Numerous studies have demonstrated that lipopolysaccharide (LPS) stimulates TGF-β1 expression. Although studies have implicated the NF-κB/METTL3/METTL14 transactivation/m6A-dependent and AMPK-dependent signaling pathways are engaged in this process in a variety of cell types, the underlying regulatory mechanism in murine macrophages is still not fully understood. To address this issue, in vitro studies were performed using the murine macrophage cell line, RAW264.7. The results showed that LPS challenge resulted in a significant increase in TGF-β1 expression at both mRNA and protein levels. Subsequent studies revealed that the MAPK (including p38, Erk1/2, and JNK) and NF-κB signaling pathways were activated in response to LPS stimulation, but only blocking the Erk1/2 singling pathway completely abolished LPS-induced TGF-β1 expression. Further studies revealed that the levels of a downstream regulator of the Erk1/2 pathway, EGR1, were significantly increased after LPS treatment, and its knockdown significantly reduced LPS-induced Tgf-β1 expression levels. Finally, dual luciferase reporter and ChIP-PCR assays confirmed that EGR1 is a key transcription factor in the regulation of Tgf-β1 expression by binding to its promoter region in response to LPS stimulation. In conclusion, we elucidated the molecular events by which LPS regulates TGF-β1 expression in murine macrophages through the Erk1/2-EGR1 signaling pathway. These findings provide a conceptually novel pathway for LPS-induced TGF-β1 expression beyond the known NF-κB/METTL3/METTL14 transactivation/m6A-dependent and AMPK-dependent signaling pathways.

Cancer immunotherapy is an approach used in anti‑tumor treatment; however, its efficacy is limited to specific tumor types that are inherently sensitive to immune system modulation. Expanding the scope of indications and enhancing the efficacy of cancer immunotherapy are key goals for continued advancement. Flavonoids modulate the tumor‑immunosuppressive microenvironment. Integrating flavonoids with immunotherapeutic modalities, including cancer vaccines, immune checkpoint inhibitors and adoptive immune‑cell therapy, has potential in terms of augmenting the therapeutic efficacy of immunotherapy. The present review aimed to summarize flavonoids that enhance cancer immunotherapy, focusing on their underlying mechanisms and the application of nanotechnology to overcome inherent limitations such as poor solubility, low bioavailability, rapid metabolism, and instability under physiological conditions, thereby highlighting the potential of flavonoids in advancing cancer immunotherapy.

Despite deep and growing knowledge of cytokine functions, immunotherapies based on the control of these molecules have minimally impacted cancer patient management because of limited efficacy and narrow therapeutic windows. Opportunities to enhance efficacy and mitigate side effects arise from local delivery and targeting antitumor cytokines to tumor tissue via chimeric fusion with antibodies (immunocytokines). Conversely, neutralization of protumor cytokines using antibodies, cytokine traps, or receptor antagonists offer the opportunity to increase the efficacy of conventional immunotherapy with checkpoint inhibitors while reducing their side effects. Exploiting the immunobiology of interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 in synergistic combinations with other treatments holds promise. The antagonistic neutralization of transforming growth factor-β, tumor necrosis factor, IL-1, IL-6, and CXCR1/2 chemokines and growth differentiation factor 15 also seems to be very convenient, again as part of combination strategies.

Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships between these characteristics and various cancers. Here, we integrated gene expression and DNA methylation quantitative trait loci (cis-eQTL and cis-mQTL) data from the blood to perform multi-omics Mendelian randomization analysis. Our analyses revealed 967 stem cell-associated genes (P<0.05) and 11,262 methylation sites (P<0.01) significantly related to 12 cancers. SMAD7 (cg14321542) in colon cancer, IGF2 (cg13508136) in prostate cancer, and FADS1 (cg07005513) in rectal cancer were prioritized as candidate causal genes and regulatory elements. Notably, using cis-eQTL data from the corresponding tissue sites, we detected 16 stem cell-associated genes dramatically causally associated with six cancers (FDR<0.2). The gene THBS3 was particularly common in both blood and stomach tissues and exhibited prognostic significance. Furthermore, it was markedly associated with one microbial metabolic pathway and four immunophenotypes. Functional validation using the ECC12 gastric cancer cell line revealed that the inhibition of its expression could accelerate oxidative phosphorylation and reactive oxygen species production, reduce clonal proliferation ability, and promote the apoptosis of stomach tumor cells. Additionally, based on spatial transcriptomic data from gastrointestinal cancers, the results demonstrated the clusters enriched with the most stem cell-associated genes exhibited significantly enhanced tumor-promoting potency, and the THBS3-expressing cells displayed suppressed oxidative phosphorylation. Overall, this study enhances our understanding of tumorigenic mechanisms and aids in the identification of therapeutic targets.

The transforming growth factor-β (TGFβ) paradox refers to the well-established role of TGFβ in suppressing cancer in healthy tissues yet promoting malignancy in established cancers. Although this positioned TGFβ inhibitors as a potential therapeutic strategy for malignancy, therapuetic blockade has failed in multiple clinical trials. The general lack of selection principles for defining which patients would most benefit from the addition of a TGFβ inhibitor has probably hindered its deployment. Here, we highlight the therapeutic potential in TGFβ regulation of DNA repair using human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) as an illustrative example. HPV inhibits TGFβ signalling, which in turn reduces DNA damage repair, ultimately conferring sensitivity to cancer treatments and thus contributing to the favourable prognosis of HPV-positive HNSCC. Here, we review the DNA repair deficit caused by a loss of TGFβ signalling and how this could be targeted to induce synthetic lethality. Moreover, we explore its role in predicting response to immune checkpoint inhibitors and the potential of biomarkers to select which patients with cancer could ultimately benefit from TGFβ inhibition.

