Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies due to its highly immunosuppressive tumor microenvironment (TME), which limits effective therapeutic interventions. Here, we demonstrate that V-domain immunoglobulin suppressor of T cell activation (VISTA) plays a crucial role in orchestrating macrophage polarity within the PDAC TME. Using murine PDAC models, we show that VISTA deficiency markedly impairs tumor growth, leading to prolonged survival. Functionally, VISTA deficiency is linked to a shift in tumor-associated macrophages (TAMs) from an immunosuppressive phenotype marked by secreted phosphoprotein 1 (SPP1), to one enriched for C-X-C motif chemokine ligand 9 (CXCL9), indicative of a pro-inflammatory state. This shift is accompanied by enhanced recruitment of CXCR3⁺ CD8⁺ T cells with sustained cytotoxic potential, among which terminal exhaustion-like CD8+ T cell states are less prevalent. Additionally, VISTA-deficient TAMs exhibit increased antigen cross-presentation, further amplifying CD8+ T cell response against tumors. These findings are corroborated by human PDAC data, which reflect similar immune reprogramming trends. By defining the role of VISTA in controlling Cxcl9:Spp1 ratio and modulating CD8⁺ T cell dynamics, this study positions VISTA inhibition as a promising strategy to reshape the TME and potentiate anti-tumor immunity in PDAC.

The multi-omics data represented by genomic data from patients with metastatic triple-negative breast cancer (TNBC) is crucial for precision treatment, yet data on genomic alterations in metastatic cohorts and Chinese populations remains limited. We performed targeted sequencing of 296 metastatic TNBC samples from 296 patients treated at Fudan University Shanghai Cancer Center (October 2018 to November 2020) using a 484-gene panel, identifying 796 metastatic events across 18 organ sites. We characterized the genomic landscape of TNBC metastases and identified marked enrichment of polycystin-1 (PKD1) mutations in metastatic lesions - a finding validated in an independent paired primary metastasis cohort (n = 105). Notably, PKD1 mutations were associated with resistance to anti-PD-1 therapy, as validated across 3 clinical trials (NCT03805399, NCT04129996, and NCT04395989). Multi-omics analyses, combined with functional in vitro and in vivo mechanistic studies, revealed that PKD1 modulated the "desert" tumor immune microenvironment via C-C motif chemokine ligand 2 (CCL2), and targeting CCL2 could reverse immunotherapy resistance. This comprehensive genomic characterization of metastases enhances our understanding of tumor evolution, identifies PKD1 as a previously uncharacterized regulator of immune evasion to our knowledge, and suggests a potential therapeutic strategy to overcome immunotherapy resistance.

Chemokines C-X-C Motif Chemokine Ligand 9 (CXCL9) and C-C Motif Chemokine Ligand 2 (CCL2) were previously linked to incident cognitive impairment and dementia in the Northern Manhattan Study (NOMAS). We investigated whether circulating CXCL9 and CCL2 are independently associated with the cerebral white matter disease (WMD) burden and whether WMD mediates their association with prospective cognitive outcomes. In the stroke-free, prospective, community-dwelling NOMAS cohort (age≥50) we examined white matter hyperintensity volume (WMHV) on brain MRI and serum chemokine levels. WMHV was normalized, log-transformed, and standardized. Cognitive status was assessed at MRI and again 12.2±1.3 years later to adjudicate incident cognitive decline and dementia. Multivariable linear regression models with either CXCL9 or CCL2 (in quartiles) as exposures and WMHV as the outcome were adjusted for socio-demographics and key contributors to WMD, including vascular risk factors (Model 1), kidney function (2), and APOE ε4 status (3). Mediation of the CXCL9-cognitive outcome association by WMHV was tested using Monte Carlo integration. Among 1,179 participants (mean age 70±9 years; 60% female), elevated CXCL9 (Q4 vs. Q1) was associated with greater WMHV (Model 1: β=0.20, 95%CI 0.06-0.34). This association persisted even after adjusting for kidney function (Model 2: β=0.17, 95%CI 0.03-0.34) and APOE ε4 status (Model 3: β=0.19, 95%CI 0.04-0.33). CXCL9 (Q4 vs. Q1) effect magnitude in Model 3 approximated ~4 years of aging (β=0.05/year, 95%CI 0.04-0.06), exceeding that of hypertension (β=0.16, 95%CI 0.05-0.27), with a stepwise trend present across quartiles (β/quartile increase=0.07, 95%CI 0.02-0.12, p=0.003). Among 1,166 participants (dementia-free at MRI), the indirect, WMHV-mediated pathway was statistically significant for the association of CXCL9 with incident cognitive decline (ACME 0.009, 95%CI 0.002-0.018, p=0.016) and with dementia (ACME 0.008, 95%CI 0.003-0.016, p=0.004). CCL2 showed no association with WMHV. Greater CXCL9 levels were associated with greater white matter lesion load, independent of vascular, renal, and genetic factors, suggesting a role in WMD pathogenesis. WMHV mediated CXCL9's association with cognitive decline and dementia risk. This IFN-γ-induced monokine (MIG) warrants further evaluation as a biomarker of white matter and cognitive health as well as a potentially modifiable therapeutic target.

