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PubMed2004

Lymphocyte development and function in the absence of retinoic acid-related orphan receptor alpha.

The orphan nuclear receptor, retinoid acid-related orphan receptor (ROR)alpha, is essential for the development of cerebellar Purkinje cells and bone tissue. RORalpha may also play a critical role in lymphocyte development and function because staggerer mice, a natural mutant strain with a disrupted expression of RORalpha, have reduced thymic and splenic cellularity. In this report, we analyzed the role of RORalpha in lymphocyte development by examining lymphoid compartments in RORalpha(-/-) mice and Rag-2(-/-) mice reconstituted with RORalpha(-/-) bone marrow. We found that T and B cell development was severely defective in RORalpha(-/-) mice, but not in Rag-2(-/-)/RORalpha(-/-) chimeric mice. We also analyzed cellular and humoral immune responses in Rag-2(-/-)/RORalpha(-/-) chimeric mice. Our results show that serum IgG levels were elevated in Rag-2(-/-)/RORalpha(-/-) chimeric mice after immunization with a T-dependent Ag compared with control chimeras. IFN-gamma production by RORalpha(-/-) CD8(+) T cells after TCR stimulation was also increased. Furthermore, RORalpha(-/-) mast cells and macrophages produced an increased amount of TNF-alpha and IL-6 upon activation. These results indicate that RORalpha indirectly regulates lymphocyte development by providing an appropriate microenvironment and controls immune responses by negatively regulating cytokine production in innate immune cells and lymphocytes.

Animals↗

PubMed2026

Next-generation macrophage engineering in cancer therapy: From TAM reprogramming to CAR-macrophages.

Macrophages are central regulators of the tumor microenvironment (TME), shaping immune suppression, angiogenesis, metabolism, and therapeutic resistance in solid cancers. While early strategies sought to deplete tumor-associated macrophages (TAMs) or block monocyte recruitment, limited efficacy and compensatory mechanisms revealed the need for functional reprogramming rather than elimination. Recent advances in viral vectors, CRISPR-Cas genome editing, and RNA-based delivery platforms have enabled precise genetic modification of macrophages, giving rise to chimeric antigen receptor macrophages (CAR-Ms) and related engineered products. Beyond antigen targeting, effective macrophage engineering requires stabilization of pro-inflammatory identity, resistance to tumor-induced repolarization, metabolic reinforcement, and integration of checkpoint modulation pathways. This review synthesizes current strategies across DNA, mRNA, and siRNA-based platforms, highlighting convergent design principles that connect TAM reprogramming with CAR-M development. We discuss reshaping phagocytosis checkpoints, metabolic and transcriptional stabilization, cytokine augmentation, and synthetic receptor architecture, emphasizing combinatorial and context-aware engineering, while proposing new candidate gene targets. Engineered macrophages are thus evolving from simple effector cells into programmable immune coordinators capable of converting immunologically "cold" tumors into inflamed, therapy-responsive niches.

CAR-M↗

PubMed1989

Immunoresponse of tissue infiltrating lymphocytes in bladder tumors.

Local immunocompetence was evaluated immunohistochemically in patients with bladder tumors before and after local injections of an immunomodulator. The subpopulations of tissue infiltrating lymphocytes (TIL) were examined by staining six serial sections with Leu4, Leu7, Leu10, LeuM3, OKT4, and OKT8 antibodies. T cells predominated over B cells in 19 of 25 bladder tumors. T cell infiltration was prominent around tumor cells, and it was marked in non-invasive tumors. B cells were rare in the stroma. In patients with low-stage tumors, OKT8 cells were more prominent than OKT4 cells. NK cells accumulated within cancer nests but their infiltration was scanty in invasive bladder tumors. Before surgery, immunomodulators (OK-432, IL-2) were injected intratumorally. Their administration resulted in marked increase of T and NK cells, irrespective of the stage of disease; there was a slight increase in B cells. These findings suggest that local immunosurveillance plays a role against bladder tumors. Further studies are required to elucidate host immune responses in the microenvironment of the cancer site, as well as the systemic immune reaction.

