating physiological muscle hypertrophy, and suppressing myocyte apoptosis and muscle atrophy. In addition, LIF plays a critical role in modulating the inflammatory and extracellular matrix remodeling following exercise-induced muscle damage, thereby supporting efficient muscle repair and regeneration. This review elaborates on the biological mechanisms by which LIF regulates skeletal muscle atrophy and contributes to the enhancement of skeletal muscle function. It also highlights the biological characteristics of myogenic LIF and discusses future directions for basic and applied research on exercise interventions targeting LIF signaling pathways.

Breast cancer is one of the most common malignant tumors worldwide, with metastasis being the leading cause of mortality among patients. Bone is the most frequent site of metastasis in breast cancer, accounting for approximately 70% of metastatic cases. Before bone metastasis, primary breast cancer cells secrete circulating factors (e.g., exosomal RNAs, metabolites, and cytokines) to precondition the bone microenvironment and establish a supportive pre-metastatic niche (PMN). After dissemination, tumor cells further hijack the bone niche by releasing receptor activator of nuclear factor-κB ligand (RANKL), parathyroid hormone-related protein (PTHrP), and transforming growth factor-β (TGF-β), thereby disrupting bone homeostasis through osteoclast activation and osteoblast dysregulation. Bone matrix degradation subsequently releases latent growth factors that in turn fuel tumor cell proliferation, thereby establishing a self-reinforcing vicious cycle. Meanwhile, breast cancer cells actively induce local immunosuppression and promote angiogenesis, remodeling a pro-tumor bone niche conducive to metastatic outgrowth. This review highlights the immunosuppressive roles of immune cells and key molecular mediators in the vicious cycle, systematically analyzes intercellular crosstalk within both the bone PMN and the hijacked niche, and summarizes emerging therapeutic strategies (including novel targeted inhibitors, immune-based combinations, epigenetic modulation, and nanomedicines) beyond conventional treatments. These insights provide a theoretical framework and identify promising therapeutic targets for future treatment strategies against breast cancer bone metastasis.

The colonic epithelial barrier is a multilayered defense system comprising the mucus layer, intestinal epithelial cells (IECs), and the underlying lamina propria. These components collectively maintain mucosal homeostasis and restrict microbial translocation. Disruption of this barrier is a hallmark of chronic intestinal inflammation particularly in IBDs, and is primarily driven by pro-inflammatory cytokines, such as TNF-α, IFN-γ, IL-1β, and IL-6. TNF-α and IFN-γ synergistically induce epithelial cell apoptosis and tight junction disassembly through mechanisms involving TNFR2 upregulation, myosin light chain kinase (MLCK) activation, and adherens junction destabilization. IL-1β amplifies paracellular permeability via NF-κB-dependent MLCK induction and OCLN downregulation, while IL-6 promotes barrier leakiness by upregulating CLDN-2 and sustaining self-reinforcing inflammatory loops that maintain chronic inflammation and impede epithelial repair. This leads to persistent immune-cell infiltration, chronic tight junction remodeling, and failure of barrier replenishment. Consequently, leaky colon facilitates microbial and antigen translocation into the lamina propria, further activating immune cells and perpetuating pro-inflammatory signaling. This review synthesizes current evidence and studies on the cooperative and self-reinforcing roles of pro-inflammatory cytokines, providing insight into the mechanisms underlying chronic intestinal barrier dysfunction and highlighting the need for therapeutic strategies that simultaneously target multiple inflammatory axes to restore barrier integrity in inflammatory bowel disorders.

Regenerative repair following tissue injury depends on tightly coordinated signaling networks that determine whether healing culminates in functional restoration or fibrotic scarring. Among these regulators, fibroblast growth factor-2 (FGF2) has emerged as a key modulator of repair outcomes. Mechanistically, FGF2 promotes inflammation resolution, proliferation, vascularization, and re-epithelialization. A central feature of its activity is dynamic cross-talk with transforming growth factor-β (TGF-β), a dominant driver of extracellular matrix deposition and fibrosis. Accumulating evidence indicates that FGF2 inhibits TGF-β-mediated profibrotic signaling, thereby shifting tissue remodeling toward regeneration rather than pathological outcomes. This interaction is supported by both preclinical and clinical evidence showing that FGF2 accelerates wound closure and improves scar architecture. However, despite the compelling biological rationale, the widespread clinical translation of FGF2 has been limited by rapid protein degradation and concerns about proliferative signaling in oncogenic contexts. These limitations have constrained its incorporation into standard therapeutic strategies for chronic wounds and fibrotic disorders. This review provides a synthesis of current mechanistic insights into FGF2 signaling and elucidates its regulatory interplay with TGF-β that favors regenerative repair over fibrosis. We evaluated clinical trial evidence and examined next-generation strategies to overcome translational barriers, including molecular engineering, chimeric growth factor design, and advanced stabilization approaches. By clarifying the regulatory role of FGF2 in the repair trajectory, we highlight its potential to recalibrate fibrotic responses and improve regenerative outcomes.