Modulating NOS2 of radiotherapy-recruited CCR2+ macrophages enhances radiosensitivity of hepatocellular carcinoma.

Fibroblast-derived CCL2 driven by MIF promotes joint capsule fibrosis via macrophage polarization regulation.

Silencing CCL5 suppresses ferroptosis to alleviate calcific aortic valve disease through chemokine pathway inhibition.

Succinate-mediated activation of the GPR91/MALT1/NF-κB/CCL2 pathway in macrophages contributes to pulmonary fibrosis.

Integrative epidemiology and multi-omics reveal a frailty-associated ACKR1 redox axis linking cadmium exposure to atherosclerosis.

Enhancement of B7-H3 chimeric antigen receptor-T cell efficacy via the coexistence effect of IL-7, IL-15 and CCL19 for pancreatic and lung xenograft tumors.

Renal fibrosis, a progressive pathological feature of chronic kidney disease (CKD), is driven by impaired autophagic processes and persistent immune activation. The molecular mechanisms that interconnect these pathways remain inadequately understood. This study investigates the role of regulator of G-protein signaling 19 (RGS19), a novel autophagy-associated gene, in the pathogenesis of renal fibrosis. By analyzing transcriptomic data from the Gene Expression Omnibus (GEO) and applying machine learning algorithms, RGS19 was identified as a key fibrosis-related gene. In both in vitro and in vivo renal fibrosis models, we validated its functional role, focusing on autophagic flux and immune responses. We observed that RGS19 expression was elevated in fibrotic kidneys and correlated with increased CD8 + T cell infiltration. Knockdown of RGS19 using siRNA led to reduced p62 accumulation, suppressed rapamycin (p-mechanistic target of rapamycin (mTOR)) activity, and restored LC3B-II levels, reflecting enhanced autophagic flux. Additionally, the secretion of T cell chemoattractants, such as C-X-C motif chemokine ligand 9 (CXCL9) and C-X-C motif chemokine ligand 10 (CXCL10), was diminished. Notably, targeted delivery of RGS19 siRNA via RDYH58 nanoparticles effectively alleviated renal fibrosis in murine models by reducing collagen deposition and immune cell infiltration. These findings suggest that RGS19 plays a central role in linking autophagy dysfunction with immune activation in renal fibrosis and highlight its potential as a therapeutic target for CKD.