Adjuvants, Immunologic↗

PubMed1999

Efficient inducation of local and systemic antitumor immune response by liposome-mediated intratumoral co-transfer of interleukin-2 gene and interleukin-6 gene.

Interleukin 2 (IL-2) expressing plasmid and interleukin 6 (IL-6)-expressing plasmid were encapsulated in liposome and administrated intratumoraly into tumor-bearing mice 4 days after subcutaneous inoculation of B16F10 melanoma cells. The results showed that treatment of tumor-bearing mice with IL-2 gene or IL-6 gene transfer inhibited the growth of subcutaneous tumor and prolonged the survival of tumor-bearing mice significantly when compared with the treatment of PBS or control gene transfer mediated by liposome (P < 0.01). Combined transfer of IL-2 gene and IL-6 gene was found to elicit inhibitory effects on the growth of B16F10 tumor more significantly and prolonged the survival period of tumor-bearing mice more obviously. We investigated the local immunity in tumor microenvironment and found that IL-2 and IL-6 gene transfer could significantly increase the expression of lymphocyte function-associated antigen-1 on tumor infiltrating lymphocytes (TIL) and MHC-I molecule on tumor cells freshly isolated from the tumor mass. The NK and CTL activity of TIL increased markedly after the combined transfer of these two cytokine genes. We also observed the systemic antitumor immune response in the tumor-bearing mice and demonstrated that NK and CTL activity of splenocytes and the production of IL-2, tumor necrosis factor and interferon-gamma from splenocytes increased obviously in mice after the combined transfer of IL-2 and IL-6 gene. In conclusion, local and systemic antitumor immunity of the tumor-bearing host could be induced efficiently after the combined gene transfer. The enhanced specific and non-specific antitumor immunity might be responsible for the more potent antitumor effects of the combined gene therapy.

Animals↗

PubMed2001

Intracerebral regulation of immune responses.

Major progress has been made over the last years in our understanding of the mechanisms underlying immune privilege and immune surveillance of the central nervous system (CNS). Once considered a passive process relying only on physical barriers, immune privilege is now viewed as a more complex phenomenon, which involves active regulation of immune reactivity by the CNS microenvironment. Evidence has also emerged that the immune system continuously and effectively patrols the CNS and that dysregulated immune responses against CNS-associated (exogenous or self) antigens are involved in the pathogenesis of various neurological diseases. In this article we shall briefly review current knowledge of how the immune response is regulated locally in the CNS and which cell types and molecular mechanisms are involved in shaping intracerebral immune responses.

Antigen-Presenting Cells↗

PubMed2026

Secreted protein circuits in the gastrointestinal tumour microenvironment: determinants of immunotherapy response and resistance.

Immune checkpoint blockade has transformed treatment in selected gastrointestinal (GI) cancers, yet primary resistance, incomplete responses and acquired resistance remain common. This heterogeneity is not explained by tumour-cell genomics alone; extracellular signalling programmes within the tumour microenvironment can determine immune recruitment, access and adaptation to therapy. The tumour secretome-including cytokines, chemokines, growth factors, complement components, matricellular proteins, soluble checkpoint molecules and extracellular-vesicle-associated cargo-regulates immune-cell recruitment, exclusion, suppression, tertiary lymphoid structure formation and exhaustion across anatomical and molecular contexts. Across gastric and esophageal cancers, colorectal cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma and biliary tract cancers, recurrent suppressive circuits include TGF-β, VEGF, CXCL12-CXCR4, CXCL8/IL-8-CXCR1/2, CCL2-CCR2, CSF1-CSF1R, IL-6-family cytokines, SPP1/osteopontin, periostin, galectins, DKK1, MIF, complement and soluble or vesicular PD-L1. Conversely, CXCL9/10/11-CXCR3 signalling and CXCL13-associated tertiary lymphoid structures characterise immune-permissive states that can support checkpoint responsiveness. We organise these circuits into four overlapping functional modules-myeloid-enriched, fibroblast-driven exclusion, angiogenic-immunosuppressive and immune-permissive-and apply a four-level evidence hierarchy that separates clinical validation from mechanistic inference. Clinically useful secretome biomarkers will therefore need to integrate cellular source, spatial localisation, receptor context, temporal dynamics and linkage to actionable immune-state transitions.

