Search Results (1,010)

Satellite glial cells (SGCs) play a critical role in the development and maintenance of chronic pain through complex interactions with inflammatory mediators and the opioid pathway. This systematic review synthesizes recent advances in the molecular mechanisms underlying SGC activation and implications for chronic pain management, particularly in conditions associated with the dorsal root ganglia (DRG) and trigeminal ganglia (TG). A systematic search was conducted in four databases (PubMed, Embase, Scopus, and Web of Science) covering studies published between January 2004 and May 2026. After screening 111 records, 19 studies were included. This review highlights how pro-inflammatory cytokines such as IL-1β, IL-1α, and TNF-α, as well as neurotransmitters like ATP and glutamate, contribute to SGC activation, neuroinflammation, and pain modulation. It also explores the role of receptors like CXCR4, TLR4, and P2X7 in SGCs in enhancing analgesic effects and their contributions to opioid tolerance and hyperalgesia. The findings underscore the potential of targeting SGCs to improve pain management outcomes across various pain models, including neuropathic, cancer-related, and visceral pain. Despite promising insights, variability in study methodologies and the complexity of glial–neuronal interactions present challenges. Future research should focus on standardizing experimental protocols and developing targeted therapies to modulate SGC activity to offer hope for patients suffering from chronic pain, particularly in managing opioid tolerance. Full article

Acute myeloid leukemia (AML) develops within a bone marrow environment that influences leukemic stem cell behavior, residual disease, and response to therapy. This review examines evidence that the marrow microenvironment is not only a site of leukemic growth, but can actively shape AML initiation, maintenance, and treatment resistance. Clinical observations such as donor cell leukemia after allogeneic transplantation, together with experimental models in which stromal or osteolineage abnormalities induce myeloid disease, suggest that altered niches may contribute to leukemogenesis in selected settings. In established AML, vascular and endosteal compartments provide adhesive, chemokine, inflammatory, and metabolic signals that promote leukemic-cell retention, quiescence, survival, and chemotherapy tolerance. AML cells also remodel the surrounding marrow, suppressing normal hematopoiesis and generating stromal, endothelial, osteoblastic, adipocytic, and immune-cell programs that favor leukemic persistence. These interactions are especially relevant to drug resistance, including resistance to venetoclax-based therapy, where cytokine-mediated changes in apoptotic dependence, fatty-acid metabolism, mitochondrial adaptation, and stromal support may all contribute. Several therapeutic approaches have attempted to disrupt niche-mediated protection, including targeting CXCL12/CXCR4 signaling, adhesion pathways, inflammatory circuits, Hedgehog signaling, and metabolic dependencies. Although early-phase studies have shown activity in some AML subsets, randomized evidence remains limited and results have been inconsistent. We discuss how a better understanding of microenvironmental biology may help define when niche-directed therapy is most likely to complement conventional and molecularly targeted AML treatment. Full article

Background: The C-X-C chemokine receptor type 7 (CXCR7), also known as atypical chemokine receptor 3 (ACKR3), primarily signals through β-arrestin and plays a pivotal role in tumor progression, inflammation, and neurodegenerative diseases. CXCR7 antagonists block chemokine binding and dampen β-arrestin signaling. Accordingly, identification of such antagonists is highly desirable for therapeutic development against CXCR7 driven pathologies. Methods: Through microscale thermophoresis (MST) screening of a Food and Drug Administration (FDA)-approved drug library, entacapone was identified as a CXCR7 binder. The NanoBit complementation assay was employed to evaluate the effect of entacapone on CXCR7 mediated β-arrestin 1/2 recruitment. Molecular docking was performed to predict the binding pocket and binding sites. Results: Entacapone specifically bound to CXCR7 with a Kd value of 6.04 µM. Although entacapone did not directly activate CXCR7, it selectively inhibited CXCL12 and VUF11207 induced β-arrestin 1 recruitment with no significant effect on β-arrestin 2 recruitment. Molecular docking suggested that entacapone interacted with key residues via hydrophobic contacts, including Trp100, Phe124, Gln301, and Leu305, and formed hydrogen bonds with Ser103, Asn108, and Tyr51 in the transmembrane core, collectively suggesting a possible binding mode compatible with stabilizing the receptor in an inactive conformation. Conclusions: Entacapone, a clinically well established COMT inhibitor, is reported for the first time as a novel biased antagonist of CXCR7, providing a new candidate molecule for drug repurposing. Full article

Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two therapeutic radioconjugates derived from the high-affinity CXCR4 antagonist LY2510924. Methods: The PET tracer [¹⁸F]AlF-NOTA-SC and therapeutic radioconjugates [¹⁷⁷Lu]Lu-BL02 and [¹⁶¹Tb]Tb-BL02 were synthesized and evaluated. Radiolabeling efficiency, molar activity, and in vitro binding affinity were assessed. Specificity and uptake were evaluated in CXCR4-expressing U87.CD4.CXCR4 and MM.1S cells, with cytotoxic potential being analyzed via clonogenic survival assays. In vivo biodistribution and pharmacokinetics were evaluated in MM.1S xenograft mouse models, supported by longitudinal SPECT imaging. Results: All radioconjugates were obtained with high radiochemical purity (>98%). The constructs showed nanomolar affinity for human CXCR4; in vitro assays confirmed specific uptake in CXCR4-positive cells, and both therapeutic agents demonstrated dose-dependent cytotoxicity. In vivo, all compounds displayed comparable tumor uptake with low off-target accumulation. Co-injection studies confirmed consistent pharmacokinetics across agents, while SPECT/CT imaging demonstrated gradual tumor clearance of [¹⁷⁷Lu]Lu-BL02 over seven days. Conclusions: The radiopharmaceutical trio [¹⁸F]AlF-NOTA-SC, [¹⁷⁷Lu]Lu-BL02, and [¹⁶¹Tb]Tb-BL02 demonstrates the feasibility of a CXCR4-targeted theranostic approach for imaging and treating hematologic malignancies. The observed tumor washout highlights the need for further structural optimization to enhance tumor retention and therapeutic efficacy, providing a clear direction for future development toward clinical translation. Full article

Salivary adenoid cystic carcinoma (SACC) is an immunologically cold malignancy with limited response to current immunotherapies. Integrated transcriptomic profiling of peripheral blood, primary tumors, lung metastases, and a two-donor single-cell dataset revealed compartment-specific expression signatures and, through computational inference, systemic immune dysregulation marked by hematopoietic suppression, T-cell exhaustion, compensatory myelopoiesis, and an immature B-cell expansion. To explore the transcriptional basis of this peripheral immune aberration, blood-derived RNA-seq was interrogated, identifying only 32 unique genes meeting |log2FC| > 1 and q < 0.05 among 34,999 transcripts; qPCR confirmed concordant upregulation of IL33 and CCL14, providing directional rather than confirmatory support, suggesting peripheral immune molecular aberrations that still require validation through broader differential gene expression validation. Complementing this transcriptomic signature, detection of MYB-NFIB fusion transcripts matching tumor tissue in one patient’s blood suggested that tumor-derived signals may access the circulation, although cohort validation remains necessary. Extending these peripheral observations to tissue compartments, we applied expression stratification, correlation networks, ligand-receptor mapping, and a virtual gain-loss model to computationally predict regulatory associations involving IL17RB/OLIG1/NOTCH1 in primary tumors and a CD24/IL17RB/MYB/MYBL2/CXCL13/CXCR5 module in lung metastases. At the single-cell level, cluster 10 emerged as a cell-cycle-high tumor population with transcriptional overlap with proliferating immune progenitors, providing a potential cellular basis for tumor cell entry into the circulation. Collectively, these computational inferences generate testable hypotheses for multicompartment immune dysregulation in SACC, positioning IL17RB as a candidate molecule that warrants prospective validation in SACC-specific preclinical models. Full article