Allergic diseases, including asthma and food allergies, pose a global public health challenge. However, the complex immunopathological mechanisms have not been fully elucidated yet. Although T helper 2 (Th2) cells are regarded as central drivers, they cannot fully explain the clinical heterogeneity and therapeutic resistance of these diseases. This review aimed to systematically illustrate the key roles and regulatory mechanisms of T helper 9 (Th9) cells and their effector cytokine interleukin-9 (IL-9) in various allergic diseases. Th9 cells differentiate under the synergistic induction of transforming growth factor-β (TGF-β) and interleukin-4 (IL-4), and their specific transcription factors (such as Spi-1 proto-oncogene (PU.1), Interferon Regulatory Factor 4 (IRF4)) and epigenetic modifications jointly regulate IL-9 expression. IL-9 acts on mast cells, B cells, eosinophils, and epithelial cells, forming a positive-feedback inflammatory amplification loop that connects adaptive immunity to structural tissue cells. Although drug development targeting IL-9 (such as enokizumab) has faced challenges, intervention strategies targeting key nodes of this axis remain a highly promising research direction. The Th9/IL-9 axis, as a critical hub linking immune activation and pathological tissue changes, provides a new theoretical framework for understanding the heterogeneity of allergic diseases and represents a potential therapeutic target.

Periodontitis is a multifactorial inflammatory disease of the tooth-supporting tissues caused by dental biofilm and mediated by the host immune response. Interleukin-1 is a key pro-inflammatory cytokine implicated in periodontal inflammation, connective tissue breakdown, and disease progression. Beyond microbial and environmental factors, genetic polymorphisms affecting interleukin-1 activity contribute to interindividual variability in disease susceptibility, progression, and treatment response. This review examines the association between interleukin-1 gene polymorphisms and periodontitis risk across different populations, ethnic groups, clinical conditions and demographics. Data were retrieved from the PubMed database, covering publications from 2007 to 2024, using the following search strategy: ("periodontitis" OR "periodontal disease") AND ("interleukin-1" OR "IL-1") AND "polymorphism". Only human studies investigating the association between interleukin-1 polymorphisms and susceptibility to periodontal diseases were selected. Exclusion criteria included animal studies, meta-analyses and review articles. Although results are sometimes conflicting, most studies identify interleukin-1 polymorphisms as significant genetic risk factors for periodontal diseases, suggesting-at least to some extent-shared genetic susceptibility across populations or among different ethnic groups within a given population. Understanding population- and ethnicity-related genetic influences may improve risk assessment, enable early identification of susceptibility, and support the development of personalized preventive and therapeutic strategies.