Humans↗

PubMed2006

Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis.

Accumulating evidence indicates that the cellular microenvironment plays a key role in follicular lymphoma (FL) pathogenesis, both within tumor lymph nodes (LNs) and in infiltrated bone marrow where ectopic LN-like reticular cells are integrated within malignant B-cell nodular aggregates. In normal secondary lymphoid organs, specific stromal cell subsets provide a highly specialized microenvironment that supports immune response. In particular, fibroblastic reticular cells (FRCs) mediate immune cell migration, adhesion, and reciprocal interactions. The role of FRCs and their postulated progenitors, that is, bone marrow mesenchymal stem cells (MSCs), in FL remains unexplored. In this study, we investigated the relationships between FRCs and MSCs and their capacity to sustain malignant B-cell growth. Our findings strongly suggest that secondary lymphoid organs contain MSCs able to give rise to adipocytes, chondrocytes, osteoblasts, as well as fully functional B-cell supportive FRCs. In vitro, bone marrow-derived MSCs acquire a complete FRC phenotype in response to a combination of tumor necrosis factor-alpha and lymphotoxin-alpha1beta2. Moreover, MSCs recruit primary FL cells that, in turn, trigger their differentiation into FRCs, making them able to support malignant B-cell survival. Altogether, these new insights into the cross talk between lymphoma cells and their microenvironment could offer original therapeutic strategies.

Bone Marrow Cells↗

PubMed2026

Non-coding RNA 7SK drives tumor resistance by coupling local oncogenic activation with global transcriptional repression.

The conserved non-coding RNA 7SK is a well-established global transcriptional repressor, yet its context-specific functions in cancer and therapy resistance remain paradoxical. Here, we resolve this paradox by uncovering a dual-axis mechanism through which 7SK drives colorectal cancer (CRC) resistance. By integrating single-cell multi-omics with functional assays, we demonstrate that 7SK not only selectively activates the JUN transcriptional network to fuel tumor proliferation but also reduces global transcriptional entropy to stabilize an immunosuppressive microenvironment and promote immune escape. This "local activation-global suppression" paradigm is conserved across multiple cancer types, positioning 7SK as a potential pan-cancer therapeutic target. Our findings reveal 7SK as a dynamic modulator that balances oncogene-specific transcription with global transcriptional suppression across cancers, providing a new framework for understanding and targeting ncRNA-mediated resistance.

Humans↗

PubMed2001

Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients.

In women with ovarian cancer, suppression of components of the immune system may promote tumour development. Previous studies in ovarian cancer have demonstrated that decreased expression and function of the T-cell receptor (TcR)-associated signal transducing zeta-chain correlates with deficient immune responsiveness of T cells. In this study, sera and ascitic fluids obtained from woman with advanced ovarian cancer were found to suppress the expression of TcR-associated zeta chain. This suppression of zeta chain expression was dose-dependent and was not observed with biologic fluids obtained from healthy women. The factor responsible for the loss of zeta chain was purified from ascites and characterized as a protein with an appropriate molecular weight of 14 kD. Suppression of T-cell TcR-zeta was specific, since neither lck nor ZAP-70 expression was affected, while zeta chain was almost completely suppressed. This selective suppression of TcR-zeta expression by the 14 kD ascites-derived factor was shown to operate at the mRNA level. By defining the mechanism through which this protein modulates TcR-zeta chain levels, it might be possible to ultimately prevent the suppressive influences of the tumour microenvironment and restor immune competence in patients with ovarian carcinoma.