Background: The cellular heterogeneity and spatial organization patterns of the tumor microenvironment (TME) play a crucial role in colorectal cancer (CRC) progression, but their spatial distribution and cellular communication mechanisms require further elucidation. This study aims to systematically dissect the cellular heterogeneity and spatial organization characteristics of the CRC microenvironment by integrating single-cell and spatial transcriptomic data. Methods: Single-cell RNA sequencing and spatial transcriptomics data of primary CRC were integrated to characterize the TME. Intercellular signaling patterns were elucidated through communication analysis, spatial niche clustering, ligand–receptor pair analysis, and spatial expression mapping. The ESTIMATE algorithm was applied to assess the correlation between TME scores and pathway-associated genes. Drug sensitivity prediction was performed using the oncoPredict. Results: Single-cell analysis identifies nine major cell types, revealing significant cellular heterogeneity. Intercellular communication analysis demonstrates that the MIF signaling pathway plays a prominent role within the TME communication network, with MIF-(CD74+CD44) and MIF-(CD74+CXCR4) identified as dominant receptor complexes. Spatial transcriptomic analysis reveals distinct spatial functional partitioning of these signaling axes. Signaling flow analysis indicates an immunosuppressive “tumor–immune” axis mediated by MIF signaling from tumor epithelial cells to immune cells. MIF expression is negatively correlated with ImmuneScore, while its receptors CD74, CD44, and CXCR4 are positively correlated. Drug sensitivity analysis reveals potential associations between key genes (MIF, CD74, CD44, and CXCR4) in the MIF pathway and various anti-tumor drugs. Conclusions: Our study reveals the cellular heterogeneity of the CRC microenvironment from multiple perspectives, elucidates the key mechanisms of the MIF signaling pathway, and provides potential therapeutic targets for CRC treatment. Full article

Plerixafor is a clinically approved CXCR4 antagonist that mobilizes hematopoietic stem cells by disrupting CXCL12/CXCR4 retention signaling. However, its biochemical effects on melanocytes and pigmentation remain unexplored. We investigated how Plerixafor modulates CXCR4 signaling in melanocytes and evaluated its potential as a pro-melanogenic agent using in vitro and in vivo approaches. Human PIG1 melanocytes were treated with 10 nM Plerixafor with or without hydroquinone (HQ), followed by qPCR for MITF and tyrosinase expression, flow cytometry for CXCR4/CXCR7 and integrin profiling, transwell migration assays, β-arrestin siRNA knockdown, Western blotting, subcellular fractionation, and ChIP-qPCR for β-catenin binding to MITF regulatory regions. A murine HQ-induced depigmentation model was used to test topical Plerixafor on pigmentation, hair follicles, melanogenic gene expression, and systemic safety markers. Plerixafor significantly increased MITF and tyrosinase mRNA and enhanced melanocyte migration while counteracting HQ-induced suppression of melanogenic genes. In addition, it reduced cell-surface CXCR4 (consistent with β-arrestin-mediated receptor internalization) without altering CXCR7, c-KIT, or N-cadherin. β-Arrestin knockdown abolished Plerixafor-induced ERK phosphorylation and melanogenic responses, confirming β-arrestin dependence. Plerixafor promoted β-catenin nuclear translocation and direct β-catenin occupancy at MITF promoter/enhancer TCF/LEF motifs. In vivo, topical Plerixafor restored HQ-induced depigmentation, increased hair follicle number and melanin content, and upregulated cutaneous MITF and tyrosinase without hepatic, renal, or inflammatory toxicity. Plerixafor functions as a biased CXCR4 ligand in melanocytes, influencing the β-arrestin–β-catenin–MITF signaling axis to drive melanogenesis and re-pigmentation. These findings identify β-arrestin-dependent CXCR4 signaling as a tractable pharmacologic mechanism for therapeutic re-pigmentation in pigmentary disorders. Full article

Drug resistance remains a significant challenge in the clinical treatment of acute myeloid leukemia (AML). Therefore, there is an urgent need to develop a novel combinatorial therapy strategy, aiming to overcome drug resistance and improve therapeutic outcomes in AML. Herein, we developed a covalent organic framework bispecific nanosystem, namely glucose oxidase-loaded iron porphyrin covalent organic framework coated with bone marrow stromal cell membrane and functionalized with anti-CD3 and anti-PD-L1 antibodies (abbreviated FeC-G@M-C&P). The fabricated FeC-G@M-C&P displayed good cascade catalytic activity. The bone marrow stromal cell membrane endowed the nanosystem with robust targeting ability, which further triggered abundant reactive oxygen species (ROS) production for chemodynamic therapy. Moreover, bone marrow stromal cell membrane component suppressed the migration and adhesion of C1498 cells by interfering with the CXCR4/CXCL12 axis. Meanwhile, anti-CD3 and anti-PD-L1 antibodies improved T cell activation, relieved immune suppression, and jointly enhanced T cell-mediated immune responses against leukemia cells. Experimental results indicated that the FeC-G@M-C&P plus T cells group showed better anti-leukemia effects compared with other groups, which can be attributed to the integration of chemodynamic therapy, CXCR4/CXCL12 axis blockade therapy and immunotherapy. Collectively, the fabricated nanosystem provided a promising approach for the combined treatment of AML. Full article