Polydeoxyribonucleotide (PDRN) has been shown to have consistent regenerative and anti-inflammatory properties in a wide range of applications. Selective activation of the A2A receptor (A2AR) and induction of the phosphate scavenger system constitute its primary actions, which overlap the mechanism of skin regeneration after a surgical procedure; thus, PDRN can potentially be added to the post-surgical aesthetic surgery protocol of laser resurfacing, chemical peeling, microneedling, and radiofrequency. Literature search was conducted in the PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online), Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases with the following keywords: polydeoxyribonucleotide (PDRN) or polynucleotide, wound repair, aesthetic recovery, erythema, scar, lasers, and skin regeneration. No stipulated date limit was applied. Interventional and observational human studies, any available relevant preclinical evidence, and published systematic reviews were included. The studies were chosen based on their applicability to the biological processes of PDRN and their clinical application in skin repair situations that can be implemented in aesthetic practice. Narrative synthesis was used for thematic analysis. The pro-resolving immune reaction of PDRN works through a two-pronged mechanism: balancing the pro-inflammatory cytokine A2AR-mediated action (tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1 beta) and vascular endothelial growth factor-mediated nucleotide provisioning to growing keratinocytes and fibroblasts. There is human clinical evidence (including randomized controlled trials (RCTs), comparative cohort studies, and split-face trials) that PDRN enhances the period of re-epithelialization, erythema, scarring, and melanogenesis, which are the direct clinical outcomes with respect to post-procedural aesthetic recovery. PDRN has also shown non-inferior short-term cosmetic results compared to hyaluronic acid filler, with indications of greater biostimulatory stability. The adverse event profile in all published studies is invariably positive. The limitations of the technique, however, are a lack of RCTs (with human aesthetic cohorts), small sample sizes, variability in formulations, and a lack of long-term follow-up. Thus, the findings discussed in the current paper make PDRN an appealing and bio-plausible clinical partner in enhancing post-surgical recovery of patients undergoing aesthetic surgery. The available mechanistic and translational evidence establishes a credible biological basis for integrating PDRN into post-procedural care. On the basis of this evidence, its use may be considered a reasonable adjunct in clinical practice, subject to individual patient assessment and institutional protocol.

Transforming growth factor-β (TGF-β) is one of the most complex and context-dependent cytokines in the immune system. Its signaling pathway regulates differentiation, functions, and microenvironment-specific adaptations of immune cells through Smad-dependent and Smad-independent pathways. In normal physiological conditions, TGF-β maintains immune tolerance, regulates T-cell fate determination, and participates in tissue repair. In pathological conditions, aberrant TGF-β signaling drives fibrosis, tumor immune evasion, and chronic inflammatory responses. In recent years, innovative technologies such as single-cell omics and spatial transcriptomics have revealed the dynamic characteristics of TGF-β signaling in different cell lineages and microenvironments. These techniques have deepened the understanding of its molecular circuits and immune regulatory networks. Therapeutic strategies targeting TGF-β, including receptor kinase inhibitors, bispecific antibodies, and nanotechnology-based delivery systems, have shown potential in disease models such as fibrosis and tumors, but still face challenges such as toxicity, side effects, and disease stage dependence. This article reviews the multidimensional mechanism of TGF-β signaling in immune homeostasis, fibrosis, and tumor progression; assesses its prospects and limitations as a therapeutic target; and proposes future directions for clinical translation through patient stratification and disease staging, precise nanodelivery, and combination therapy, providing a theoretical basis for precise intervention in immune-related diseases.

CD38 is a transmembrane protein and ectoenzyme that mainly degrades nicotinamide adenine dinucleotide (NAD+). Studies have revealed increased numbers of CD38-expressing NK (CD3-CD38+CD56+) cells in many diseases. CD38+ NK cell proportions in the peripheral blood and synovial fluid are increased in patients with rheumatoid arthritis (RA), and these cells produce high levels of interferon-γ (IFN-γ) and low levels of transforming growth factor-β (TGF-β), suppressing the differentiation of CD4+ T cells to regulatory T cells (Tregs) to disrupt immune tolerance. CD38+ NK cell proportions in the peripheral blood and tumor tissues are also increased in patients with colorectal cancer (CRC). However, CD38+ NK cells produce low levels of IFN-γ and NAD+ and high levels of TGF-β and adenosine (ADO) and can promote Treg differentiation and macrophage polarization to tumor-associated macrophages (TAMs) to interrupt immune surveillance. CD38+ NK cells were not detected in CD38-KO tumor-bearing mice, and their xenograft tumors grew slowly. Furthermore, the expression of heat shock 70-kDa protein 1B (HSPA1B), a known tumor suppressor, was decreased in CD38+ NK cells from CRC patients but increased in the NK subset from RA patients. HSPA1B can suppress the signaling activity of NF-κB, a regulator of proinflammatory cytokine production. CD38 and CD16 cooperate on the NK cell membrane; most CD38+ NK cells are CD38+CD16+ NK cells that can suppress Treg differentiation. The proportion of CD38+CD16- NK cells among CD38+ NK cells in the peripheral blood was increased in patients with CRC or other tumors. The above results suggest that CD38+CD16+ and CD38+CD16- NK cells have opposing regulatory effects on CD16, HSPA1B and NF-κB signaling and cytokine secretion, leading to opposing effects on immune balance. This review provides a reference for understanding disrupted immune tolerance and surveillance, though the evidence is preliminary.