Lung diseases, including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are associated with various etiological factors and are characterized by high mortality rates. Current treatment strategies primarily focus on lung-protective ventilation and careful fluid management. Despite over 50 years of basic and clinical research, effective treatment options remain limited, and the search for novel strategies continues. Traditionally, platelets have been viewed primarily as contributors to blood coagulation; however, recent research has revealed their significant role in inflammation and immune regulation. While the relationship between platelet count and ALI/ARDS has remained unclear, emerging studies highlight the "dual role" of platelets in these conditions. On one hand, platelets interact with neutrophils to form neutrophil extracellular traps (NETs), promoting immune thrombosis and exacerbating lung inflammation. On the other hand, platelets also play a protective role by modulating inflammation, promoting regulatory T cell (Treg) activity, and assisting in alveolar macrophage reprogramming. This dual functionality of platelets has important implications for the pathogenesis and resolution of ALI/ARDS. This review examines the multifaceted roles of platelets in ALI/ARDS, focusing on their immunomodulatory effects, the platelet-neutrophil interaction, and the critical involvement of platelet-Treg cell complexes in shaping the inflammatory environment in ALI.

In the 21st century, significant breakthroughs have been made in the research of chronic liver disease. New biochemical markers of pathogenicity and corresponding drugs continue to emerge. However, current treatment strategies remain unsatisfactory due to complex pathological changes in the liver, including vascular dysfunction, myofibroblast-like transition, and local tissue necrosis in liver sinusoids. These challenges have created an urgent need for innovative, synergistic treatments. Mechanical mechanics is a growing field, with increasing evidence suggesting that mechanical signals play a role similar to that of biochemical markers. These signals influence response speed, conduction intensity, and functional diversity in regulating cell activities.

This review summarizes the three main mechanical characteristics involved in the progression of "liver fibrosis-cirrhosis-hepatocellular carcinoma" and provides an in-depth interpretation of several mechanically-related targets. Finally, current and cutting-edge therapeutic strategies are proposed from a cellular perspective. Despite the many challenges that remain, this review is both relevant and significant.

Pancreatic cancer is characterized by its aggressive nature and poor prognosis, ranking among the most lethal malignancies. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a crucial role in cancer progression. This study investigated the relationship between hypoxia-inducible factor-1α (HIF-1α) and transforming growth factor-β1 (TGF-β1) in regulating ECM protein expression in pancreatic cancer.

PANC-1 cells were cultured under both normoxic and hypoxic conditions. Pharmacological inhibition of HIF-1α and TGF-β1, as well as TGF-β1 stimulation, were employed to evaluate ECM protein expression. HIF-1α knockdown experiments and co-immunoprecipitation were performed to assess molecular interactions. Clinical specimens were analyzed for HIF-1α and TGF-β1 expression.

HIF-1α was found to modulate ECM protein expression through the TGF-β1/Smad signaling pathway. Pharmacological inhibition of either HIF-1α or TGF-β1 significantly decreased the expression of ECM proteins, while TGF-β1 stimulation enhanced their production. HIF-1α knockdown abolished TGF-β1-induced ECM protein expression, indicating that HIF-1α is essential for TGF-β1-mediated ECM regulation. Co-immunoprecipitation experiments revealed a physical interaction between HIF-1α and TGF-β1. Clinical specimens showed significantly elevated expression of both HIF-1α and TGF-β1 in pancreatic cancer tissues compared to adjacent normal tissues, correlating with advanced disease stages.

These findings elucidate a novel mechanism where HIF-1α and TGF-β1 cooperatively regulate ECM production in pancreatic cancer, providing potential therapeutic targets for intervention.

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy with poor prognosis and high relapse rates. While the TNFAIP8 gene family (TNFAIP8, TNFAIP8L1, TNFAIP8L2, and TNFAIP8L3) is implicated in cancer and immune regulation, its role in AML remains unclear. This study utilized bioinformatics analyses to investigate their expression, prognostic significance, genetic alterations, and immune associations in AML.

The expression levels and clinical significance of TNFAIP8 family genes in AML were evaluated using UCSC XENA databases. Kaplan-Meier survival analysis was performed to assess overall survival (OS) differences, and receiver operating characteristic (ROC) curves were utilized to evaluate the prognostic predictive abilities of these genes. Genetic alterations were analyzed using the cBioPortal platform, while immune infiltration was examined through ssGSEA and Spearman correlation analysis. Functional enrichment analysis of co-expressed genes was conducted using the KEGG and GO databases.

TNFAIP8, TNFAIP8L1, TNFAIP8L2, and TNFAIP8L3 were significantly overexpressed in AML tissues compared to normal tissues (P < 0.001). However, Kaplan-Meier survival analysis revealed no significant association between their expression levels and OS in AML patients. ROC curve analysis showed that TNFAIP8L2 had the highest predictive accuracy (AUC = 1.000) among the family members, followed by TNFAIP8L1 (AUC = 0.728), TNFAIP8 (AUC = 0.709), and TNFAIP8L3 (AUC = 0.629). Clinicopathological analysis indicated that TNFAIP8 and TNFAIP8L1 expressions were associated with poor cytogenetic risk, while TNFAIP8L3 expression correlated strongly with elevated bone marrow blasts (P < 0.001). Mutation analysis revealed a low frequency of genetic alterations, with TNFAIP8L1 being the only gene with mutations in 0.53% of cases. Immune infiltration analysis demonstrated that TNFAIP8 and TNFAIP8L3 were positively correlated with myeloid-derived suppressor cells (MDSCs), while TNFAIP8L1 expression was associated with natural killer (NK) cell enrichment.

TNFAIP8 family genes play distinct roles in AML pathogenesis and immune regulation. TNFAIP8L2 shows promise as a prognostic biomarker, while TNFAIP8 and TNFAIP8L1 may indicate adverse cytogenetic risk. The study highlights their potential as therapeutic targets in AML.

Several human lymphocyte subsets express the novel secretory IgA receptor FCRL3 (Fc receptor-like 3). Secretory IgA binding to FCRL3 diminishes the inhibitory capacity of regulatory T cells and promotes a T helper 17-like phenotype. Here, we report that in CD4+ regulatory T cells and CD8+ terminal effector T cells secretory IgA induced a shared inflammatory gene signature that included PTGS2 encoding COX2, and the prototypic inflammatory cytokine genes IL1A, IL1B, and IL8. Secretory IgA in regulatory T cells also elevated gene transcripts required for lineage identity and function. Secretory IgA promoted interleukin (IL)-1β, IL-6, IL-8, IL-10, interferon γ, and tumor necrosis factor α protein secretion by both T cell types. Moreover, secretory IgA promoted NLRP3 inflammasome activation in regulatory T cells. Pharmacologic COX2 and NLRP3 inhibitors partially rescued the inhibitory competence of regulatory T cells, suggesting respective mechanistic roles. We propose that secretory IgA provokes a coordinated inflammatory response in regulatory and effector T cells to facilitate mucosal pathogen clearance.