Adult↗

PubMed2003

Interactions of lactic acid bacteria with human intestinal epithelial cells: effects on cytokine production.

As a participant in the mucosal immune response, the intestinal epithelial cell must respond to a variety of stimuli, including lactic acid bacteria (LAB) consumed in the diet. The objective of this study was to compare the abilities of several strains of LAB to modulate cytokine secretion by human intestinal epithelial cell (IEC) line HT-29. Certain strains of Lactobacillus rhamnosus, Lactobacillus delbrueckii, and Lactobacillus acidophilus suppressed the production of the chemokine RANTES by stimulated HT-29 IEC, although the magnitude of this suppression varied depending on the nature of the bacterial growth medium. Similarly, specific strains showed growth condition-dependent suppression of HT-29 interleukin-8 (IL-8) production. Strain-dependent effects were also seen for the suppression of tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) production. The binding of several of these bacterial strains to the HT-29 cell line was also examined. Different strains were found to have differing abilities to interact with IEC, with L. rhamnosus R0011 being the strain that generally had the most extensive effects on HT-29 cytokine production and also bound to HT-29 IEC most effectively. Modulation of IEC cytokine production has the potential to profoundly affect the mucosal microenvironment, influencing the immune response to pathogens and other ingested antigens.

Bacterial Adhesion↗

PubMed2026

SYT8 Drives Colorectal Cancer Progression and Immune Evasion via the SETD1A-H3K4me3 Axis.

By integrating transcriptomic data from The Cancer Genome Atlas, Gene Expression Omnibus, and a self-established colorectal cancer (CRC) cohort, it was identified that synaptotagmin 8 (SYT8) is significantly up-regulated in tumors and is predictive of poor prognosis. Single-cell RNA sequencing, immunohistochemistry, and immunofluorescence experiments demonstrate that SYT8 expression is largely confined to tumor cells, predominantly in the nucleus. Functional assays reveal that depletion of SYT8 impairs, whereas its overexpression enhances, CRC cell proliferation and invasion. Transcriptomic profiling indicates an enrichment of cell cycle and epithelial-mesenchymal transition signatures. Mechanistically, co-immunoprecipitation/mass spectrometry identifies SET domain containing 1A (SETD1A) as a direct SYT8-interacting partner. The SYT8-SETD1A axis forms a positive-feedback loop that increases histone H3 lysine 4 trimethylation (H3K4me3) levels and drives the transcription of protumorigenic genes. Immune profiling further indicates that high SYT8 expression correlates with increased regulatory T-cell infiltration, suggesting an immunosuppressive microenvironment and potential resistance to immunotherapy. Collectively, SYT8 promotes CRC progression through the SETD1A/H3K4me3-mediated activation of the cell cycle, induction of epithelial-mesenchymal transition, and remodeling of the immune microenvironment. Therefore, SYT8 is established as a prognostic biomarker and serves as a therapeutic target in colorectal cancer.

Humans↗

PubMed1987

The thymus gland in secondary immunodeficiency.

The microenvironment within the thymus gland and various thymic hormones facilitates the maturation of prothymocytes to functional T lymphocytes. Abnormal thymic morphology is a hallmark feature of several primary and secondary immunodeficiencies. Thymus glands from patients with the acquired immunodeficiency syndrome or graft-vs-host disease and from patients receiving cyclosporine A therapy are depleted of thymocytes, have a striking reduction in thymic epithelial cell mass, and are virtually devoid of Hassall's corpuscles. In malnourished individuals, similar thymic atrophy is present, although the Hassall's corpuscles are present and cystically dilated. Absence of differentiation antigens or anomalous expression of major histocompatibility antigens occurs on thymic epithelial cells in these conditions, and resembles immunologic abnormalities of the thymus in severe combined immunodeficiency. In acquired immunodeficiency syndrome, graft-vs-host disease, and cyclosporine therapy, there is an expansion of cytotoxic/suppressor (CD8) lymphocytes. Experimental evidence suggests that in many situations, such cells may cause damage to the thymic epithelium. The damage to the thymic epithelium may alter the thymic microenvironment and contribute to the immune dysfunction observed in these patients. In addition, a damaged microenvironment may hinder therapeutic efforts to reconstitute immunity.