Pregnancy complications such as miscarriage, preterm birth (PTB), and luteal phase defects (LPD) are significant reproductive health issues globally, with both physical and psychological implications. This review aims to examine the role of natural progesterone in pregnancy-related disorders, specifically threatened and recurrent miscarriage, PTB, and LPD. Additionally, it examines how natural progesterone's immune-modulating actions, including both direct and indirect involvement, contribute to maintaining pregnancy. This narrative review was conducted using PubMed, Google Scholar, and reference screening to identify English-language studies examining the role of natural progesterone in miscarriage, PTB, and LPD. Emphasis was placed on progesterone's immunomodulatory actions, including cytokine regulation and the activity of the progesterone-induced blocking factor (PIBF), and their relevance to pregnancy maintenance. Natural progesterone demonstrates clinical benefit in managing threatened miscarriage, recurrent pregnancy loss, preterm labor, and LPD. Evidence shows that it is well-tolerated with manageable side effects, reducing miscarriage rates, preventing PTB, and improving LPD outcomes through its effects on the maternal-fetal interface. This review also highlights progesterone's dual immunomodulatory action, direct cytokine regulation, and indirect influence via PIBF, which together contribute to improved pregnancy maintenance and outcomes. Natural progesterone supports pregnancy by preventing miscarriages, preterm labor, and LPD through its direct and indirect immunomodulatory mechanisms. Clinically, it is well-tolerated with no serious or unexpected adverse events. However, gaps remain in fully understanding its effectiveness, emphasizing the need for further research.

Atopic diseases arise from an immunological imbalance where regulatory mechanisms are unable to preserve or restore homeostasis, leading to chronic inflammatory conditions affecting epithelial organs. This may involve homeostasis, deficient or insufficient regulatory T cells (Tregs) or other aberrant regulatory mechanisms. Type 2 (T2) immunity is a conserved response that evolved to combat large helminth parasites (worms), venoms, and toxins involving both innate and adaptive immune pathways. Many T2 cytokines and alarmins act to recruit and activate innate and adaptive immune cells, and they also lead to mucous production, hyperplasia, and tissue remodeling. These responses were designed to enhance expulsion of parasites, repair the barrier and elicit protective mechanical reflexes such as scratching or coughing. Today, with reduced parasitic exposure serving as an opposing influence on T2 immunity, it is hypothesized that T2 responses may be triggered by low amounts of environmental stimuli in genetically susceptible individuals, leading to unchecked T2 inflammation and atopic diseases at multiple barrier surfaces. This paper reviews the evidence linking host T2 immunity with T2 inflammatory mechanisms in atopic diseases and explores the hypothesis that these diseases may be perpetuated from a central imbalance between Th2 vs. Th1, Th3, and Tregs, influenced by tissue-dependent, local environmental-insult-driven innate cell responses, interconnected by a cycle of self-amplifying cytokine signaling.

Exercise rehabilitation harnesses immune metabolic remodeling to drive coordinated skeletal muscle regeneration, bone homeostasis, and systemic immune adaptation. Physical activity functions as a controlled metabolic stressor that reprograms immune cell metabolism-shifting macrophages from glycolytic M1 to oxidative M2 phenotypes, expanding regulatory T cells through fatty acid oxidation and ketone body signaling, and modulating neutrophils, NK cells, and B cells via lactate, succinate, itaconate, ROS, NAD⁺, and gut-derived SCFAs. These metabolic shifts regulate immune cell polarization, efferocytosis, cytokine profiles, and growth factor release (IGF-1, amphiregulin, GDF-15), creating an optimal regenerative niche for satellite cell activation, proliferation, and differentiation in muscle while supporting bone remodeling through mechanosensory osteocyte signaling and osteokine secretion (osteocalcin, sclerostin, RANKL/OPG). Distinct exercise modalities generate characteristic immune-metabolic signatures: aerobic training promotes sustained oxidative phosphorylation and anti-inflammatory tolerance beneficial for both muscle and bone; resistance training induces controlled glycolytic bursts followed by anabolic M2 polarization, muscle hypertrophy, and improved bone microarchitecture; HIIT generates oscillatory stress that trains innate immune memory and enhances muscle-bone resilience. Energy-sensing pathways (AMPK, mTOR, HIF-1α, SIRT1/3, PGC-1α) and metabolite checkpoints integrate mechanical loading with immune and endocrine signals to balance pro-regenerative inflammation with timely resolution across the musculoskeletal system. Clinically, this framework enables precision rehabilitation protocols based on immune metabolic phenotyping, lactate kinetics, and skeletal imaging (BMD, microarchitecture) to optimize outcomes in sarcopenia, osteosarcopenia, postoperative recovery, chronic inflammatory diseases, cancer cachexia, and post-viral syndromes. Exercise-induced immune metabolic remodeling thus serves as a master regulator of muscle-bone-immune coupling, offering a mechanism-driven foundation for next-generation rehabilitation medicine that enhances tissue repair, bone quality, and systemic homeostasis.