Although it has been shown that abnormal expression of Wilm's tumor gene 1 (WT1) is associated with the occurrence of leukemia, the specific mechanism via which it induces leukemia cells to differentiate into macrophages remains poorly understood. Based on the prediction that the microRNA miRNA-132-3p is the miRNA that possibly lies upstream of the WT1 gene, we hypothesized that miRNA-132-3p may participate in the polarization process of macrophages through regulating expression of the WT1 gene. The focus of the present study was therefore to investigate the role of the miRNA-132-3p/WT1 signaling axis in the differentiation of THP-1 leukemia cells into macrophages induced by PMA. The results obtained indicated that, compared with the control group, the proliferation of THP-1 cells was clearly inhibited by PMA, and the cell cycle was arrested at G0/G1 phase, associated with an upregulation of CD11b and CD14 expression. Induced by PMA, the expression level of miRNA-132-3p was increased, WT1 expression was decreased, and the expression level of TGF-β1 was increased. Following transfection with miRNA-132-3p mimics, however, the expression of WT1 in the THP-1 cells was downregulated, with upregulation of the CD11b and CD14 antigens, whereas this downregulation of WT1 mediated by miRNA-132-3p mimics could be reversed by co-transfection with WT1 vector, which was accompanied by downregulation of the CD11b and CD14 antigens. The luciferase activity of the co-transfected miRNA-132-3p mimic + WT1-wild-type (WT) group was found to be statistically significantly lower compared with that of the co-transfected miRNA-132-3p mimic + WT1-mutated (MUT) group. Furthermore, chromatin immunoprecipitation experiments showed that WT1 was able to directly target the promoter of the downstream target gene TGF-β1, which led to the negative modulation of TGF-β1 expression, whereas downregulation of WT1 led to an upregulation of the expression of TGF-β1, which thereby promoted the differentiation of THP-1 cells into macrophages. Taken together, the present study has provided evidence, to the best of the authors' knowledge for the first time, that the miRNA-132-3p/WT1/TGF-β1 axis is able to regulate the committed differentiation of leukemia cells into macrophages.

The development of immune checkpoint inhibitors has revolutionized the treatment of patients with cancer. Targeting the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1(PD-L1) interaction using monoclonal antibodies has emerged as a prominent focus in tumor therapy with rapid advancements. However, the efficacy of anti-PD-1/PD-L1 treatment is hindered by primary or acquired resistance, limiting the effectiveness of single-drug approaches. Moreover, combining PD-1/PD-L1 with other immune drugs, targeted therapies, or chemotherapy significantly enhances response rates while exacerbating adverse reactions. Multispecific antibodies, capable of binding to different epitopes, offer improved antitumor efficacy while reducing drug-related side effects, serving as a promising therapeutic approach in cancer treatment. Several bispecific antibodies (bsAbs) targeting PD-1/PD-L1 have received regulatory approval, and many more are currently in clinical development. Additionally, tri-specific antibodies (TsAbs) and tetra-specific antibodies (TetraMabs) are under development. This review comprehensively explores the fundamental structure, preclinical principles, clinical trial progress, and challenges associated with bsAbs targeting PD-1/PD-L1.

Lichen sclerosus (LS) is a chronic inflammatory skin disorder primarily affecting the anogenital region, leading to symptoms such as itching, pain, and sexual dysfunction, all of which significantly impact patients' quality of life. Due to the non-specific nature of its early symptoms, diagnosis is often delayed. This review examines the cytokine networks involved in LS, with a focus on immune activation, the role of T-helper (Th)1 cells, and the interaction between inflammatory mediators and the extracellular matrix, particularly in fibrosis. By providing an updated understanding of LS immunopathogenesis, this review highlights key mediators involved in disease progression and offers insights into personalized treatment strategies that may improve patient outcomes. Additionally, current therapeutic approaches and future directions in LS management are discussed.

This study evaluates dynamic changes in platelet derived growth factor C (PDGF-C) and transforming growth factor β1 (TGF-β1) levels after percutaneous coronary intervention (PCI) in patients with premature coronary artery disease (PCAD) and their combined predictive value for major adverse cardiac and cerebrovascular events (MACCE).

A total of 100 PCAD patients admitted to the hospital from July 2021 to July 2023 who had completed 2 years of follow-up were retrospectively selected as the research objects. The patients were divided into MACCE group and non-MACCE group according to the occurrence of MACCE. The changes of serum PDGF-C and TGF-β1 levels were compared before operation, 1 year after operation and 2 years after operation. Cox regression was used to test the influencing factors. Receiver operating characteristic (ROC) curve was used to predict the predictive value. The decision curve was used to analyze the predicting value of serum PDGF-C and TGF-β1.

Compared with that before operation, serum PDGF-C levels increased, while TGF-β1 levels decreased at 1 year and 2 years post-PCI (P<0.05). The levels of hs-CRP, HDL-C, MPV and PDGF-C in the MACCE group were higher than those in the non-MACCE group, and the level of TGF-β1 was lower than that in the non-MACCE group (P<0.05). The hs-CRP, MPV and PDGF-C were identified as independent risk factors for MACCE (HR>1, P<0.05), and TGF-β1 was identified as a protective factor (HR<1, P<0.05). The AUC of PDGF-C levels and TGF-β1 levels n in predicting MACCE after PCI in PCAD patients were 0.796 and 0.837, respectively. Combined prediction has higher sensitivity and specificity than individual markers. The decision curve showed that within the threshold range of 0.141-0.202 and 0.216-0.998, the net return rate of the combination of PDGF-C and TGF-β1 levels in predicting MACCE after PCI in PCAD patients was better than that of either alone.

hs-CRP, MPV, PDGF-C and TGF-β1 were the influencing factors of MACCE in PCAD patients after PCI. Combined detection of PDGF-C and TGF- β1 enhanced predictive accuracy for MACCE, offering potential value for risk stratification in PCAD patients post-PCI.

Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These cells are pivotal in eliminating circulating tumor cells (CTCs) from the bloodstream, thus limiting cancer spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating tumor growth at distant sites. In this review, we first discuss the biology of NK cells, focusing on their functions within the tumor microenvironment (TME), the lymphatic system, and circulation. We then examine the immune evasion mechanisms employed by cancer cells to inhibit NK cell activity, including the upregulation of inhibitory receptors. Finally, we explore the clinical implications of monitoring circulating biomarkers, such as NK cells and CTCs, for therapeutic decision-making and emphasize the need to enhance NK cell-based therapies by overcoming immune escape mechanisms.

Large soft tissue injuries require several weeks to heal and frequently leave fibrotic scars that can negatively impact tissue function. However, the applicability of traditional skin and mucous membrane transplantation for the treatment of lesions in the ocular surface and urethra is limited owing to the unique locations and functions of these tissues. Oral mucosa has been widely used in the repair of such injuries owing to its reduced propensity for inducing an inflammatory response, angiogenesis, and scarring. Enhancing chronic wound healing while avoiding scar formation requires a broader understanding of the cellular and molecular pathways that drive wound repair in the oral mucosa. This review integrates current knowledge on the mechanisms underlying the resistance of the oral mucosa to inflammation and its application as a graft material, highlighting its challenges and potential advancements. The aim of this review is to offer insights into future therapeutic strategies for wound healing and related conditions.

Background: The EGF domain-specific O-GlcNAc transferase (EOGT), a migrasome marker, plays emerging roles in cancer biology through O-GlcNAcylation modifications, yet its pan-cancer functions and therapeutic implications remain underexplored. This study aimed to systematically characterize EOGT's oncogenic mechanisms across malignancies, with particular focus on hepatocellular carcinoma (HCC) progression and sorafenib resistance. Methods: Multi-omics analysis integrated TCGA/GTEx data from 33 cancer types with spatial/single-cell transcriptomics and 10 HCC cohorts. Functional validation employed Huh7 cell models with EOGT modulation, RNA sequencing, and ceRNA network construction. Drug sensitivity analysis leveraged GDSC/CTRP/PRISM databases, while immune microenvironment assessment utilized ESTIMATE/TIMER algorithms. Results: EOGT showed cancer-specific dysregulation, marked by significant upregulation in HCC correlating with advanced stages and poor survival. Pan-cancer analysis revealed EOGT's association with genomic instability, tumor stemness, and angiogenesis. Experimental validation demonstrated EOGT's promotion of HCC proliferation and migration. A novel exosomal circ_0058189/miR-130a-3p/EOGT axis was identified, showing that circ_0058189 was upregulated in HCC tissues, plasma samples and exosomes of sorafenib-resistant cells. Conclusion: This study establishes EOGT as a pan-cancer angiogenesis biomarker, while elucidating its role in therapeutic resistance via exosomal circRNA-mediated regulation, providing mechanistic insights for targeted intervention strategies.

On-pump coronary artery bypass grafting (CABG) triggers inflammatory responses as a result of surgical stress and extracorporeal circulation, which affect platelet and leukocyte activation while enhancing their intimate crosstalk. Given this, the study presented here aimed to investigate platelet-T cell interaction after CABG focusing on the changes in immunomodulatory subtypes of regulatory T Cells.

Blood samples were obtained from twenty patients undergoing on-pump CABG at 5 different time points of 24 h before, immediately, 2 h, 24 h, and one week after surgery. Total leukocyte and lymphocyte counts were determined using an automatic cell counter. Platelet P-selectin expression, frequencies of CD4+ and CD8+ T cells, platelet-T cell aggregates (PTCAs), and regulatory T cells derived from CD4+ (T4reg) and CD8+ (T8reg) cells, were assessed by flow cytometry.

A significant increase in total leukocyte count occurred immediately after CABG, whereas, conversely, lymphocyte and CD4+ T cells but not CD8+ T cells decreased 2 h after surgery. However, all these changes returned to pre-CABG baseline levels within a week. Platelet P-selectin expression increased immediately after surgery, followed by a two-hour delay after PTCA, and both returned to baseline after one week. T4regs and T8regs showed a similar increase and decrease trend, where T8regs but not T4regs returned to baseline one week after surgery.

CABG surgery induces an inflammatory response that activates platelets and enhances P-selectin expression, facilitating PTCA formation. This mechanism is critical for the dynamics and differentiation of T cells, which play an essential role in post-CABG modulation of immune responses.

Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.

This study aimed to explore the potential mechanism of Xiexin Tang in improving type 2 diabetes mellitus from the perspective of intestinal barrier function. The results indicated that Xiexin Tang could notably promote the expression of GPRs while suppressing the expression of HDACs in colon epithelial cells, then significantly elevate the levels of TGF-β1 and IL-18 to regulate the differentiation of T cells and further maintain the intestinal immune homeostasis. Meanwhile, it could markedly inhibit the inflammatory signaling pathway to improve intestinal barrier function, relieving type 2 diabetes mellitus.

Cardiac fibrosis is a physiological process that involves the formation of scar tissue in the heart in response to injury or damage. This process is initially a protective measure characterized by enhanced fibroblasts, which are responsible for producing extracellular matrix proteins that provide structural support to the heart. However, when fibrosis becomes excessive, it can lead to adverse outcomes, including increasing tissue stiffness and impaired cardiac function, which can ultimately result in heart failure with a poor prognosis. While fibroblasts are the primary cells involved in cardiac fibrosis, immune cells have also been found to play a vital role in its progression. Recent research has shown that immune cells exert multifaceted effects besides regulation of inflammatory response. Advanced research techniques such as single-cell sequencing and multiomics have provided insights into the specific subsets of immune cells involved in fibrosis and the complex regulation of the process. Targeted immunotherapy against fibrosis is gaining traction as a potential treatment option, but it is still unclear how immune cells achieve this regulation and whether distinct subsets are involved in different roles. To better understand the role of immune cells in cardiac fibrosis, it is essential to examine the classical signaling pathways that are closely related to fibrosis formation. We have also focused on the unique properties of diverse immune cells in cardiac fibrosis and their specific intercommunications. Therefore, this review will delve into the plasticity and heterogeneity of immune cells and their specific roles in cardiac fibrosis, which propose insights to facilitate the development of anti-fibrosis therapeutic strategies.