Acquired Immunodeficiency Syndrome↗

PubMed2026

Integrated single-cell and bulk transcriptomic analysis identifies a novel senescent fibroblast subtype associated with poor prognosis in acral melanoma.

BACKGROUND: Acral melanoma (AM) exhibits significant intratumoral heterogeneity, but its tumor microenvironment (TME) and immune regulation remain unclear. This study aims to dissect TME heterogeneity and establish a prognostic model based on key cell subpopulations. METHODS: We collected AM single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). Unsupervised clustering, CellChat, and Scissor analysis were performed to characterize cellular heterogeneity, cell-cell communication, and prognosis-related cell subpopulations. Kaplan-Meier analysis was used to assess the prognostic value of key genes, which were further validated by multiplex immunohistochemistry (mIHC). RESULTS: In AM, Mel_C2, C7, and C9 with high SEMA6A and KIT expression were strongly linked to poor prognosis. We further identified a senescent fibroblast subpopulation (sCAF_CDKN2A) characterized by high fibroblast senescence signature (FSS) scores. Integrating Scissor analysis of fibroblast subtypes with bulk prognostic data, we identified COL3A1, VCAN, and KIT as prognosis-associated genes upregulated in poor-outcome-related fibroblast subsets. Cell-cell communication analysis revealed that sCAF_CDKN2A engages in an immunosuppressive network, interacting with regulatory T cells (Tregs) via MIF signaling and receiving signals from exhausted CD8+ T cells through PPIA-BSG interactions. Using transcription factor expression patterns from these fibroblast subtypes, we constructed a prognostic model that effectively stratified patients into distinct risk groups with significant differences in overall survival (OS). mIHC confirmed significantly higher protein levels of SEMA6A and COL3A1 in tumor tissues compared to matched normal tissues. CONCLUSIONS: We established a novel prognostic model for AM and identified sCAF_CDKN2A as an immunosuppressive senescent fibroblast subpopulation driving poor prognosis.

Acral melanoma↗

PubMed2025

Oral Lachnoanaerobaculum Levels and Survival in Patients With Head and Neck Cancer.

