Unveiling the key mechanisms of FOLR2+ macrophage-mediated antitumor immunity in breast cancer using integrated single-cell RNA sequencing and bulk RNA sequencingWu, Jiang, Li
et alBreast Cancer Res (2025) 27 (1), 31
Abstract: Breast cancer (BRCA) is a common malignant tumor, and its immune microenvironment plays a crucial role in disease progression. In this research, we utilized single-cell RNA sequencing and bulk RNA sequencing technologies, combined with in vivo and in vitro experiments, to thoroughly investigate the immunological functions and mechanisms of FOLR2+ macrophages in BRCA. Our findings demonstrate a significant enhancement in the interaction between FOLR2+ macrophages and CD8+ T cells within the tumor tissues of BRCA patients. FOLR2 is closely associated with T cell infiltration in the tumor microenvironment of BRCA patients, particularly with CD8+ T cells. By secreting CXCL9 and engaging with CXCR3, FOLR2+ macrophages can activate the functionality of CD8+ T cells, thereby promoting cancer cell apoptosis. Further animal experiments confirm that FOLR2+ macrophages activate CD8+ T cells through the CXCL9-CXCR3 axis, exhibiting an antitumor immunity effect in BRCA. FOLR2+ macrophages play a crucial role in antitumor immunity in BRCA through the CXCL9-CXCR3 axis.© 2025. The Author(s).
Prognostic model based on M2 macrophage-related signatures for predicting outcomes, enhancing risk stratification, and providing therapeutic insights in diffuse large B-cell lymphomaGuo, Duan, Cen
Heliyon (2024) 10 (24), e41007
Abstract: The tumor microenvironment (TME) in lymphoma is influenced by M2 macrophages. This research proposes an novel predictive model that leverages M2 macrophage-associated genes to categorize risk, forecast outcomes, and evaluate the immune profile in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) undergoing R-CHOP therapy.Gene expression data and clinical information from DLBCL patients were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Co-expressed genes linked to M2 macrophage in DLBCL were analyzed using CIBERSORT. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to explore associated signaling pathways. The M2 macrophage-related gene prognostic model was developed and validated using Cox and LASSO regression. Prognostic signature genes were verified by single-cell RNA-seq analysis.92 M2 macrophage-related genes were identified based on bulk-seq data. MS4A4A, CCL13, LTB, CCL23, CCL18, XKR4, IL22RA2, and FOLR2 were used to construct the risk model. AUC values for 1-, 3-, and 5-year survival were 0.74, 0.72, and 0.72, respectively. High-risk patients demonstrated elevated immune scores and poorer overall survival. The high-risk subgroup also exhibited greater sensitivity to both chemotherapeutic agents and immune checkpoint inhibitors.This study presents an accurate and reliable M2 macrophage-related risk model, enhancing understanding of distinct prognostic subsets in DLBCL. It offers potential novel drug options for future treatments.© 2024 The Authors. Published by Elsevier Ltd.
Folate-targeted nanoparticles for glutamine metabolism inhibition enhance anti-tumor immunity and suppress tumor growth in ovarian cancerChen, Jiang, Zheng
et alJ Control Release (2025) 379, 89-104
Abstract: Ovarian cancer (OC) is a highly malignant gynecological tumor, and its effective treatment is frequently impeded by drug resistance and recurrent tumor growth. The reprogramming of glutamine metabolism in ovarian cancer is closely associated with tumor progression and the immunosuppressive tumor microenvironment. Recently, targeting metabolic reprogramming has emerged as a promising approach for cancer therapy. However, the application of such therapies is often constrained by their significant toxicity to normal tissues. In this study, we fabricated folate-targeted nanoparticles (FA-DCNPs) that co-encapsulate the glutamine metabolism inhibitor 6-diazo-5-oxo-L-norleucine (DON) and calcium carbonate (CaCO3). These nanoparticles alleviate damage to normal tissues by specifically targeting tumor cells via folate receptors (FOLR) mediation. Under acidic conditions, the FA-DCNPs release DON and Ca2+, generating a synergistic anti-tumor effect by impeding glutamine metabolism and inducing calcium overload. Additionally, FA-DCNPs target M2 phenotype tumor-associated macrophages (TAMs) via FOLR2, attenuating M2-TAMs activity. When partially phagocytosed by M0-TAMs, the nanoparticles restrict glutamate production, inhibiting polarization towards the M2 phenotype. This resulted in an increased proportion of M1-TAMs, thereby improving the tumor immune microenvironment. Our study explores a nanotherapeutic strategy that enhances the biosafety of anti-glutamine metabolism therapy through folate targeting, effectively suppresses tumor cell proliferation, and enhances the anti-tumor immune response.Copyright © 2025 Elsevier B.V. All rights reserved.
Spatial and single-cell transcriptomics reveal cellular heterogeneity and a novel cancer-promoting Treg cell subset in human clear-cell renal cell carcinomaSong, Zhu, Geng
et alJ Immunother Cancer (2025) 13 (1)
Abstract: Clear cell renal cell carcinoma (ccRCC) is the most common histologic type of RCC. However, the spatial and functional heterogeneity of immunosuppressive cells and the mechanisms by which their interactions promote immunosuppression in the ccRCC have not been thoroughly investigated.To further investigate the cellular and regional heterogeneity of ccRCC, we analyzed single-cell and spatial transcriptome RNA sequencing data from four patients, which were obtained from samples from multiple regions, including the tumor core, tumor-normal interface, and distal normal tissue. On the basis, the findings were investigated in vitro using tissue and blood samples from 15 patients with ccRCC and validated in the broader samples on tissue microarrays.In this study, we revealed previously unreported subsets of both stromal and immune cells, as well as mapped their spatial location at finer resolution. In addition, we validated the clusters of tumor cells after removing batch effects according to six characterized gene sets, including epithelial-mesenchymal transitionhigh clusters, metastatic clusters and proximal tubulehigh clusters. Importantly, we identified a special regulatory T (Treg) cell subpopulation that has the molecular characteristics of terminal effector Treg cells but expresses multiple cytokines, such as interleukin (IL)-1β and IL-18. This group of Treg cells has stronger immunosuppressive function and was associated with a worse prognosis in ccRCC cohorts. They were colocalized with MRC1 + FOLR2 + tumor-associated macrophages (TAMs) at the tumor-normal interface to form a positive feedback loop, maintaining a synergistic procarcinogenic effect. In addition, we traced the origin of IL-1β+ Treg cells and revealed that IL-18 can induce the expression of IL-1β in Treg cells via the ERK/NF-κB pathway.We demonstrated a novel cancer-promoting Treg cell subset and its interactions with MRC1 + FOLR2 +TAMs, which provides new insight into Treg cell heterogeneity and potential therapeutic targets for ccRCC.© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
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