Increasing evidence suggests that inflammatory protein factors are closely associated with the underlying mechanisms of cervical cancer. Therefore, 2-sample Mendelian randomization (MR) analysis was performed to assess the potential correlation between circulating inflammatory protein levels and cervical cancer risk. A 2-sample MR study, using genetic variants related to inflammatory proteins as instrumental variables, was conducted to improve the accuracy of cervical cancer diagnosis. By analyzing 14,824 individuals, 91 plasma proteins having strong association with single nucleotide polymorphisms were chosen as instrumental variables, with cervical cancer (909 cases and 238,249 controls) serving as outcome variables. The analysis of causal effects was completed using random effect inverse variance weighted, weighted median/mode, and MR-Egger. Sensitivity analysis was performed using Cochran Q test, funnel plots, leave-one-out analyses, MR-Egger intercept tests, as well as reverse MR analysis. Our analysis showed that C-C motif chemokine ligand 19 (CCL19), monocyte chemotactic protein-3 (MCP-3), and interleukin-12 (IL-12) was related to the risk of cervical cancer. Additionally, the inverse variance weighted method indicated that both CCL19 (OR: 1.479, 95% CI: 1.207-1.813, P = .0002) and IL-12 (OR: 1.171, 95% CI: 1.019-1.345, P = .0253) significantly increased the risk of cervical cancer. Nevertheless, MCP-3 levels may protect individuals from developing cervical cancer (OR, 0.647; 95% CI: 0.442-0.947, P = .0253). Furthermore, consistent outcomes were achieved in the sensitivity analysis. In our study, MR analysis of 91 inflammatory proteins revealed potential causal associations between CCL19, MCP-3, IL-12, and the etiology of cervical cancer. We believe that related inflammatory proteins will provide potential treatment opportunities for clinical interventions in cervical cancer.

Pancreatic ductal adenocarcinoma remains largely refractory to current immunotherapies due to a profoundly immunosuppressive tumor microenvironment dominated by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). These cells form a coordinated network that suppresses cytotoxic T lymphocytes and fosters tumor progression. Key mechanisms include Tregs secreting inhibitory cytokines like transforming growth factor β and interleukin-10, and upregulating immune checkpoints such as cytotoxic T-lymphocyte-associated protein 4 and programmed death 1. MDSCs deplete essential nutrients like arginine and generate reactive oxygen species, while TAMs polarized to an M2 phenotype produce chemokines including C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 12, which recruit more suppressive cells. Single-cell transcriptomic studies have uncovered prognostically relevant cellular subsets, such as caspase-4-high Tregs, highlighting this heterogeneity. Reciprocal signaling via interleukin-10 and transforming growth factor β creates a self-reinforcing immunosuppressive loop. Emerging therapeutic strategies aim to disrupt this axis by depleting Tregs (e.g. , anti-CD25), blocking MDSC recruitment (e.g. , CCR2 inhibitors), or reprogramming TAMs (e.g. , CD40 agonists), often in combination with programmed death 1/programmed death-ligand 1 blockade. An integrated approach targeting these populations holds promise for converting pancreatic ductal adenocarcinoma into an immunologically responsive tumor.

Anaemia is common in rheumatoid arthritis (RA), but the role of erythroid-lineage cells is unclear. We investigated the function of CD45+ erythroid progenitor cells (CD45+ EPCs) in RA. We analysed CD45+ EPC frequency in patients with RA and mice with collagen-induced arthritis (CIA). Transcriptomics, functional studies and mechanistic assays (Transwell and dual-luciferase reporter assays, chromatin immunoprecipitation followed by quantitative PCR) were used. Therapeutic potential was tested in RA synovial organoids and via splenectomy/adoptive transfer in mice with CIA. CD45+ EPCs were expanded in RA circulation and CIA mouse spleens, correlating positively with disease activity and negatively with haemoglobin. They displayed an immunosuppressive transcriptome, enriched for transforming growth factor (TGF)-β and chemokine signalling. RA-derived CD45+ EPCs showed enhanced proliferation and TGF-β/reactive oxygen species production. High C-C Motif Chemokine Receptor 2 (CCR2) expression made them susceptible to recruitment by macrophage-derived C-C Motif Chemokine Ligand 2 (CCL2). In RA synovial organoids, CD45+ EPCs suppressed growth and inflammation via TGF-β, while organoid-conditioned media promoted their migration via CCL2. Recruited CD45+ EPCs suppressed M1 and promoted M2-like macrophage polarisation. The transcription factor SPI1 was upregulated in RA CD45+ EPCs, bound the TGFB1 promoter and drove TGF-β production. In vivo, splenectomy worsened CIA, whereas adoptive transfer of CD45+ EPCs ameliorated arthritis. We identify CD45+ EPCs as a novel, SPI1-driven immunosuppressive population in RA. Recruited via the CCR2-CCL2 axis, they attenuate inflammation by modulating macrophages through SPI1/TGF-β signalling, revealing a new immunoregulatory axis and potential therapeutic targets.

