Hepatocellular carcinoma (HCC) commonly develops in the context of chronic liver injury and fibrosis, and its immune evasion and therapeutic resistance are shaped not only by tumor-intrinsic factors but also by persistent interactions between the tumor stroma and immune cells. Hepatic stellate cells (HSCs) represent an important source of cancer-associated fibroblasts (CAFs) in HCC. HSC-derived CAFs can restrict the infiltration and function of effector T cells and promote the accumulation of immunosuppressive cells through CAF-associated and multicellular signaling networks, including TGF-β/SMAD, IL-6/STAT3, CXCL12/CXCR4, and CCL2/CCR2, as well as through extracellular matrix remodeling, vascular abnormalities, hypoxia, and metabolic reprogramming. Importantly, mediators such as IL-6 and CCL2 are not specific to HSC-derived CAFs and can also be produced by immune cells, hepatocytes, and other cellular populations within the HCC microenvironment. Conversely, cytokines released by distinct T-cell subsets, including IL-17A, TGF-β, IL-10, IFN-γ, and TNF-α, can in turn shape CAF activation, inflammatory states, and matrix-remodeling programs, thereby establishing a dynamic immune-stromal feedback loop. Focusing on the heterogeneity of CAFs and T cells, this review systematically summarizes the major mechanisms underlying bidirectional crosstalk between HSC-derived CAFs and T cells and their stage-specific roles in chronic liver injury, HCC initiation, progression, and therapeutic resistance. We further discuss potential therapeutic strategies involving CAF modulation, stromal remodeling, combination immunotherapy, and patient stratification. Current evidence suggests that this crosstalk axis may provide an important framework for understanding immune exclusion and therapeutic resistance in HCC. However, its clinical translation remains constrained by CAF heterogeneity, limited targeting specificity, insufficient causal evidence in humans, and safety concerns in the setting of underlying liver disease.

Aminoacyl-tRNA synthetases (aaRSs) generate the aminoacyl-tRNA pool required for protein synthesis, yet selected family members also participate in nutrient sensing, stress adaptation, metabolite-dependent protein modification and extracellular immune communication. This dual biology creates a recurrent interpretive problem in cancer: an aaRS signal can reflect canonical translational demand in tumor cells, a mitochondrial program specific to immune cells, protein modification driven by lactate or amino acids, an interferon-responsive state, a secreted ligand or extracellular vesicle cargo. This review provides a mechanistic, critically appraised synthesis rather than a catalog of the aaRS family. We reconnect aminoacylation, codon-dependent translation and aaRS-specific translational stress with tumor biology and then apply a source-resolved framework based on cellular source, molecular form, localization, receiving pathway and immune output. Mechanistic strength and clinical maturity are graded independently, with direct evidence of immune function recorded separately. Representative mechanisms include substrate-specific AARS1/AARS2 lactylation, context-dependent LARS1 programs driven by codon demand, LARS2-dependent mitochondrial translation in tumor-infiltrating regulatory T cells (TI-Tregs) and regulatory B cells (Bregs), activation of Toll-like receptor 2/6 (TLR2/6) by the unique domain embedded in CARS1 (UNE-C1), WARS1 tryptophanylation intrinsic to CD8+ T cells, KARS1 and GARS1 circuits that depend on molecular form, and additional QARS1, MARS1, RARS1 and VARS1 mechanisms. Several modules show strong preclinical immune causality and human association, but none has prospective clinical validation in treated patients. aaRS-informed biomarkers and therapeutic targeting should therefore be developed as complementary, context-dependent strategies.

Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide. Accurate early detection, timely diagnostic stratification, and robust prognostic risk assessment are essential for optimizing clinical outcomes and improving survival duration. However, conventional serological biomarkers demonstrate limited diagnostic performance owing to suboptimal sensitivity and specificity, while standard chemotherapy and targeted therapies provide only modest survival benefits in GC. Marked inter- and intratumoral heterogeneity further characterizes GC as a biologically complex and treatment-resistant malignancy. To date, significant progress has been made in comprehensively delineating the complex molecular pathogenesis of GC, providing a strong rationale for the development of novel biomarkers and promising therapeutic targets. The aim of this review is to systematically summarize recent advances ranging from aberrant genetic and epigenetic alterations; dysregulation of oncogenic signaling pathways; sophisticated crosstalk within the tumor microenvironment; intricate microbiota-inflammation interactions; fundamental discoveries to potential clinical translation, including novel biomarkers for early detection, diagnosis and prognostic stratification; and emerging therapeutic strategies for GC. Collectively, this work provides a conceptual framework for advancing precision medicine in GC.

The tumor microenvironment (TME) of gastric adenocarcinoma is exceptionally heterogeneous, and epithelial-mesenchymal transition (EMT) is a central mechanism promoting local invasion and metastatic spread. Even so, how EMT-programmed cells are spatially arranged within tumor tissue, how they interact with neighboring immune populations, and which molecular nodes might be exploited therapeutically remain incompletely defined.