Interleukin-2 (IL-2) is a cytokine vital for CD8+ T cell activation and proliferation, holding great potential for cancer immunotherapy. Nevertheless, inherent shortcomings of short half-life, activation of regulatory T (Treg) cells, and systemic toxicity limit its application. To tackle these, a circular RNA (cRNA)-based IL-2 therapy using immunomodulatory lipid nanoparticles [ursodeoxycholic acid lipid nanoparticles (ULNPs)] and sustained-release hydrogel was developed. Fusing fragment crystallizable (Fc) region into IL-2 and encoding this fusion protein IL-2-Fc (IL-2F) in cRNA (cRNAIL-2F) greatly extend the half-life. ULNPs containing ursodeoxycholic acid, a transforming growth factor-β1 inhibitor, suppress the function of Treg cells. Consequently, the ULNPs-cRNAIL-2F formulation promotes CD8+ T cells and suppresses Treg cells, increasing the CD8+/Treg ratio for effective immunotherapy. Furthermore, a locally administrated hydrogel loading with ULNPs-cRNAIL-2F sustains the release, enhancing efficacy and reducing toxicity. This innovative approach achieves remarkable tumor inhibition in both melanoma and orthotopic glioma models with or without surgery, offering a promising future for cancer immunotherapy.

PM2.5 (fine particulate matter) is an air pollutant widely present in urban and industrial areas, which has emerged as a significant threat to human health. Specifically, long-term exposure to PM2.5 could lead to various lung diseases, including pulmonary fibrosis and Chronic Obstructive Pulmonary Disease (COPD). The Glycoprotein A Repetitions Predominant (GARP) protein, a key receptor and regulator for TGF-β1, has recently emerged as a vital cytokine in PM2.5-induced pulmonary pathological changes. As a membrane glycoprotein, GARP binds to TGF-β, keeping it in an active state. Herein, PM2.5 treatment upregulated GARP and promoted Epithelial-Mesenchymal Transition (EMT) via TGF-β/SMAD signaling pathway activation. Conversely, lentinan (a shiitake mushroom-derived polysaccharide) effectively reversed the PM2.5-induced GARP upregulation, alleviating EMT. This study elucidates the role of GARP in PM2.5-induced EMT through the TGF-β/SMAD pathway in pulmonary epithelial cells and discusses the therapeutic potential of lentinan.

Cervical cancer (CC) is one of the most deadly cancers in women, its current treatments still result in poor outcomes and developing the novel targets and therapeutic strategies are urgently needed. Qiu's Cervical Prescription (QCP) is one of the traditional Chinese medicines used in the treatment of cervical cancer in China. Although its curative effect is remarkable, the internal mechanism of its treatment is still poorly understood. Recent studies have shown that LncRNA ATB might be used as a new proliferation marker for cancer diagnosis and prognosis. This study aimed to investigate the possible mechanism of action of QCP in the treatment of cervical cancer.

The functional assays of migration and invasion in vitro using transwell assays and wound healing assays was performed to confirm the pro-carcinogenic effect of LncRNA ATB, and the changes of migration and invasion of HeLa cells were observed after treatment with QCP containing drug serum. The changes in tumor volume, general condition of transplanted tumor-bearing mice and expression of LncRNA ATB pathway-related proteins were detected by qPCR, Western blotting and HE staining after treatment with the QCP.

We induced LncRNA ATB knockdown and overexpression in cervical cancer cell lines and detected the biological behavior changes in vitro. Furthermore, we established murine models using stable LncRNA ATB-shRNA HeLa cells or overexpression LncRNA ATB cells or normal Hela cells with QCP to evaluate how suppression of LncRNA ATB affects tumor growth.

We showed that potential mechanism of QCP in the treatment of cervical cancer may be through inhibition of the LncRNA ATB/miR-126/TGFβ1 signaling axis. In conclusion, QCP may be a promising approach for the treatment of CC.

Pelvic organ prolapse is a condition that significantly affects women's quality of life. The pathological mechanism of pelvic organ prolapse is not yet fully understood, and its pathogenesis is often caused by multiple factors, including the metabolic imbalance of the extracellular matrix. This study aims to investigate the role of miR-5195-3p, a microRNA, in the pathology of pelvic organ prolapse and its regulatory mechanism. Using various molecular biology techniques such as real-time reverse transcription Polymerase Chain Reaction (PCR), fluorescence in situ hybridization, immunohistochemistry, and Western blot, miR-5195-3p expression was examined in vaginal wall tissues obtained from pelvic organ prolapse patients. Results revealed an up-regulation of miR-5195-3p expression in these tissues, showing a negative correlation with the expression of extracellular matrix-related proteins. Further analysis using bioinformatics tools identified Lipoxygenase (LOX) as a potential target in pelvic organ prolapse. Dual luciferase reporter gene experiments confirmed LOX as a direct target of miR-5195-3p. Interestingly, regulating the expression of LOX also influenced the transforming growth factor β1 signaling pathway and had an impact on extracellular matrix metabolism. This finding suggests that miR-5195-3p controls extracellular matrix metabolism by targeting LOX and modulating the TGF-β1 signaling pathway. In conclusion, this study unveils the involvement of miR-5195-3p in the pathological mechanism of pelvic organ prolapse by regulating extracellular matrix metabolism through the LOX/TGF-β1 axis. These findings reveal new mechanisms in the pathogenesis of pelvic organ prolapse, providing a theoretical foundation and therapeutic targets for further research on pelvic organ prolapse treatment.

Serum Cystatin S (CST4), a secretory protein that inhibits cellular matrix degradation, significantly influences the tumor microenvironment and tumor progression. However, the prognostic value of serum CST4 in gastric cancer (GC) remains unclear. This study aims to explore serum CST4's utility in GC prognostic assessment.