IMPORTANCE: The oral microbiome plays a critical role in cancer treatment responses, yet its influence on outcomes in patients with head and neck squamous cell carcinoma (HNSCC) undergoing (chemo)radiotherapy remains poorly understood. Identifying specific microbiome signatures associated with treatment effectiveness could provide novel prognostic biomarkers and therapeutic targets. OBJECTIVE: To investigate the association between salivary Lachnoanaerobaculum spp abundance and treatment outcomes in patients with HNSCC undergoing (chemo)radiotherapy and to explore potential mechanisms. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study analyzed saliva samples from patients with HNSCC who were enrolled in 2 independent prospective biomarker studies (SALIVA and ZissTrans) and underwent definitive (chemo)radiotherapy. Oral microbiome composition was assessed using 16S rRNA gene sequencing. Tumor-infiltrating lymphocytes (TILs) were evaluated via immunohistochemistry in patients with available data. Findings were further assessed using data from The Cancer Microbiome Atlas and The Cancer Genome Atlas. Sample collection occurred from 2008 to 2011 (SALIVA) and from 2017 to 2022 (ZissTrans), and the data for this study were analyzed from July to December 2024. EXPOSURE: Definitive (chemo)radiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was locoregional recurrence-free survival (LRFS) and a secondary outcome was overall survival (OS). Additional secondary analyses evaluated the association between Lachnoanaerobaculum spp levels and TIL levels, and the incidence of severe radiation-induced oral mucositis. RESULTS: The analysis included 92 patients with HNSCC (mean [SD] age, 61.1 [7.9] years; 15 female [16.3%] 77 male [83.7%] individuals) and found that higher Lachnoanaerobaculum spp abundance was associated with substantially improved LRFS (median, 69 vs 11 months; hazard ratio [HR], 0.50; 95% CI, 0.29-0.86) and OS (median, 75 vs 27 months; HR, 0.54; 95% CI, 0.30-0.98). This finding was confirmed by multivariable Cox regression (LRFS: HR, 0.50; 95% CI, 0.25-1.00; OS: HR, 0.37; 95% CI, 0.16-0.85). TILs were evaluated in 76 patients (82.2%) and showed that increased Lachnoanaerobaculum spp levels were associated with higher CD4-positive and CD8-positive TIL counts. Lachnoanaerobaculum spp abundance showed no meaningful association with severe radiation-induced oral mucositis. Data from The Cancer Microbiome Atlas (n = 157) indicated that higher intratumoral Lachnoanaerobaculum spp levels were associated with improved OS (HR, 0.62; 95% CI, 0.39-0.98). Transcriptomic analyses in The Cancer Genome Atlas cohort further supported an immune-stimulated tumor microenvironment in Lachnoanaerobaculum-high tumors. CONCLUSIONS AND RELEVANCE: This prognostic study found that higher salivary Lachnoanaerobaculum spp abundance was associated with improved tumor control and survival in patients with HNSCC undergoing (chemo)radiotherapy. These findings support further investigation into microbiome-targeted interventions to improve HNSCC treatment effectiveness.

Humans↗

PubMed2006

Regulation of immune cell entry into the central nervous system.

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS to not disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses can be mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly controlling immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid (CSF) barrier, which protect the CNS from the constantly changing milieu within the bloodstream, also strictly control immune cell entry into the CNS. Under physiological conditions, immune cell migration into the CNS is kept at a very low level. In contrast, during a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis, immunocompetent cells readily traverse the BBB and likely also the choroid plexus and subsequently enter the CNS parenchyma or CSF spaces. This chapter summarizes our current knowledge of immune cell entry across the blood CNS barriers. A large body of the currently available information on immune cell entry into the CNS has been derived from studying experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Therefore, most of this chapter discussing immune cell entry during CNS pathogenesis refers to observations in the EAE model, allowing for the possibility that other mechanisms of immune cell entry into the CNS might apply under different pathological conditions such as bacterial meningitis or stroke.

Animals↗

PubMed1995

Posttransfusional, LKM-1-autoantibody-positive hepatitis C virus infection, cryoglobulinemia, and aplastic anemia.

Aplastic anemia is occasionally caused by viral hepatitis, hepatitis C virus being the most important factor. Pathogenetically, decreased bone marrow function, abnormalities of the bone marrow microenvironment, and immune-mediated suppression of hematopoiesis are important. Hepatitis C virus infection is associated with a variety of extrahepatic manifestations including autoimmune features like cryoglobulinemia, Sjögren's syndrome, and autoimmune hepatitis. Here we report the case of a 42-year-old man with aplastic anemia due to posttransfusional hepatitis C virus infection associated with cryoglobulinemia and LKM-1 autoantibodies. Following a triple immunosuppressive therapy, there was a complete reconstitution of the bone marrow. Serum HCV-RNA as well as plus- and minus-stranded HCV-RNA in peripheral blood mononuclear cells (PBMC) were detected before immunosuppressive therapy. After therapy, serum HCV-RNA persisted. Furthermore, PBMC now were positive for plus-stranded RNA only. However, in bone marrow-derived precursor cells we failed to demonstrate HCV molecules after therapy. This would argue for reconstituted PBMC from newly generated uninfected precursor cells. It remains unclear as to whether the autoimmune character of the disease or the hepatitis C virus infection itself have contributed to the pathogenesis of the aplastic anemia.

