Burixafor, a CXCR4 inhibitor with a differentiated kinetics profile: results of a phase 2 study for rapid cell mobilization in multiple myeloma and lymphoma patients undergoing transplant.

Inhibition of CXCR2 improves motor coordination through attenuating white matter lesions in Parkinson's disease models.

Di-n-butyl phthalate induces NF-κB-mediated senescence-associated secretory phenotype to promote epithelial proliferation, epithelial-mesenchymal transition, and benign prostatic hyperplasia.

Targeting HGF/MET and CXCL1/CXCR2 axes bypasses resistance to KRASG12C inhibitors in NSCLC.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous malignancy characterized by the proliferation of skin-homing CD4+ T cells and profound immune dysregulation within the tumor microenvironment (TME). This review synthesizes evidence on chemokine–receptor networks that govern malignant T-cell trafficking among blood, skin, and lymph nodes, the formation of immunosuppressive niches, and clinically actionable biomarker candidates. Among the best-supported axes, CCL17/CCL22–CCR4 and CCL27/CCL28–CCR10 mediate skin tropism, CCL19/CCL21–CCR7 contributes to lymph node homing, and CXCL12–CXCR4 supports skin trafficking and is associated with disease progression. In contrast, CCR2/CCR5/CCR6/CCR8-centered circuits and CXCR3/CXCR5 pathways are emerging regulators of myeloid recruitment, regulatory T-cell accumulation, and context-dependent immune activation. Therapeutically, agents targeting chemokine pathways, most notably the CCR4 monoclonal antibody Mogamulizumab, have demonstrated clinical efficacy, while emerging inhibitors of CCR6, CCR5, and CXCR4 offer promising avenues for intervention. We further highlight how recent single-cell and other high-dimensional omics studies refine cell-type–specific chemokine sources and receptor expression, enabling more precise mapping of chemokine-driven intercellular communication programs in CTCL TME remodeling and better prioritization of therapeutic targets and biomarkers.

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer‐related mortality, characterized by intrinsic resistance to conventional therapies and limited effective treatment options. In this study, we investigated the role of the CXCR2 axis in PDAC therapy resistance. CXCR2, a chemokine receptor, is actively involved in inflammation, tumor angiogenesis, and metastasis. Our working hypothesis is that CXCR2 contributes to PDAC chemotherapy resistance. To test this, we generated gemcitabine‐resistant (GemR) lines using T3M4 and CD18/HPAF (CD18) cell lines. Baseline expression of CXCL1, CXCL5, and CXCL8 ligands was higher in GemR cells compared to parental cells. Upon gemcitabine treatment, parental cells exhibited a greater increase in CXCL1 and CXCL8 expression than GemR cells. Further analysis in T3M4 cells revealed a dose‐ and time‐dependent increase in CXCL1 and CXCL8 expression following gemcitabine exposure. Next, we assessed whether targeting CXCR2 could enhance the therapeutic response. We treated parental and GemR cell lines with gemcitabine in combination with a CXCR2 antagonist, Navarixin. Notably, lower concentrations of gemcitabine combined with Navarixin were more effective than higher concentrations of gemcitabine alone in GemR cell lines. In both parental and GemR xenograft models, combination therapy with Navarixin and gemcitabine demonstrated superior antitumor and antimetastatic activity compared to either treatment alone. In conclusion, these findings highlight the critical role of the CXCR2 axis in PDAC therapy resistance. Targeting CXCR2 enhances gemcitabine efficacy, offering a potential therapeutic strategy to overcome resistance in PDAC.