To investigate the causal relationship between inflammatory proteins and Alzheimer's disease (AD) and the mediating role of plasma metabolites therein. Using Mendelian mandomization (MR) methods and publicly available genome-wide association study (GWAS) data, we selected 91 single nucleotide polymorphisms (SNPs) that were strongly linked to inflammatory proteins without reverse causality with AD as the outcome. A bidirectional two-sample MR analysis was performed. Inflammatory proteins with causal links to AD were identified via inverse variance weighted (IVW) analysis. A mediation MR analysis was then performed using 1400 plasma metabolites to assess their mediating role in this causal pathway. The preliminary bidirectional MR analysis identified 3 inflammatory proteins that had a potential positive causal association with AD without reverse causality: Axin-1, C-X-C motif chemokine ligand 11 (CXCL11), and interleukin-12β (IL-12β). Elevated levels of Axin-1 were positively causally associated with AD risk (OR=1.082, 95% CI: 1.009-1.159; P=0.026), while CXCL11 (OR=0.951, 95% CI: 0.914-0.990; P=0.026) and IL-12β (OR=0.959, 95% CI: 0.926-0.994; P=0.026) were negatively causally associated with AD risk. Sensitivity analyses indicated that these causal effects exhibited no heterogeneity or pleiotropy. In the mediation analysis, 18 plasma metabolites with causal links to AD were identified, among which 3 plasma metabolites exhibited mediating effects in the inflammatory protein-AD causal relationship. Methyl-4-hydroxybenzoate sulfate partially mediated the effect between Axin-1 and AD (20.10%). Pregnenetriol sulfate partially mediated the effect between CXCL11 and AD (18.20%). The ratio of spermidine to ornithine played an important mediating role between IL-12β and AD, with a mediating effect of 43.40%. This study reveals how specific inflammatory proteins influence AD risk via plasma metabolites and provides genetic evidence for inflammatory-metabolic interactions in AD to facilitate the identification of potential biomarkers and targets for early detection and intervention of AD.

Colorectal cancer (CRC) is a significant global health challenge, characterized by an increasing incidence rate and high mortality rate. Early detection and effective treatment are crucial to improving patients' quality of life. Cytokines and chemokines are key modulators of the tumor microenvironment, influencing the recruitment of immune cells, angiogenesis, proliferation, and metastasis. This narrative review summarizes the current knowledge regarding the potential diagnostic and therapeutic applications of selected cytokines and chemokines in CRC. We discuss their potential as biomarkers for early detection, prognosis, and prediction of treatment response. We also highlight emerging therapeutic strategies targeting cytokine and chemokine pathways, including immune checkpoint inhibitors, modulation of chemokine signaling, and the direct use of cytokines to enhance antitumor immunity, with particular emphasis on interleukin-6 (IL-6), C-X-C motif chemokine ligand 8 (CXCL8), C-C motif chemokine ligand 2 (CCL2), and the C-X-C motif chemokine ligand 12 (CXCL12)-C-X-C chemokine receptor type 4 (CXCR4) axis, which show consistent associations with tumor stage, metastasis, and treatment response. Integrating cytokine- and chemokine-based approaches with combination therapies could lead to more effective conventional treatments. In summary, this review emphasizes the potential of cytokines and chemokines as diagnostic tools and therapeutic targets, paving the way for more personalized and effective treatment strategies for colorectal cancer.