Adult↗

PubMed2026

Moving Beyond Morphology to Multiplexed Molecular Imaging as the Next Frontier in Diagnostic Pathology.

Diagnostic pathology has long relied on the morphologic interpretation of hematoxylin and eosin-stained tissues to guide diagnosis and assess prognostic features. Although pathologists intuitively recognize spatial patterns and architectural organization, these assessments remain largely qualitative and difficult to quantify systematically. Immunohistochemistry and immunofluorescence have introduced molecular specificity but are limited in multiplexing capacity, whereas bulk genomic and transcriptomic assays provide high molecular depth but lose spatial context by averaging signals across heterogeneous cell populations. Recent advances in spatial proteomics-including mass spectrometry-based imaging and cyclic immunofluorescence-now enable multiplexed, single-cell protein analysis within intact tissue architecture. These technologies have revealed complex immune and stromal microenvironments, spatially organized biomarkers predictive of therapeutic response, and molecular gradients underlying disease progression. By integrating histologic and molecular information, spatial proteomics bridges traditional microscopy with high-dimensional omics, allowing quantitative, spatially resolved insights into tissue organization and disease mechanisms. This review summarizes recent developments in multiplexed spatial proteomics from both scientific and pathologic perspectives, highlighting how these technologies extend beyond morphology to quantify histologic patterns, refine biomarker discovery, and facilitate clinical translation. The review also examines translational challenges and barriers to clinical implementation, including costs, standardization requirements, and workflow integration.

Humans↗

PubMed2025

Identification and external validation of a prognostic signature based on myeloid-derived suppressor cells-related LncRNAs to evaluate survival prognosis and treatment efficacy in invasive breast carcinoma.

BACKGROUND: Originating in the hematopoietic tissue, myeloid-derived suppressor cells (MDSCs) significantly contribute to tumor-related immunological processes. However, their relationship with long noncoding RNAs (lncRNAs) and breast cancer remains incompletely understood. In this study, we introduced MDSCs-associated lncRNAs as novel prognostic biomarkers to assess outcomes in patients with invasive breast carcinoma (BRCA). METHODS: Information regarding BRCA cases, including clinical and genomic details, was obtained from the TCGA repository. Predictive indicators were discovered, and their reliability underwent thorough verification. A clinically useful nomogram was developed following application-based validation. Additional investigations encompassed functional analysis, TMB assessment, TME profiling, immunotherapy efficacy forecasting, and drug sensitivity testing along with target identification. Long non-coding RNA expression was measured using reverse transcription quantitative PCR. RESULTS: A risk stratification model incorporating eight MDSCs-related lncRNAs effectively predicted patient outcomes. Kaplan-Meier (K-M) survival analysis clearly indicated a much worse prognosis among patients classified as high-risk (p < 0.001). The nomogram accurately forecasted overall survival (OS). Analysis of functional enrichment revealed that pathways associated with epithelial cells showed activity among patients at higher risk. Characterization of the tumor microenvironment showed increased immune cell presence in those classified as low-risk. Conversely, individuals with greater risk displayed higher tumor mutational burden. TIDE and IPS analyses indicated superior immunotherapy responsiveness in the low-risk BRCA subgroup. Among 47 drugs with notable IC50 variations, Ribociclib, PD173074, KU-55933, NU7441, and nutlin-3a exhibited lower IC50 values within the low-risk group, whereas Lapatinib demonstrated greater efficacy among the high-risk group. Moreover, 10 potential therapeutic agents and their targets were predicted for high-risk patients. RT-qPCR validation confirmed the robustness of the model. CONCLUSIONS: We successfully verified a new model of molecular markers of MDSCs-related lncRNAs, offering critical insights for predicting outcomes and guiding therapeutic decisions in BRCA cases.

Bioinformatics↗