This study investigated how granulocyte colony-stimulating factor (G-CSF) regulates colon cancer (CC) progression through epigenetic activation of the kruppel-like factor 5 (KLF5)/chemokine receptor type 4 (CXCR4) axis. Human CC LoVo cells were exposed to G-CSF (20ng/mL) alone in combination with si-KLF5, oe-CXCR4, or the CXCR4 antagonist AMD3100 for 24h. Malignant behaviors were evaluated by CCK-8, colony formation, and Transwell assays. H3K27ac modification on the KLF5 promoter and KLF5 binding to the CXCR4 promoter were examined using immunofluorescence, dual-luciferase reporter, and ChIP assays. An orthotopic LoVo xenograft mouse model was used to assess tumor growth, metastasis, and epithelial-mesenchymal transition (EMT) marker expression. KLF5 and CXCR4 mRNA and protein levels were measured in CC cells and tissues via RT-qPCR and western blot. G-CSFenhanced LoVo cell proliferation, migration, and invasion in a dose-dependent manner, concomitant with increased H3 acetylation and histone H3 lysine 27 (H3K27ac) acetylation. Mechanistically, G-CSF upregulated KLF5 expression via H3K27ac modification, promoting CXCR4 transcriptional activation. Inhibition of KLF5 or CXCR4 partially reversed G-CSF-induced EMT and malignant phenotypes. In vivo, G-CSF accelerated tumor growth and metastasis through the KLF5/CXCR4 signaling pathway, confirming its pro-tumorigenic role. G-CSF drives CC progression by enhancing H3K27ac-dependent upregulation of KLF5, which transactivates CXCR4 to promote EMT, proliferation and metastasis. Targeting the G-CSF/KLF5/CXCR4 axis may represent a potential therapeutic strategy for advanced CC.

Apelin-13 regulated thrombotic inflammation and induced homing of EPCs to promote the dissolution and recanalization of deep vein thrombosis.

NR4A2 induces perineural invasion in head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma via CXCL5/CXCR2 signaling axis.

Dual developmental effects of ARX poly-alanine mutations on human cortical excitatory and inhibitory neurons.

Although the inhibitory role of photobiomodulation (PBM) in glial scar formation after spinal cord injury (SCI) has been identified, its effects on fibrous scar formation and the underlying mechanisms remain unexplored. To assess fibrous scar deposition, Sirius Red, Masson's trichrome, and immunostaining of extracellular matrix molecules after SCI were performed. Fibroblast viability was evaluated using the CCK-8 assay, whereas migration capacity was measured using Transwell and scratch assays. RNA sequencing was performed on macrophages subjected to inflammation with and without PBM intervention. To validate the mechanism in vivo, CXCL3 and a CXCR2 inhibitor were administered to mice intraperitoneally. Findings demonstrated that PBM treatment suppressed fibrous scar formation post-SCI. Temporal profiling revealed distinct patterns of macrophage and fibroblast infiltration after injury, with fibroblast migration influenced by the macrophage-conditioned medium. RNA sequencing analysis identified CXCL3 as a key mediator of macrophage-fibroblast crosstalk under PBM modulation. More specifically, PBM downregulated CXCL3 expression in macrophages, thereby attenuating fibrous scar progression.

Glioblastoma is the most aggressive adult brain tumour, characterised by resistance to therapy and high recurrence due to diffuse infiltration. We developed a physiologically relevant co-culture model, combining patient-derived glioblastoma cell lines with cortical-like neural spheroids differentiated from human induced pluripotent stem cells. Using high-content imaging, we demonstrate that GBM20 and GBM1 cell lines migrate directionally along axons toward neural spheroids in live imaging assays and infiltrate spheroids extensively in endpoint assays, unlike non-cancerous neural stem cells. A proof-of-principle drug screen identified PF 573228 (FAK inhibitor) and motixafortide (CXCR4 inhibitor) as potent suppressors of GBM20 and GBM1 infiltration, respectively. Bulk RNA sequencing revealed gene expression profiles correlating with invasive behaviour and drug sensitivity. This platform offers a valuable model for studying glioblastoma infiltration along axons and provides proof-of-principle that migration can serve as a measurable and actionable phenotype to screen therapeutic vulnerabilities in glioblastoma.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-30914-5.