IL-17, a pleiotropic cytokine, activates downstream signaling pathways through the IL-17 receptor (IL-17R), influencing the expression and regulation of inflammatory mediators, growth factors, and matrix metalloproteinases, thereby modulating various biological processes. Recent studies have shown that IL-17 exhibits dynamic biphasic effects during tissue repair: in the acute phase, it accelerates tissue repair by promoting epithelial regeneration, angiogenesis, and the recruitment of reparative immune cells, whereas in the chronic phase, excessive activation leads to uncontrolled inflammation and fibrosis progression. This "double-edged sword" effect shows significant heterogeneity across different tissues, including the skin, lungs, and intestines. Despite the widely recognized dual roles of IL-17, the field still lacks a holistic perspective that systematically explains how this duality is regulated across different tissue environments. This review outlines recent advances in IL-17's functional dichotomy and identifies cellular origin, injury phase, and local microenvironment as critical regulatory determinants. We aim to elucidate under what circumstances and why IL-17 promotes tissue repair rather than exacerbates fibrosis, and discuss the implications of these insights for developing therapeutic strategies tailored to distinct clinical scenarios.

This review summarizes the mechanistic and therapeutic relevance of Signal Transducer and Activator of Transcription 3 (STAT3) in systemic lupus erythematosus (SLE) and lupus nephritis (LN), with an emphasis on how structural information can inform drug development. STAT3 integrates cytokine- and growth factor-driven JAK-STAT signaling, supports pathological T cell differentiation, B cell activation, and renal inflammation, and has therefore emerged as a potential therapeutic node in lupus. Current pharmacological evidence includes traditional Chinese medicine-derived compounds, repurposed or conventional immunomodulators, and clinically advancing JAK-STAT pathway inhibitors; however, most agents act through upstream or indirect modulation rather than direct STAT3 targeting. Structure-informed analyses of candidate compounds further suggest differential druggability across STAT3 domains, with the CCD and SH2 domain providing plausible binding surfaces, whereas the DBD remains comparatively inaccessible. Together, current evidence supports STAT3 as a mechanistically important and therapeutically tractable axis in SLE and LN, while highlighting the need for biochemical, cellular, and in vivo validation of domain-selective inhibitors, dual-domain engagement strategies, and degrader-based approaches.