Stem cell seeding is an important approach for the treatment of osteoporotic bone defects. However, existing seeding methods rely on carriers such as scaffolds to retain cells within the defect, making it difficult for cells to adhere directly to the complex surface of the bony wall. In this study, mesenchymal stem cells (MSCs) were delivered into in vivo bone defects with a handheld electrospinning device as an improved cell seeding strategy. First, flow cytometry and related assays confirmed that electrospinning had minimal effects on MSCs viability. MSCs were then immobilised by electrospinning in the calvarial defects of osteoporotic rats. Single-cell sequencing indicated that, compared with intraosseous injection, this approach effectively increased MSCs retention. The ElectroSpinning Group (ESG) also exhibited elevated expression of osteogenic marker proteins and enhanced bone repair. To elucidate the mechanism by which ESG promotes osteogenesis, this study first compared differences in bone repair between osteoporotic and normal rats. Tissue mRNA sequencing and related analyses verified that osteoporotic defects were characterised by reduced levels of the homing factor c-c motif chemokine ligand 2 (CCL2) and disruption of the osteogenic microenvironment. mRNA sequencing and related assays revealed that ESG upregulated CCL2 expression in response to these features of the osteoporotic microenvironment, thereby promoting the homing of endogenous stem cells. This study then employed electrospinning to seed green fluorescent protein (GFP)-labelled MSCs. Upon detection of green fluorescence in tissue sections, flow cytometry confirmed the retention of MSCs and was applied to quantify the recruitment of endogenous stem cells. With regard to microenvironmental modulation, this study focused on tumour necrosis factor-stimulated gene 6 (TSG6). The results indicated that, in ESG, MSCs increased regulatory T-cell infiltration and inhibited M1 macrophage polarisation via TSG6, thereby correcting the local microenvironmental imbalance. When TSG6 was blocked, these improvements in immunomodulation were attenuated. In summary, this study presents a novel stem cell delivery strategy that enables direct immobilization of MSCs at bone defect sites. Compared with non-electrospun MSCs, electrospun MSCs enhance autologous stem cell homing and modulate immunity to improve the osteogenic microenvironment, thereby promoting bone repair.

Skeletal stem cells (SSCs) and their lineage derivatives play essential roles in bone development, maintenance, and regeneration. In addition to their physiological functions, SSCs have been implicated in primary bone tumor development and bone metastasis. Recent lineage-tracing studies have identified fibroblast growth factor receptor 3 (Fgfr3)-positive endosteal stem cells as a distinct SSC population residing along the endosteal surface of juvenile long bones. This review comprehensively synthesizes previous studies on skeletal stem cells and their lineage derivatives, integrating findings from lineage-tracing approaches, genetically engineered mouse models, and bone tumor models. By organizing current knowledge of SSC hierarchy and differentiation, we provide a framework for understanding how SSC-derived lineages contribute to both bone homeostasis and cancer-related processes. Fgfr3+ endosteal stem cells give rise to osteoblasts and C-X-C motif chemokine ligand 12 (Cxcl12)-positive bone marrow reticular stromal cells that organize the hematopoietic niche. In temporally controlled Fgfr3-creER; Trp53fl/fl models, Trp53 deletion within the endosteal stem cell niche rapidly induces high-penetrance osteosarcoma, indicating that this niche is particularly vulnerable to malignant transformation. Beyond tumor initiation, SSC-derived Cxcl12-expressing stromal cells differentiate into cancer-associated fibroblasts that promote metastatic colonization, angiogenesis, and immunosuppression in bone. Collectively, these findings highlight Fgfr3+ endosteal stem cells as candidate cells of origin for osteosarcoma and underscore the dual role of SSC-derived lineages in both tumor initiation and progression. Targeting SSC-derived endosteal niches may provide new therapeutic opportunities for bone malignancies.

Liver resection is the primary curative treatment for early-stage hepatocellular carcinoma (HCC); however, high recurrence rates remain a major challenge in the absence of effective prognostic and preventive strategies. Here, we identified surgery-induced C-C motif chemokine ligand 11 (CCL11) as a pivotal driver of HCC recurrence through dual mechanisms of immunosuppression and tumor invasiveness. Elevated postoperative circulating CCL11 levels correlated strongly with HCC recurrence and poorer survival, and their integration with clinical parameters enhanced the predictive accuracy of HCC recurrence. Mechanistically, hepatic injury-induced CCL11 recruited immunosuppressive CCR5+CD206+ M2-like macrophages into the residual liver. These macrophages exhibited enhanced PD-L1 expression via activation of the CCL11/IKK/IκB/NF-κB1 axis and promoted regulatory T cell (Treg) induction from naïve CD4+ T cells. Concurrently, CCL11-CCR3 signaling in HCC cells activated PI3K/AKT/MafK to upregulate MMP13, enhancing the invasion ability of HCC cells. In orthotopic models, CCL11 enrichment increased tumor burden and extrahepatic metastases, while post-resection anti-CCL11 therapy reduced HCC recurrence and extended the survival rate of tumor-bearing mice. Our findings unveil CCL11 as a master regulator of the pro-tumorigenic niche post-resection, driving recurrence through coordinated immune evasion and promoting tumor invasiveness. Targeting the CCL11-CCR5/CCR3 axis presents a promising strategy to improve HCC surgical outcomes.