Background and rationaleThe incidence and mortality of breast cancer (BC) continue to increase, making it a matter of public health concern worldwide. Despite the various strides made in breast cancer (BC) research, the molecular mechanisms driving its progression remain incompletely understood, particularly the role of key regulatory genes in tumor development and therapy resistance. TGFβ-1, IL19, CXCR4, BMP1, VCAN, and WNT2 have been implicated to be instrumental to critical oncogenic pathways; however, their cumulative contribution toward the pathophysiology of BC has not yet been investigated. Therefore, the present study utilizes an integrative bioinformatics approach to decipher their functional relevance, providing a basis for targeted therapies.Methods and analytical approachTGF-β1, IL19, CXCR4, BMP1, VCAN, and WNT2 are among the important genes in BC that we have studied in great detail using bioinformatics techniques that detail differential gene expression analysis for their dysregulation in BC. Their broader oncogenic implications were then clarified by performing pan-cancer and pathway enrichment analyses. Molecular docking studies were employed to comprehend the functional interactions and potential therapeutic targets in protein-protein interaction (PPI) networks.Key findingsIt is demonstrated by our study that TGFβ-1 and CXCR4 are critical factors in the tumorigenesis of BC and their inhibition shows interference with tumor-associated pathways in a synergistic way. Computational modelling suggests that concomitant inhibition of these two targets, with D4476 and AMD3100, may show therapeutic value through modulation of certain key signalling cascades.Conclusion and significanceThis study provide new insights into the molecular basis of BC and support the idea of targeting TGFβ-1 and CXCR4 together for therapy. The above findings lay the foundation for future in vitro and in vivo experiments aimed at demonstrating that inhibition of both factors would be a viable strategy to improve the therapeutic outcome in BC.

White matter injury in young rats with cerebral palsy: the role of massage in regulating exosomes via the chemokine axis.

Abstract Chronic kidney disease (CKD) often leads to renal fibrosis driven by CXCR4-mediated inflammation and tissue remodeling. This study aims to identify potential inhibitors of membrane-embedded CXCR4 isoform I through molecular docking and dynamics simulations. The AlphaFold-predicted human CXCR4 structure (AF-P61073-F1) was used for molecular dynamics simulations in GROMACS. Molecules with optimal ADME profiles and the top three lowest Glide scores were evaluated. Membrane simulations using RMSD, RMSF, SASA, Gyration, PCA, FEL, and per-residue decomposition analysis showed that compound 4993 interacted most stably with CXCR4. Additional simulations further confirmed 4993’s strong potential as a CXCR4 inhibitor. Furthermore, the membrane thickness, area per lipid, and Interdigitation analyses indicated that compound 4993 maintained favorable interactions contributing to membrane stability. These findings suggest that 4993 could play a significant role in modulating membrane properties, potentially contributing to its predicted effects, without implying confirmed therapeutic efficacy. Future studies should investigate the molecular mechanisms of CXCR4 interaction and their implications for drug development. The computational study concluded that membrane-embedded CXCR4 small-molecule inhibitor, such as compound 4993, has the potential to target CXCR4 and reduce kidney damage.