We built a large-scale, multi-layered analytical pipeline that combined single-cell transcriptomics (approximately 250,000 cells drawn from two independent patient cohorts), Visium-based spatial transcriptomics processed through Bayesian cell2location deconvolution, niche-level SpaTopic modeling, deep-learning histology analysis (ResNet50 feature extraction paired with CellProfiler-derived morphometrics), and ensemble survival modeling spanning over one hundred algorithmic combinations. Gaussian mixture modeling was used to define EMT-high cell states, the Scissor framework was applied to link fibroblast subsets to patient mortality, and a multi-tier filtering scheme was used to nominate druggable candidate genes. The top candidate, PVR/CD155, was interrogated experimentally by RT-qPCR, Western blotting, immunohistochemistry, and siRNA knockdown in AGS cells. We further evaluated PVR druggability by molecular docking, a 100-nanosecond molecular dynamics trajectory, and MM/GBSA binding-energy estimation using PP-121 as a candidate ligand.

Sub-clustering identified seven fibroblast subclusters: Fib_APOD, Fib_COL4A1, Fib_SLPI, Fib_COL1A1, Fib_CCL4, Fib_STMN1, and Fib_S100B. The SLPI-high subset preferentially localized to peritoneal metastases. Phenotype-guided Scissor mapping nominated a survival-associated fibroblast program enriched within COL4A1-expressing fibroblast states. PVR/CD155 was prioritized as an EMT-linked candidate gene; single-cell expression profiling showed that PVR was most frequently detected in endothelial, epithelial and fibroblast compartments, with low detection in lymphoid and plasma cells. PVR/CD155 was significantly upregulated in gastric cancer cell lines and tumor tissues. PVR/CD155 knockdown in AGS cells decreased proliferation, migration and invasion, supporting a tumor cell-intrinsic functional role rather than establishing PVR as a stromal immune biomarker. Molecular docking and dynamics simulations identified PP-121 as a candidate PVR-binding ligand for future biochemical validation.

The proposed framework connects single-cell resolution with spatial and histological data, produces validated prognostic tools and nominates PVR/CD155 as a tumor cell-intrinsic EMT-associated target candidate for gastric cancer. Stromal or immune regulatory roles of PVR remain plausible but require direct compartment-specific and functional validation.

Only a subset of epithelial cells can initiate progressive lung adenocarcinoma (LUAD), yet the founder cell states that confer this competence remain poorly defined.

We established a barcoded Kras ^G12D, Trp53 loss mouse LUAD organoid model that couples 15-nucleotide lineage tracing with single-cell RNA sequencing (scRNA-seq) before and after syngeneic transplantation. Candidate markers for expansion states were further evaluated using wild-type lung organoid, spatial transcriptomics, and independent human scRNA-seq datasets.

Barcoded organoids generated LUAD-like tumors. Paired barcode recovery identified expanded, diminished and failed lineages and showed that expanded lineages were enriched for surfaceome genes associated with stemness. Among candidate surface markers, Plxna2 showed the strongest enrichment in baseline organoid cells that expanded after transplantation and marked cells with stronger stemness features. These cells underwent stage-specific reprogramming, with early EMT and inflammatory adaptation followed by late metabolic and MYC programs rebound within an immunosuppressive microenvironment. Wild-type lung organoid analysis showed that Plxna2 marks an alveolar remodeling state sharing expansion signature. Spatial transcriptomics placed Plxna2 ^high tumor epithelial cells in EMT-rich and stromal-interface niches. Human LUAD scRNA-seq cohorts further showed enrichment of PLXNA2 ^high malignant cells within expansion and stemness states.

These findings identify PLXNA2 as a candidate marker of expansion state and provide a lineage-based framework for discovering tumor-initiating programs in LUAD.