Diabetic retinopathy (DR) reflects retinal microvascular injury and systemic immune-metabolic stress, and most public DR transcriptomic datasets lack paired microbiome/metabolomic profiles. We used gutMGene v2.0 as a curated microbe/metabolite–host gene prior and integrated it with peripheral blood transcriptomics from GSE221521. Candidate genes were refined by weighted gene co-expression network analysis (WGCNA), repeated resampling, cross-dataset assessment, mechanism scoring, peripheral blood mononuclear cell (PBMC) single-cell localization and filamin A (FLNA)-centered single-cell gene regulatory network (GRN) virtual knockout. The gutMGene prior contained 238 host genes; 15 DR-associated genes overlapped this prior, and WGCNA retained ten candidate gut microbe and microbial metabolite-related genes (GMMRGs): FLNA, AKT1, IRAK1, BCL10, CDK6, CTSD, JUP, CXCL1, CXCR2 and IL4R. Resampling prioritized FLNA as the most consistent candidate. Cross-dataset assessment localized the strongest signal to type 2 diabetes (T2D) PBMCs, retinal endothelial cells and advanced proliferative diabetic retinopathy with diabetic macular edema (PDR + DME) retinal tissue, with weaker separation in whole blood, broad retinal tissue and six-donor type 1 diabetes (T1D) PBMCs. FLNA virtual knockout predicted cell-context-dependent perturbation of immune-related transcriptional programs, including IL4R in DR B cells and CTSD in DR monocytes/NK cells. This prior-guided study identifies FLNA within a ten-gene GMMRG set as a circulating host-response signal that links curated microbe/metabolite–host records to immune-vascular and cytoskeletal remodeling in DR. Full article

Chemotherapy resistance in triple-negative breast cancer (TNBC) remains a critical clinical challenge, with a substantial proportion of patients failing to achieve pathological complete response following neoadjuvant chemotherapy (NAC). Using an integrative single-cell RNA sequencing (scRNA-seq), bulk transcriptomic, and spatial proteomic framework, we aimed to identify the malignant epithelial subset driving this resistance and the intercellular signaling axes through which it reprograms the tumor microenvironment (TME). scRNA-seq analysis of NAC-treated breast tumors revealed a Fatty Acid–EMT co-expressing epithelial subset (FA-EMT) that is selectively enriched in the chemotherapy-resistant residuum. Critically, FA-EMT co-expression—rather than either program individually—most powerfully predicted chemotherapy resistance and reduced overall survival across two independent bulk transcriptomic cohorts comprising 277 TNBC patients (p < 0.001). CellChat ligand–receptor analysis established FA-EMT cells as the dominant TME signaling hub, deploying MDK–NCL and MIF–CD74–CXCR4 axes to simultaneously suppress adaptive and innate anti-tumor immunity via T-cell exhaustion, Treg activation, and the expansion of myeloid-derived suppressor cells. Spatial CyCIF validation in a published paclitaxel-resistant TNBC mouse model (n = 69 cores) confirmed significant Metabolic-EMT enrichment in resistant tumor cores (p = 0.0085) with physical co-localization with immunosuppressive MDSC and Treg populations. These findings establish the FA-EMT subset as a key cellular driver of treatment failure in TNBC and nominate MDK–NCL and MIF–CD74–CXCR4 as mechanistically grounded therapeutic targets with the potential to dismantle the FA-EMT-driven immunosuppressive niche and sensitize chemotherapy-resistant TNBC to cytotoxic treatment. Full article