Vitiligo fluctuates between progressive and quiescent states, complicating decisions about when to intervene, how to select therapy, and how to monitor response. In this review, we integrate bedside phenotypes with multi-level molecular readouts to summarize emerging evidence linking clinical signs and biological signals to disease activity and treatment response in clinical studies. For staging, tool-free and standardized assessments such as Koebner phenomenon, confetti-like depigmentation, Wood's lamp, and dermoscopy provide visible clues associated with active disease. Measurements from blood, suction blister fluid, and tissue offer complementary insights into local and systemic immune activation, suggesting how molecular signals may relate to progression. For stratification, factors including age, lesion site, disease stability, comorbidities, and dermoscopic border features have been tentatively associated with differential responses to therapies such as phototherapy or transplantation. Similarly, lower baseline levels of inflammatory, chemotactic, and cytotoxic markers have been informally aligned with better outcomes in clinical studies. For monitoring, the response phase typically mirrors a reversal of progression: waning inflammatory signaling, reduced effector-cell burden, and partial recovery of melanogenic programs provide molecular parallels to clinical improvement. Across these domains, the interferon-γ (IFN-γ)-C-X-C motif chemokine ligand 9/10 (CXCL9/CXCL10)-cluster of differentiation 8 positive T-cell (CD8⁺ T-cell) axis emerges as the most recurrent immune signature, demonstrating reproducible associations with activity, prognosis, and treatment response. Future work should prioritize harmonized definitions of disease activity, standardized sampling standards, and multicenter validation of integrated biomarker panels. It is equally critical to determine whether proposed biomarker thresholds relate to clinically meaningful endpoints, thereby translating early-stage discoveries into reliable frameworks for staging, stratification, and monitoring.

Patients with chronic kidney disease (CKD) are at high risk of cardiovascular complications. We have shown that Ngal (neutrophil gelatinase-associated lipocalin)/lcn2 is involved in aldosterone-induced cardiac remodeling and inflammation. Here, we investigated the role of Ngal in the progression of cardiorenal syndrome. CKD was induced in rats via 5/6 nephrectomy in wild-type and Ngal knockout rats. Cardiorenal functions were assessed 3 months after subtotal nephrectomy or sham operation. Cardiac fibroblasts were isolated from wild-type rats and incubated with or without rNgal (recombinant Ngal) and Gal-3 (galectin-3). Cardiac perfusion was less impaired in CKD Ngal knockout than in CKD wild type. Left ventricle interstitial fibrosis was more severe in CKD wild type than in sham but was blunted in CKD Ngal knockout rats. Levels of Gal-3, Col1 (collagen 1), Ccl2 (C-C motif chemokine ligand 2), and IL-6 (interleukin-6) were high in cardiac fibroblasts incubated with rNgal. A similar pattern was observed in cells treated with recombinant Gal-3. Both Ngal and Gal-3 induced activation of the Tlr4 (toll-like receptor 4)-Myd88 (myeloid differentiation primary response 88) pathway. The effects of rNgal were blunted by concomitant treatment with Gal-3 or Tlr4 inhibitors, suggesting that Gal-3 contributes to Ngal-induced cardiac fibrosis and inflammation by activating the Tlr4-Myd88 pathway. In both MEDIA-DHF (Metabolic Road to Diastolic Heart Failure) and BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) cohorts, elevated levels of Ngal and Gal-3 were associated with advanced diastolic dysfunction and adverse clinical outcomes, particularly among patients with impaired renal function. In CKD rats, Ngal was involved in cardiac remodeling via a Gal-3/Tlr4-dependent pathway, increasing inflammation and fibrosis, and correlated to cardiac outcomes in the MEDIA-DHF and BIOSTAT-CHF cohorts.