Jul 2026· International Immunopharmacology· Vol 186, pp.
117123
· 0 citations· 25 references
Medicine
TL;DR
After combined treatment, uHCC patients were characterized by macrophages_FOLR2, CD8Teff, and LSEC, indicating a remodeling of the immune microenvironment.
Abstract
Background
The mechanisms underlying immune microenvironment remodeling remain unclear for patients with unresectable hepatocellular carcinoma (uHCC) undergoing transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). This study aims to identify the key features that change following the combination therapy in patients with uHCC.
Methods
Single-cell transcriptomic profiling was conducted on uHCC samples from the control group, pre-treatment group, and post-treatment group. The Cancer Genome Atlas (TCGA) database was obtained for prognostic analysis. Enriched genes and pathways were identified, and the association and underlying mechanisms of the identified sub-cluster of cells were elucidated in relation to other cellular components.
Results
A total of 82,687 cells were obtained from seven patients with uHCC. In the pre-treatment group, the CancerCells_1 was associated with epithelial-mesenchymal transition, indicating a poor prognosis, as evidenced by data from 370 HCC patients in TCGA database. In the post-treatment group, a high proportion of macrophages_FOLR2 was observed corresponding to an elevated interferon response signature score and a diminished pro-angiogenic signature score. The exhaustion of CD8+ effector T cell (CD8Teff) was mitigated by downregulating the notable expression of BHLHE40 and CXCL13. Following treatment, there was an increase in liver sinusoidal endothelial cell (LSEC), while both angiogenesis and TGF-β pathway scores were reduced. Notable changes were observed in the interactions across different cells, particularly concerning the key signatures of LGALS9_HAVCR2, CSF1_CSF1R, and VEGFB_FLT1.
Conclusion
After combined treatment, uHCC patients were characterized by macrophages_FOLR2, CD8Teff, and LSEC, indicating a remodeling of the immune microenvironment.
A single-cell-resolved ferroptosis gene signature with strong prognostic and therapeutic implications for ESCC is presented, showing that knockdown of CDCA3 lead to the downregulation of ferroptosis inhibitor-related genes and upregulation of ferroptosis-promoting genes, thereby enhancing the sensitivity to RSL3-induced ferroptosis.
Qing Xu, Yu Ma, Xuanqi Huang et al.· Frontiers in Oncology· 0 citations
Background Bladder cancer (BLCA) is a common malignancy, with muscle-invasive bladder cancer (MIBC) associated with a 5-year survival rate below 50%. Cancer-associated fibroblasts (CAFs) are heterogeneous stromal components of the tumor microenvironment (TME) that contribute to tumor progression, therapy resistance, and immune evasion. However, the molecular basis of CAF diversity and immune regulation in BLCA remains incompletely understood. Methods We analyzed single-cell transcriptomic data from GEO dataset GSE135337 using dimensionality reduction, unsupervised clustering, differential expression analysis, GO/KEGG/GSEA, diffusion pseudotime inference, and LIANA ligand–receptor analysis. TCGA-BLCA bulk transcriptomic data (n = 408 total; n = 401 after stage filtering) were used for score validation. RT–qPCR was performed to assess selected myCAF- and iCAF-associated genes in RT4 and T24 bladder cancer cells. Results Analysis of 9,253 post-QC cells across two non-paired specimens (6,035 adjacent-tissue; 3,218 tumor) yielded 9 DE-marker-annotated cell populations. Among 1,923 retained adjacent-tissue fibroblasts, two transcriptionally distinct states were identified: Homeostatic fibroblasts (n = 1,197; enriched for COL1A1, DCN) and CCL2-high activated-like fibroblasts (n = 726; CCL2 log2FC = 0.806, FDR = 8.08 × 10−11). No fibroblast-like cells were retained in the tumor specimen. Diffusion pseudotime positioned CCL2-high cells at a later within-sample state (median DPT 0.813 vs. 0.672; FBLN1 rho = −0.808). Exploratory LIANA analysis identified 1,347 fibroblast-outgoing ligand–receptor interactions. A pre-specified six-gene myCAF score (ACTA2, COL1A1, MMP11, MYL9, TAGLN, TPM2) tracked pathological stage in TCGA-BLCA (P = 1.60 × 10−12) and showed an unadjusted overall survival association (HR = 1.21, 95% CI: 1.02–1.42, P = 0.025) that attenuated to non-significance after age and stage adjustment (HR = 1.03, P = 0.748); the association was not replicated in GSE31684 (n = 93; log-rank P = 0.443). RT–qPCR confirmed higher expression of ACTA2, POSTN, MMP11, FAP, IL6, and CXCL12 in T24 versus RT4 cells (4.33–16.56-fold; all BH-adjusted q < 0.01). Conclusion Single-cell transcriptomics of publicly available BLCA data identifies two transcriptionally distinct fibroblast states in adjacent tissue and supports an exploratory ligand–receptor interaction framework. A six-gene myCAF-associated score tracks pathological stage but does not independently predict overall survival after covariate adjustment and was not replicated in an independent cohort. These findings constitute an exploratory computational framework warranting prospective validation with primary CAF populations and adequately powered multi-specimen cohorts.
Yan-Dong He, Wen-Long Lu, Guan-Qun Ju et al.· Frontiers in Cell and Develo...· 0 citations
In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.