Hepatocellular carcinoma (HCC) arises predominantly in cirrhotic livers and remains one of the leading causes of mortality related to chronic liver disease. Chronic inflammation, immune dysfunction, and tissue remodeling sustain hepatocarcinogenesis, making circulating cytokines promising candidates for clinical biomarkers. To critically synthesize evidence on the role of interleukin-6 (IL-6) and interleukin-10 (IL-10) as biomarkers associated with HCC occurrence, staging, therapeutic response, and prognosis in individuals with cirrhosis. A narrative review was performed based on a structured literature search in PubMed/MEDLINE, SciELO, Europe PMC, and publishers' databases (2010-2025), using descriptors related to hepatocellular carcinoma, cirrhosis, IL-6, IL-10, prognosis, and biomarkers. Clinical studies assessing serum or plasma cytokine levels, meta-analyses, mechanistic reviews, and contemporary clinical guidelines were prioritized. The majority of clinical studies indicate a consistent association between elevated IL-6 levels and poor prognosis, increased tumor burden, systemic inflammation, and inferior outcomes following both systemic and locoregional therapies. For IL-10, the evidence supports elevated levels in a substantial proportion of patients with HCC, with signals of association with tumor-related immunosuppression and worse outcomes in advanced disease, although some studies suggest a context- and disease-stage-dependent role. IL-6 demonstrates greater consistency as a biomarker of progression and prognosis in cirrhosis-associated HCC, whereas IL-10 emerges as an immune regulatory marker with heterogeneous behavior depending on disease etiology, tumor stage, and the tumor microenvironment. Standardization of assay methodologies, cutoff values, and multivariable prognostic models is essential for clinical implementation. O carcinoma hepatocelular (CHC) emerge majoritariamente em fígados cirróticos e permanece como uma das principais causas de mortalidade relacionada a doença hepática crônica. A inflamação crônica, a disfunção imune e a remodelação tecidual sustentam a hepatocarcinogênese, tornando citocinas circulantes candidatas a biomarcadores clínicos. Sintetizar criticamente evidências sobre o papel da interleucina-6 (IL-6) e da interleucina-10 (IL-10) como biomarcadores associados a ocorrência, estadiamento, resposta terapêutica e prognóstico do CHC em indivíduos com cirrose. Revisão narrativa baseada em busca estruturada em PubMed/MEDLINE, SciELO, Europe PMC e bases de editoras (2010-2025), utilizando descritores relacionados a hepatocellular carcinoma, cirrhosis, IL-6, IL-10, prognosis e biomarkers. Foram priorizados estudos clínicos com dosagem sérica/plasmática, metanálises, revisões mecanísticas e diretrizes contemporâneas. A maioria dos estudos indica associação entre IL-6 elevada e pior prognóstico, maior carga tumoral, inflamação sistêmica e desfechos inferiores em terapias sistêmicas e locorregionais. Para IL-10, as evidências sustentam elevação em uma fração relevante de pacientes com CHC, com sinal de associação a imunossupressão tumoral e piores desfechos em doença avançada, embora alguns trabalhos sugiram papel dependente de contexto e fase da doença. IL-6 apresenta consistência maior como biomarcador de progressão e prognóstico no CHC sobre cirrose, enquanto IL-10 se destaca como marcador de regulação imune com comportamento heterogêneo conforme etiologia, estadiamento e microambiente tumoral. A padronização de ensaios, pontos de corte e modelos multivariados é essencial para adoção clínica.

Transforming growth factor-β (TGF-β) belongs to a family of structurally and functionally related cytokines that play essential roles in embryonic development, tissue homeostasis, and cell fate regulation. Dysregulation of TGF-β signaling contributes to a broad spectrum of diseases, including cancer, fibrosis, and immune disorders. In cancer, TGF-β exhibits a context-dependent dual role, functioning as a tumor suppressor during early stages while promoting invasion, metastasis, escape from immune surveillance, and tumor microenvironment remodeling in advanced-stage cancer through effects on stromal cells, extracellular matrix deposition, and angiogenesis. This functional duality makes therapeutic targeting both attractive and challenging. Although current strategies mainly focus on ligand neutralization or receptor kinase inhibition, accumulating evidence indicates that TGF-β activity is also regulated beyond the receptor level, including receptor trafficking, co-receptor function, nucleocytoplasmic shuttling, indirect pathway modulation, and epigenetic regulation. In this review, we emphasize regulatory mechanisms that can be modulated by existing drugs, clinical candidates, or experimentally tractable compounds, rather than providing an exhaustive overview of the broader regulatory landscape of TGF-β signaling. We further highlight opportunities for drug repurposing and discuss how synergistic combination strategies may improve therapeutic efficacy and overcome resistance in TGF-β-driven cancers, supporting a broader therapeutic framework beyond canonical receptor inhibition. See also the graphical abstract(Fig. 1).

Glioblastoma is the most aggressive form of brain tumor resulting in low overall patient survival rates of 12-15 months post diagnosis. Several factors contribute to the complexity of the tumor, including tumor heterogeneity, blood-brain barrier complications, genetic defects, cancer stem cell generation, and immune evasion. These factors can result in the progression of glioblastoma and are controlled by signaling pathways. Some of the signaling pathways involved in glioblastoma progression include ERK, NF-κB, Wnt, and PI3K/AKT/mTOR. Our and others' previous studies have found that TIM-3 and TGF-β signaling is altered in glioblastoma patients and may contribute to cancer progression. Immune promoting pathways such as STING have also been studied in glioblastoma to enhance anti-tumor immunity; however the interconnecting roles of these pathways are not well described. This review highlights the role of these three key cancer-related pathways in glioblastoma and their mechanistic link. Better understanding these links may result in improved treatment targets or disease progression biomarkers.