Background: Adolescents and young adults (AYA) with papillary thyroid carcinoma (PTC) often present with more extensive cervical lymph node metastasis (LNM) than older adults (AD). We aimed to identify age-associated molecular and immune features that might explain this phenotype and to explore potential translational implications for managing aggressive AYA PTC. Methods: We analyzed clinical and transcriptomic data from 501 PTC cases in The Cancer Genome Atlas (TCGA), stratified as AYA (<30 years, n = 64) and AD (≥30 years, n = 437). An institutional RNA-seq cohort (n = 13; 7 AYA, 6 AD) was used to screen for differentially expressed genes (DEGs). DEGs were defined by p ≤ 0.05 and |log2 fold change| ≥ 1. Intersection with invasion- and dissemination-related gene sets yielded a final age-related DEG list. Functional enrichment (GO/KEGG via DAVID), PPI network analysis (STRING, Cytoscape/cytoHubba), and immune deconvolution (CIBERSORT LM22) were performed. Protein-level validation was carried out by immunohistochemistry (IHC) in an independent cohort (n = 56; 28 AYA, 28 AD). Statistical comparisons used chi-square/Fisher's exact tests for categorical variables, t-tests or nonparametric tests for continuous variables, and EdgeR with FDR correction for transcriptomic analyses. Results: In TCGA, LNM was more frequent in AYA than in AD (62.1% vs. 47.8%, p = 0.031). From intersected analyses, we identified 239 core DEGs distinguishing highly invasive, age-related tumors. Key upregulated genes in AYA included CXCR4, OPCML and S100A2; downregulated genes included ATP1A3, CHL1, HLA-DRA and IL-1β. Enriched pathways involved extracellular matrix organization, cell adhesion, calcium signaling and canonical oncogenic cascades (PI3K-Akt, MAPK, Wnt, Ras). Immune deconvolution showed reduced naïve B cells, M1 and M2 macrophages and resting mast cells and an increased proportion of M0 macrophages in AYA tumors. IHC validated differential protein expression for seven markers. Collectively, the data indicate an immune-suppressed, immune-excluded microenvironment in AYA PTC. Conclusions: AYA PTC exhibits distinct molecular and immune features that may underlie its propensity for lymphatic dissemination. These findings support evaluation of translational strategies, such as CXCR4 inhibition, restoration of antigen presentation, and macrophage reprogramming, to convert "cold" tumors into immune-permissive lesions. Validation in larger, prospective, multicenter cohorts is required.

Osteosarcoma is the most common malignant bone tumor in children and adolescents, characterized by high heterogeneity and a complex tumor microenvironment (TME). Despite multimodal treatments, survival rates have stagnated, highlighting the need for new therapeutic options. Single-cell RNA sequencing (scRNA-seq) offers a powerful tool to dissect heterogeneity and uncover mechanisms of progression and immune evasion. A narrative literature review, guided by PRISMA principles, was conducted through October 2024 via PubMed and Scopus databases to assess scRNA-seq contributions to osteosarcomagenesis. A total of 107 studies were analyzed to highlight the identification of tumor subpopulations, signaling pathways, diagnostic and prognostic biomarkers, and therapeutic assessments. Our analysis highlights the critical role of scRNA-seq in revealing the complexity of the osteosarcoma TME. Studies identified distinct immune and non-immune cell subpopulations, with TXNIP+ and IFIT1+ macrophages, KAZALD1, EGFL7, TNFSF11, and TRAIL receptors emerging as potential therapeutic targets. scRNA-seq has elucidated mechanisms of tumor progression and metastasis, including CD24 expression, and enabled the discovery of immune and stromal biomarkers within the TME. It also revealed novel therapeutic strategies, such as targeting Tregs via CXCR4 inhibition, CAFs through LOX and SERPINE1 modulation, and MCL1 in metastatic niches. Additionally, it uncovered promising drug candidates-etoposide, mevastatin, oxfendazole, HDAC inhibitors, and TIGIT blockade-as well as immunotherapies like PD-1 inhibition and adoptive CD8+ T cell therapy. scRNA-seq has transformed insights into osteosarcoma by exposing key cellular dynamics and potential therapeutic targets. While technical challenges remain, it paves the way for more personalized and effective treatment strategies. However, the current findings are subject to limitations, including technical biases in single-cell protocols and the exclusion of non-English literature, which may affect generalizability.

Glioblastoma (GBM), an aggressive brain tumor with a highly immunosuppressive microenvironment, remains a therapeutic challenge due to its resistance to conventional treatments. In this study, a novel multi-function therapeutic platform that integrates ultrasound-triggered sonodynamic therapy (SDT), STING pathway activation, and CXCR4 inhibition for synergistic immunotherapy of GBM is presented. Through systematic comparison of a series of organic molecules with subtle substituted atom alterations, a new selenium-containing compound is identified with outstanding sonodynamic properties. The high-performance sonosensitizer is co-assembled with a STING agonist prodrug, which is further cloaked with glioma cell membrane and CXCR4-targeting peptides for dual homing and immune modulation. Under ultrasound irradiation, the nanoplatform triggers robust reactive oxygen species production, in combination with the self-accelerating STING agonist release, significantly stimulating both innate and adaptive immune responses while disrupting the CXCL12/CXCR4 signaling axis to suppress immunosuppressive cell infiltration. This tripartite strategy, which integrates SDT-mediated tumor ablation, STING-induced systemic immunity, and CXCR4 blockade, synergistically suppresses primary tumor growth, prevents postoperative recurrence, and extends survival in GBM-bearing mice. This approach presents a promising sono-triggered multimodal paradigm for overcoming GBM's immunosuppressive barriers and enhancing therapeutic outcomes.