Lei Chen, Qing Wu, Cong Hong et al.· Biochemical and Biophysical...· 0 citations
Background Multiple primary lung cancer (MPLC) is an increasingly recognized subtype characterized by distinct lesions with independent origins. While recent studies have profiled the immune landscape of MPLC, its tumor-intrinsic metabolic features and immunoregulatory interactions remain largely unexplored. Methods Single-cell RNA sequencing data from 11 single primary lung cancer (SPLC) tumors and 8 samples from 4 MPLC patients were analyzed using dimensionality reduction, clustering, and cell type annotation. Subtype-specific metabolic features and intercellular communication patterns were investigated through pathway enrichment and cell-cell interaction analyses. A prognostic model was constructed using Lasso-Cox regression. Immune microenvironment characteristics were assessed using deconvolution algorithms and immune-related signatures. Drug sensitivity prediction and functional assays were performed to explore potential therapeutic implications. Results This study identified a metabolically distinct malignant epithelial subpopulation enriched in MPLC tumors, characterized by upregulation of amino acid metabolism pathways and active MHC-II-mediated interactions with immunosuppressive CD4+ Treg cells and mast cells. A metabolism-based eight-gene prognostic model was developed and validated in independent lung adenocarcinoma cohorts, effectively stratifying patient survival outcomes. High-risk patients exhibited immunosuppressive tumor microenvironment features, reduced immunotherapy response potential, and distinct drug sensitivity profiles. Functional assays confirmed that key metabolic genes, spermine oxidase (SMOX) and spermine synthase (SMS), promoted tumor proliferation and invasion, accompanied by transcriptional changes in PI3K/mTOR pathway components, highlighting their potential roles in poor prognosis and therapeutic vulnerability. Conclusion This study provides a systematic characterization of malignant subpopulations in MPLC, highlighting metabolic reprogramming and immunoregulatory features that contribute to poor prognosis. These findings provide a rationale for metabolism-based prognostic stratification and highlight potential therapeutic strategies to improve clinical outcomes.
Yuli Zhao, Hanyu Zhao, Hui-Sheng Wu et al.· Frontiers in Immunology· 0 citations
Neoadjuvant immunochemotherapy (nICT) has emerged as a promising neoadjuvant strategy for esophageal squamous cell carcinoma (ESCC). Identification of the factors affecting the responsiveness to nICT could help further improve treatment efficacy. Here, we performed single-cell analysis on 14 ESCC patients undergoing nICT and revealed tumor microenvironment (TME) features associated with differential treatment responses. Nonnegative matrix factorization (NMF) identified five coordinated cellular programs with distinct response associations. Specifically, the NMF3 program mainly comprising immunosuppressive cell subsets was enriched in the minimal or no pathological tumor regression (TRS3) group, in which regulatory T cells (Tregs) and dendritic cells (DCs) exhibited close correlation. In addition, elevated expression of mitochondrial transcription factor A (TFAM) in DCs was associated with increased Treg infiltration in the TRS3 group. A myeloid-specific Tfam knockout mouse model showed that TFAM deficiency reversed the immunosuppressive TME, inhibited tumor growth, and enhanced response to anti-PD-1 therapy in ESCC. Mechanistically, TFAM deficiency in DCs activated the STING-TBK1-IRF3 pathway, thereby promoting DC maturation to enhance anti-tumor immunity. Overall, this study characterized the TME in residual ESCC after nICT and revealed an association between elevated TFAM expression in DCs and poor responsiveness to nICT. These findings indicate the critical role of TFAM deficiency in DCs in activating anti-tumor immunity, highlighting the potential of targeting TFAM to improve the efficacy of immunotherapy and optimize therapeutic strategies.
Linyan Chen, Tang Feng, Jianfeng Zhou et al.· Cancer Research· 1 citation
Background Neoadjuvant chemoimmunotherapy (NACI) improves outcomes in resectable lung squamous cell carcinoma (LUSC), yet response varies widely and current biomarkers lack precision. Novel correlates of immunotherapy sensitivity tailored to the LUSC tumor microenvironment (TME) are urgently needed. Methods Using TCGA-LUSC transcriptomic data, we constructed a 25-gene prognostic model and applied three machine learning algorithms in combination with the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to identify core genes linked to prognosis and immunotherapy response. Immune infiltration and enrichment analyses were performed to characterize the TME. An independent pre-NACI biopsy cohort (n=36) was used for histopathological validation to explore correlations with pathological response, while single-cell RNA-seq (GSE207422) and CellChat were used to infer tumor-stromal crosstalk and explore underlying mechanisms. Results The risk score independently stratified prognosis. Among three core genes, high MBNL2 expression was associated with higher TIDE scores, lower TIDE-predicted response rates, and elevated cancer-associated fibroblast (CAF) scores. scRNA-seq revealed systematically enhanced communication between MBNL2-high tumor cells and FAP+ CAFs, with unique ligand-receptor pairs enriched in WNT and EGF pathways; FAP+ CAFs interacted with regulatory T cells via ECM remodeling and the MDK-NCL axis. Histopathological validation confirmed that low tumor-cell MBNL2 expression correlated with higher pathological response and pCR rates, reduced FAP, and decreased FOXP3 expression. Conclusion This study establishes a 25-gene prognostic model for LUSC and identifies MBNL2 as a novel correlate of poor pathological response to NACI. Elevated MBNL2 expression in tumor cells is associated with enhanced tumor-CAF crosstalk, CAF activation, and an immunosuppressive TME, laying a foundation for future mechanistic investigation.
Hao Wu, Yang Cheng, Hong-Lin Yan et al.· Frontiers in Oncology· 0 citations
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