A cohort of 334 patients with GC who underwent radical gastrectomy was assessed. Preoperative serum CST4 levels were measured alongside traditional tumor markers, correlating with clinical data and patient outcomes. The cohort was divided into training and test sets at a ratio of 3:1 for Cox regression analyses, which identified CST4 as an independent risk factor for overall survival (OS) and disease-free survival (DFS). A prognostic model was developed, validated with calibration curves, and its predictive value was evaluated using receiver operating characteristic (ROC) curves. In addition, CST4 expression was correlated with immune cell infiltration using data from The Cancer Genome Atlas (TCGA). Patients were stratified by median CST4 levels, and Kaplan-Meier curves for OS and DFS were plotted.

Cystatin S was confirmed as an independent risk factor for OS and DFS. Integrating CST4 with traditional markers and TNM pathological staging significantly enhanced the predictive value for prognosis. Cystatin S's impact on tumor progression is likely mediated through modulation of the immune microenvironment, including immune suppression and evasion.

Cystatin S is an effective biomarker for GC prognostic assessment, assisting in the evaluation of prognosis and the selection of treatment strategies for patients with GC.

Renal clear cell carcinoma (ccRCC) is a highly aggressive and common form of kidney cancer, with limited treatment options for advanced stages. Recent studies have highlighted the importance of the ubiquitin-proteasome system in tumor progression, particularly the role of ubiquitin-conjugating enzyme E2 (UBE2) family members. However, the prognostic significance of UBE2-related genes (UBE2RGs) in ccRCC remains unclear. In this study, bulk RNA-sequencing and single-cell RNA-sequencing data from ccRCC patients were retrieved from the Cancer Genome Atlas and Gene Expression Omnibus databases. Differential expression analysis was performed to identify UBE2RGs associated with ccRCC. A combination of 10 machine learning methods was applied to develop an optimal prognostic model, and its predictive performance was evaluated using area under the curve (AUC) values for 1-, 3-, and 5-year overall survival (OS) in both training and validation cohorts. Functional enrichment analyses of gene ontology and Kyoto Encyclopedia of Genes and Genomes were conducted to explore the biological pathways involved. Correlation analysis was conducted to investigate the association between the risk score and tumor mutational burden (TMB) and immune cell infiltration. Immunotherapy and chemotherapy sensitivity were assessed by immunophenoscore and tumor immune, dysfunction, and exclusion scores to identify potential predictive significance. In vitro, knockdown of the key gene UBE2C in 786-O cells by specific small interfering RNA to validate its impact on apoptosis, migration, cell cycle, migration, invasion of tumor cells, and induction of regulatory T cells (Tregs). Analysis of sc-RNA revealed that UBE2 activity was significantly upregulated in malignant cells, suggesting its role in tumor progression. A three-gene prognostic model comprising UBE2C, UBE2D3, and UBE2T was constructed by Lasoo Cox regression and demonstrated robust predictive accuracy, with AUC values of 0.745, 0.766, and 0.771 for 1-, 3-, and 5-year survival, respectively. The model was validated as an independent prognostic factor in ccRCC. Patients in the high-risk group had a worse prognosis, higher TMB scores, and low responsiveness to immunotherapy. Additionally, immune infiltration and chemotherapy sensitivity analyses revealed that UBE2RGs are associated with various immune cells and drugs, suggesting that UBE2RGs could be a potential therapeutic target for ccRCC. In vitro experiments confirmed that the reduction of UBE2C led to an increase in apoptosis rate, as well as a decrease in tumor cell invasion and metastasis abilities. Additionally, si-UBE2C cells reduced the release of the cytokine Transforming Growth Factor-beta 1 (TGF-β1), leading to a decreased ratio of Tregs in the co-culture system. This study presents a novel three-gene prognostic model based on UBE2RGs that demonstrates significant predictive value for OS, immunotherapy, and chemotherapy in ccRCC patients. The findings underscore the potential of UBE2 family members as biomarkers and therapeutic targets in ccRCC, warranting further investigation in prospective clinical trials.

Sanqi oral solution (SQ) is a traditional Chinese patent medicine, widely used to treat chronic kidney diseases (CKD) in the clinic in China. Previous studies have confirmed its anti-renal fibrosis effect, but the specific pharmacological mechanism is still unclear.

Focusing on energy metabolism in fibroblasts, the renoprotective mechanism of SQ was investigated in vitro and in vivo.

Firstly, the fingerprint of SQ was constructed and its elementary chemical composition was analyzed. In the 5/6Nx rats experiment, the efficacy of SQ on the kidney was evaluated by detecting serum and urine biochemical indexes and pathological staining of renal tissues. Lactic acid and pyruvic acid levels in serum and renal tissues were detected. PCNA protein expression in kidney tissue was detected by immunofluorescence assay and Western blot. Expression levels of HIF-1α, PKM2 and HK2 were determined by immunohistochemistry, Western blot or RT-qPCR assay. In addition, the effect of SQ intervention on cell proliferation and glycolysis was evaluated in TGF-β1-induced NRK-49F cells, and the role of SQ exposure and HIF-1α/PKM2/glycolysis pathway were further investigated by silencing and overexpressing HIF-1α gene in NRK-49F cells.

In 5/6 Nx rats, SQ effectively improved renal function and treated renal injury. It reduced the levels of lactic acid and pyruvic acid in kidney homogenates from CKD rats and decreased the expression levels of HIF-1α, PKM2, HK2, α-SMA, vimentin, collagen I and PCNA in kidney tissues. Similar results were observed in vitro. SQ inhibited NRK-49F cell proliferation, glycolysis and the expression levels of HIF-1α, PKM2 induced by TGF-β1. Furthermore, we established NRK-49F cells transfected with siRNA or pDNA to silence or overexpress the HIF-1α gene. Overexpression of HIF-1α promoted cellular secretion of lactic acid and pyruvic acid in TGF-β1-induced NRK-49F cells, however, this change was reversed by intervention with SQ or silencing the HIF-1α gene. Overexpression of HIF-1α can further induce increased PKM2 expression, while SQ intervention can reduce PKM2 expression. Moreover, PKM2 expression was also inhibited after silencing HIF-1α gene, and SQ was not effective even when given.