Abstract Leptomeningeal metastasis (LM) describes the spread of cancer into the cerebrospinal fluid (CSF) filled leptomeningeal space surrounding the brain and the spinal cord. Historically, LM is described as neoplastic meningitis, reflecting the inflammatory characteristics of the disease. Cancer infiltration into the CSF triggers the influx of leukocytes, elevation of inflammatory cytokines, and breakdown of blood-CSF barrier. To identify key mediator of cancer progression in LM induced inflammation, we performed proteomic analyses on serially collected CSF from patients in recent clinical trial. Elevated CXCL1 levels were observed in LM positive patients, and higher CSF CXCL1 levels correlate with poor progression-free survival. Using syngeneic mouse models of LM, we confirmed the expression of Cxcl1 in both cancer and host cells, including macrophages, choroid plexus epithelial cells and meningeal fibroblasts. After engraftment into the host, cancer cells dynamically modulate the Cxcl1-Cxcr2 inflammatory axis, reflexing their interaction with tumor microenvironment. To investigate the functional role of tumor and host Cxcl1, we selectively deleted Cxcl1 in both the cancer cells and host cell populations. We find that cancer cell generated Cxcl1 is essential for cancer progression while host derived Cxcl1 is dispensable. Additionally, we find that pharmacological inhibition of Cxcr2 enhances cancer sensitivity to radiation therapy. Together, these findings demonstrate that the CXCL1-CXCR2 signaling axis acts as a critical mediator of LM progression, and suggests that this signaling axis may serve as an appealing therapeutic target for this fatal complication of cancer.

Chronic limb-threatening ischemia (CLTI), a severe complication of lifestyle-related diseases such as diabetes and chronic kidney disease, remains a highly prevalent and challenging condition. Angiogenic therapy using autologous mononuclear cell or stem cell transplantation has been explored as a treatment option for CLTI patients at risk of amputation. However, its clinical efficacy has been limited, mainly due to poor cell retention at the transplantation site and impaired function of transplanted cells in CLTI patients. To address these limitations, we have developed an Injectable Cell Scaffold (ICS), a novel biomaterial designed to enhance angiogenic therapy. ICS consists of bioabsorbable polymer microspheres coated with hydroxyapatite nanocrystals and is formulated for intramuscular injection. When co-transplanted with cells, ICS enables prolonged local retention of transplanted cells and enhances their therapeutic angiogenic effects. Notably, ICS amplifies the effects of peripheral blood mononuclear cells (PBMNCs), which are easily collected but traditionally considered to have limited regenerative capacity. Building on this platform, we are conducting an exploratory, investigator-initiated clinical trial of ICS-001 at Hyogo Medical University Hospital and Oita Oka Hospital. In this trial, ICS-001 is combined with autologous stem cell CD34-rich PBMNCs mobilized by G-CSF and a CXCR4 inhibitor. This approach aims to develop a safe, cost-effective, and powerful new cell-based angiogenic therapy within the medical device framework. To date, five patients have been enrolled in the trial. No ICS-001-specific adverse events have been observed. Encouragingly, patients have shown clinical improvements in symptoms such as resting pain and ischemic ulcers. These preliminary findings suggest that ICS-001 has the potential to significantly improve the outcomes of cell-based therapies for CLTI. We report here the progress of this ongoing clinical study as a promising strategy to overcome the limitations of current angiogenic treatments for CLTI and provide an innovative therapeutic option using a combination of biomaterials and autologous cell transplantation.