Chronic lymphocytic leukemia (CLL) is characterised by the dependence of malignant cells on specialised tissue microenvironments within the bone marrow (BM) and secondary lymphoid organs (SLOs), which provide essential survival and proliferative signals. The CXCR4/CXCL12 and CXCR5/CXCL13 chemokine axes direct the trafficking of CLL cells into these anatomically distinct compartments, where stromal-derived survival signals protect them from both spontaneous and therapy-induced apoptosis. Although each chemokine axis has been extensively studied individually, no previous review has integrated both pathways into a unified mechanistic framework. This review proposes that the signal transducer and activator of transcription 3 (STAT3) function as a shared molecular hub that integrates niche-derived cytokine signals, including interleukin-6 (IL-6), IL-10, and IL-21, and may transcriptionally upregulate both CXCR4 and CXCR5, and reinforce tissue homing through a positive feedback loop. This review seeks to evaluate the expression, signalling, and clinical significance of each axis, their points of convergence and divergence and the therapeutic strategies that disrupt these parallel homing pathways. Complementing this framework, recent clinical evidence indicates that circulating CXCL13 serves as a robust prognostic biomarker in CLL, and that STAT3 inhibition may overcome bone marrow stromal-mediated cytoprotection. The CXCL12-CXCR4-STAT3-IL-10 immunosuppressive axis further drives T-cell exhaustion. Together, these pathways form an integrated oncogenic network that supports CLL cell survival, drives immune dysfunction, and promotes therapy resistance. Several important knowledge gaps remain. These include the lack of direct validation of the STAT3-CXCR5 transcriptional axis in primary CLL cells and uncertainty regarding whether CXCR4/CXCR5 dominance represents a stable transcriptional programme or a dynamic, microenvironment-driven process. Addressing these questions through single-cell transcriptomics, spatial transcriptomics, proteomics, and functional validation studies will be essential for developing rational combination therapies capable of simultaneously disrupting both homing axes. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Background: Comparative oncology uses naturally occurring cancers in companion animals to study tumor biology and therapeutic responses relevant to human cancer. Spontaneous feline tumors are increasingly recognized as useful comparative models because they arise in immunocompetent hosts, develop under shared environmental exposures, and can reproduce selected clinical, histopathologic, molecular, and therapeutic features of human malignancies. Methods: This review compares feline oral squamous cell carcinoma (FOSCC) with human head and neck squamous cell carcinoma (HNSCC), and feline mammary carcinoma (FMC) with human breast cancer, emphasizing shared pathologic, molecular, tumor microenvironment, and therapeutic features. Results: Recent immunohistochemical, genomic, transcriptomic, and biomarker studies have identified shared features between feline and human cancers. FOSCC resembles human HNSCC through aggressive local invasion, histologic features, therapeutic resistance, and recurrent alterations of TP53, MYC, and PTEN. FMC shows strong overlap with aggressive human triple-negative breast cancer, including reduced hormone receptor expression, recurrent TP53, PIK3CA, and CXCL12/CXCR4 signaling alterations, and tumor microenvironment features involving immune-checkpoint, inflammatory, and angiogenic pathways. FOSCC clinical trials and emerging clinical investigations into FMC treatments further support the use of cats for translational therapy evaluation. Conclusions: FOSCC and FMC are promising comparative oncology models for human HNSCC and aggressive breast cancer, respectively. Future multicenter studies incorporating standardized tumor classification and grading, predefined stratification criteria, and clinically meaningful endpoints will be essential to strengthen their translational value. Full article

Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), remains one of the most lethal gynecological malignancies due to late diagnosis and the development of chemoresistance. The tumor microenvironment (TME) plays an important role in disease progression, with chemokines influencing cell recruitment, angiogenesis, metastasis, and immune modification. This review synthesizes current evidence on key chemokine axes in ovarian cancer, highlighting their dual roles as prognostic biomarkers and therapeutic targets. The most important axes include CXCL12/CXCR4 (which drives tumor proliferation, angiogenesis and chemoresistance via epithelial–mesenchymal transition), CCL2/CCR2 (promoting immunosuppressive tumor-associated macrophages and resistance), and CCL5/CCR5 (enhancing pro-oncogenic signaling and Treg/MDSC infiltration). Pro-angiogenic ELR+CXC chemokines like CXCL8 induce vascularization and inflammation. On the contrary, effector chemokines (CXCL9/10/11/13) correlate with “hot” immune subtypes and improved survival in several studies. High expression of immunosuppressive chemokines predicts poorer prognosis and therapy resistance, while immune-attracting profiles associate with better outcomes and chemotherapy responsiveness. Therapeutically, inhibitors like plerixafor (CXCR4), PF-04136309 (CCR2), and maraviroc (CCR5) show preclinical promise, synergizing with chemotherapy, anti-VEGF, and checkpoint inhibitors. Chemokines also represent actionable molecular targets to overcome ovarian cancer’s “cold” immune phenotype. Future research should validate multi-chemokine signatures for patient stratification and advanced clinical trials toward personalized therapies. Full article