The mechanism of action of SQ was explored from the perspective of energy metabolism, and it was found to regulate PKM2-activated glycolysis, inhibit fibroblast activation, and further ameliorate renal fibrosis in CKD by targeting HIF-1α.

The recovery of ischemic skin flaps is a major concern in clinical settings. The purpose of this study is to evaluate the effects of engineered exosomes derived from FGF1 pre-conditioned adipose-derived stem cells (FEXO) on ischemic skin flaps.

6 patients who suffered from pressure ulcer at stage 4 and underwent skin flaps surgery were recruited in this study to screen the potential targets of ischemic skin flaps in FGF family. FGF1 was co-incubated with adipose stem cells, and ultracentrifugation was applied to extract FEXO. Transcriptome sequencing analysis was used to determine the most effective microRNA in FEXO. Animal skin flaps models were established in our study to verify the effects of FEXO. Immunofluorescence (IF), western blotting (WB) and other molecular strategy were used to evaluate the effects and mechanism of FEXO.

FGF1 was expected to be the therapeutic and diagnostic target of ischemic skin flaps, but there is still some deficiency in rescuing skin flaps. FEXO significantly improved the viability of RPSFs and endothelial cells by inhibiting oxidative stress and alleviating apoptosis and pyroptosis through augmenting autophagy flux. In addition, FEXO inhibited the over-activated inflammation responses. Transcriptome sequencing analysis showed that miR-183-5p was significantly elevated in FEXO, and inhibiting miR-183-5p resulted in impaired protective effects of autophagy in skin flaps. The exosomal miR-183-5p markedly enhanced cell viability, inhibited oxidative stress and alleviated apoptosis and pyroptosis in endothelial cells by targeting GPR137 through Pi3k/Akt/mTOR pathway, indicating that GPR137 could also be a therapeutic target of ischemic skin flap. It was also notabale that FGF1 increased the number of exosomes by upregulating VAMP3, which may be a promising strategy for clinical translation.

FEXO markedly improved the survivial rate of ischemic skin flaps through miR-183-5p/GPR137/Pi3k/Akt/mTOR axis, which would be a promising strategy to rescue ischemic skin flaps.

Triple-negative breast cancer (TNBC) is the most intractable subgroup of breast neoplasms due to its aggressive nature. In recent years, immune checkpoint inhibitors (ICIs) have exhibited potential efficacy in TNBC treatment. However, only a limited fraction of patients benefit from ICI therapy, primarily because of the suppressive tumor immune microenvironment (TIME). Trametes robiniophila Murr (Huaier) is a traditional Chinese medicine (TCM) with potential immunoregulatory functions. However, the underlying mechanism remains unclear.

The present study aimed to investigate the therapeutic role of Huaier in the TIME of TNBC patients.

Single-cell RNA sequencing (scRNA-seq) was used to systematically analyze the influence of Huaier on the TNBC microenvironment for the first time. The mechanisms of the Huaier-induced suppression of cancer-associated fibroblasts (CAFs) were assessed via real-time quantitative polymerase chain reaction (qRT‒PCR) and western blotting. A tumor-bearing mouse model was established to verify the effects of the oral administration of Huaier on immune infiltration.

Unsupervised clustering of the transcriptional profiles suggested an increase in the number of apoptotic cancer cells in the Huaier group. Treatment with Huaier induced immunological alterations from a "cold" to a "hot" state, which was accompanied by phenotypic changes in CAFs. Mechanistic analysis revealed that Huaier considerably attenuated the formation of myofibroblastic CAFs (myoCAFs) by impairing transforming growth factor-beta (TGF-β)/SMAD signaling. In mouse xenograft models, Huaier dramatically modulated CAF differentiation, thus synergizing with the programmed cell death 1 (PD1) blockade to impede tumor progression.

Our findings demonstrate that Huaier regulates cancer immunity in TNBC by suppressing the transition of CAFs to myoCAFs and emphasize the crucial role of Huaier as an effective adjuvant agent in immunotherapy.

Pancreatic cancer is distinguished by an immunosuppressive tumor microenvironment (TME) that facilitates cancer progression. The assembly of the TME involves numerous contributing factors. Migrasomes, recently identified as cellular organelles in migrating cells, play a pivotal role in intercellular signaling. However, research into their involvement in cancers remains nascent. Thus far, whether pancreatic cancer cells generate migrasomes and their potential role in TME formation remains unexplored. In this study, it was found that both murine and human pancreatic cancer cells could indeed generate migrasomes, termed pancreatic cancer cell-derived migrasomes (PCDMs), which actively promote cancer progression. Moreover, utilizing chemokine antibody arrays and quantitative mass spectrometry analysis, we observed significant differences between the chemokines, cytokines, and proteins present in PCDMs compared to their originating cell bodies. Notably, PCDMs exhibited an enrichment of immunosuppression-inducing factors. Furthermore, macrophages could directly uptake PCDMs, leading to the expression of high levels of M2-like markers and secretion of tumor-promoting factors. PCDM-induced macrophages played a pivotal role in inhibiting T cell proliferation and activation partially through ARG-1. In summary, this study provides compelling evidence that pancreatic cancer cells generate migrasomes, which play a crucial role in promoting tumor progression by contributing to an immunosuppressive TME. The exploration of migrasomes as a therapeutic target could pave the way for the development of tailored immunotherapies for pancreatic cancer.

In the tumor microenvironment (TME), the transforming growth factor-β (TGF-β) and programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling axes are complementary, nonredundant immunosuppressive signaling pathways. Studies have revealed that active TGF-β is mainly released from the glycoprotein A repetitions predominant (GARP)-TGF-β complex on the surface of activated regulatory T cells (Tregs), B cells, natural killer (NK) cells, and tumor cells. The currently available antibodies or fusion proteins that target TGF-β are limited in their abilities to simultaneously block TGF-β release and neutralize active TGF-β in the TME, thus limiting their antitumor effects.

We designed and constructed a bispecific, trifunctional antibody, namely, BPB-101, that specifically targets the GARP-TGF-β complex and/or small latent complex (SLC), active TGF-β, and PD-L1. The binding ability of BPB-101 to the different antigens was determined by ELISA, FACS, and biolayer interferometry (BLI). The blocking ability of BPB-101 to the TGF-β and PD-1/PD-L1 signaling axes was determined by reporter gene assay (RGA). The antitumor effect and biosafety of BPB-101 were determined in a transgenic mouse tumor model and cynomolgus monkeys, respectively. Stability assessments, including stability in serum, after exposure to light, after repeated freeze-thaw cycles, and after high-temperature stress tests had been completed to evaluate the stability of BPB-101.

BPB-101 bound efficiently to different antigenic proteins: the GARP-TGF-β complex and/or SLC, active TGF-β, and PD-L1. Data showed that BPB-101 not only effectively inhibited the release of TGF-β from human Tregs, but also blocked both the TGF-β and PD-1/PD-L1 signaling pathways. In an MC38-hPD-L1 tumor-bearing C57BL/6-hGARP mouse model, BPB-101 at a dose of 5 mg/kg significantly inhibited tumor growth, with a complete elimination rate of 50%. Stability assessments confirmed the robustness of BPB-101. Furthermore, BPB-101 showed a favorable safety profile in nonhuman primate (NHP) toxicity studies.

BPB-101 is a potentially promising therapeutic candidate that may address unmet clinical needs in cancer immunotherapy, thus, BPB-101 warrants further clinical investigation.

Interleukin-37 (IL-37) has anti-inflammatory properties in innate and adaptive immunity. Patients with multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), have increased serum levels of IL-37. However, it is unknown whether IL-37 has an inhibitory effect on ongoing autoimmune neuroinflammation, thus offering a potential MS therapy.

Here, we examined the effect of IL-37 in an experimental autoimmune encephalomyelitis (EAE) model after disease onset to determine if it was protective.

IL-37-treated mice developed a less severe disease than control mice, with reduced demyelination as determined by increased expression of myelin basic protein. IL-37 suppressed inflammation by decreasing infiltration of CD4 + T cells into the CNS and increasing the frequency of regulatory T cells, while IL-10 expression by CD4 + T cells decreased over time in the CNS.

Our findings confirm the immunomodulatory role of IL-37 in CNS inflammation during ongoing disease, thus indicating the potential of IL-37 as an inhibitory reagent for MS therapy.

Secondary neurological impairment mediated by neuroinflammation is recognized as a crucial pathological factor in central nervous system (CNS) diseases. Currently, there exists a lack of specific therapies targeting neuroinflammation. Given that microglia constitute the primary immune cells involved in the neuroinflammatory response, a thorough comprehension of their role in CNS diseases is imperative for the development of efficacious treatments. Recent investigations have unveiled the significance of formyl peptide receptors (FPRs) in various neuroinflammatory diseases associated with microglial overactivation. Consequently, FPRs emerge as promising targets for modulating the neuroinflammatory response. This review aims to comprehensively explore the therapeutic potential of targeting FPRs in the management of microglia-mediated neuroinflammation. It delineates the molecular characteristics and functions of FPRs, elucidates their involvement in the inflammatory response linked to microglial overactivation, and synthesizes therapeutic strategies for regulating microglia-mediated neuroinflammation via FPR modulation, thereby charting a novel course for the treatment of neuroinflammatory diseases.

T cell exclusion is crucial in enabling tumor immune evasion and immunotherapy resistance. However, the key genes driving this process remain unclear. We uncovered a notable increase of insulin-like growth factor 2 (IGF2) in immune-excluded tumors, predominantly secreted by cancer-associated fibroblasts (CAFs). Using mice with systemic or fibroblast-specific deletion of IGF2, we demonstrated that IGF2 deficiency enhanced the infiltration and cytotoxic activity of CD8+ T cells, leading to a reduction in tumor burden. Integration of spatial and single-cell transcriptomics revealed that IGF2 promoted interaction between CAFs and T cells via CXCL12 and programmed death ligand 1 (PD-L1). Mechanistically, autocrine IGF2 activated PI3K/AKT signaling by binding to the IGF1 receptor (IGF1R) on CAFs, which was required for the immunosuppressive functions of CAFs. Furthermore, genetic ablation of IGF2 or targeted inhibition of the IGF2/IGF1R axis with the inhibitor linsitinib markedly boosted the response to immune checkpoint blockade. Clinically, elevated levels of IGF2 in tumors or plasma correlated with an adverse prognosis and reduced efficacy of anti-programmed death 1 treatment. Together, these results highlight the pivotal role of IGF2 in promoting CAF-mediated immunoevasion, indicating its potential as a biomarker and therapeutic target in immunotherapy.

Trauma is a common cause of cutaneous surgical disease with an increased risk of secondary infection in cat clinics. Platelet-rich fibrin (PRF), a platelet and leukocyte concentrate containing multiple cytokines and growth factors, is known to accelerate the healing of wounds. However, how PRF affects wound healing in the cat trauma model has not been fully investigated. The study aimed to examine the impact of PRF on skin wound healing in the cat trauma model. In this study, PRF from cats was successfully produced for our investigation. The models of feline trauma were effectively established. A total of 18 cats were randomly divided into 3 groups (n = 6): (1) Control group (CON); (2) PRF group; (3) Manuka honey group (MAN, as a positive control). Experiments were performed separately on days 7, 14, 21, and 28. Our results showed that PRF was a safe and efficient method of wound healing that did not influence the cat's body temperature, respiration rate, and heart rate (HR). PRF accelerated skin wound healing in the cat trauma model based on the rate and histological observation of wound healing. In addition, PRF promoted the production of growth factors and suppressed inflammation during wound healing. PRF accelerated wound healing by increasing the formation of collagen fibers, as shown by Masson-trichrome staining. The outcomes of the PRF and MAN groups were comparable. In conclusion, PRF improves the healing of skin wounds in cats by boosting the synthesis of growth factors, reducing inflammation, and enhancing the synthesis of collagen fibers.

The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME.

The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model.

Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis.

The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) ( P < 0.01). Group 4 also showed a significant increase in regulatory T cells ( P = 0.04) and transforming growth factor-β1 levels ( P = 0.02), and a trend toward a decrease in interleukin-1β levels ( P = 0.03) at 16 weeks after transplantation as compared with control (group 1).

FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.