Objectives: Sorting nexin 9 (SNX9) participates in endocytic trafficking and has been connected to several malignancies, but its involvement in breast cancer (BC) remains incompletely resolved. This work was designed to examine whether SNX9 supports BC progression and investigate signaling and cytoskeletal processes associated with its activity. Methods: The clinical relevance of SNX9 was assessed using bioinformatics analysis of publicly available cancer databases. Lentiviral vectors were used to establish BC cell models with stable SNX9 overexpression or knockdown. Both cellular (proliferation and motility) and murine (tumor growth and metastatic colonization) experiments were implemented to functionally characterize the SNX9-mediated phenotypes. The underlying mechanisms were investigated via western blotting, immunofluorescence, co-immunoprecipitation, and pathway-focused analyses. Results: Across the analyzed datasets, greater SNX9 abundance was linked to worse overall survival outcomes in BC patients. Functionally, SNX9 upregulation conferred increased proliferative, migratory, and invasive capacities in vitro and contributed to both primary tumor enlargement and distant metastatic spread in vivo, whereas SNX9 depletion produced the reciprocal phenotypes. SNX9 silencing also increased the G2/M cell fraction and disrupted actin cytoskeletal organization mechanistically linked to reduced Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division cycle 42 homolog (Cdc42) activation and the subsequent impairment of lamellipodial and filopodial protrusion. Additionally, co-immunoprecipitation substantiated the physical coupling between SNX9 and the scaffold protein tyrosine kinase substrate with five SH3 domains (TKS5), which correlated with the invasive behavior of BC cells. Conclusion: Collectively, our findings establish SNX9 as a critical oncoprotein that drives BC progression by coordinating proliferative epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling and cytoskeletal dynamics through interactions with TKS5 and Rac1/Cdc42. Clinically, SNX9 qualifies as a promising prognostic classifier and a rational target for therapeutic intervention.

Background: Metastatic dissemination of triple-negative breast cancer (TNBC) to distant organs, such as the lungs and brain, poses a significant threat to patient survival. Nevertheless, the molecular basis driving TNBC metastasis remains largely elusive. In the present study, we elucidated the role and underlying mechanism of OTU deubiquitinase 7B (OTUD7B) in promoting TNBC metastasis. Methods: The Cancer Genome Atlas (TCGA)/K-M Plotter databases were used for determining the prognostic significance of OTUD7B in TNBC patients. Cell migration and lung colony-forming assays were performed to evaluate the metastatic potential of TNBC cells. A cycloheximide-chase assay was employed to examine the effect of OTUD7B on Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) Essential Modulator (NEMO) protein degradation in TNBC cells. Flow-cytometric analyses were performed to examine OTUD7B effects on TNBC necroptosis. Results: OTUD7B is significantly (p < 0.001) upregulated in TNBC and correlates with poor distant metastasis-free survival (log-rank p < 0.001, n = 424). Its knockdown suppresses, whereas overexpression enhances, the metastatic potential of TNBC cells in vitro and in vivo, dependent on its deubiquitinating activity. Mechanistically, OTUD7B regulates the ubiquitination of Caspase-8 and NEMO, thereby modulating NF-κB signaling through the Caspase-8-RIPK1-NEMO axis. OTUD7B depletion increases Caspase-8 activity by approximately three-fold, promotes NEMO degradation, suppresses NF-κB activation, and induces necroptosis. Conversely, OTUD7B overexpression exerts opposite effects. Pharmacological inhibition of NEMO or NF-κB attenuates OTUD7B-driven cell migration by 40-90%. Conclusions: The deubiquitinating activity of OTUD7B promotes TNBC metastasis by stabilizing the Caspase-8-RIPK1-NEMO axis, thereby activating the NF-κB signaling pathway. These results further suggest that targeting OTUD7B activity may be a promising therapeutic strategy for metastatic TNBC.

Objective: Renal cell carcinoma is a common malignancy of the urinary system. In this study, we analyzed a public clear cell renal cell carcinoma (ccRCC) dataset and identified Nephrosis 2, idiopathic, steroid-resistant (NPHS2) as a candidate gene to investigate whether epigenetic dysregulation of NPHS2 is associated with tumor microenvironment remodeling. Methods: Differential expression analysis was first performed on GSE68417 using GEO2R. In addition, clinical samples and cell-based assays were used to evaluate changes in NPHS2 expression and promoter methylation following 5'-Aza-CdR treatment. Subsequently, 786-O and A498 cells were obtained, and sunitinib-resistant 786-O/R and A498/R sublines were established. Lentiviral vectors with abnormal expression of NPHS2 were transfected into 786-O, A498, 786-O/R, and 498-R cells to detect changes in biological behaviors such as cell activity and epithelial-mesenchymal transition (EMT). Finally, a ccRCC tumor-bearing mouse model was constructed and intervened with lentiviral vectors with abnormal expression of NPHS2. Results: A total of 159 differentially expressed genes (DEGs) were identified in the GSE68417 dataset, and NPHS2 was included in all morphological changes related to cell epigenetic modifications. 5'-Aza-CdR markedly increased NPHS2 protein expression in 786-O cells (p < 0.05). Meanwhile, there was a high methylation phenomenon in the promoter region of the NPHS2 gene in ccRCC tissue (p < 0.05). In vitro, NPHS2 overexpression suppressed malignant cell behavior, attenuated EMT, and weakened immune evasion in ccRCC cells (p < 0.05). Finally, upregulating NPHS2 could inhibit the growth of ccRCC (p < 0.05) without causing significant changes in liver and kidney functions or malignant pathological damage in mice. Conclusion: These findings support an association between promoter hypermethylation and NPHS2 downregulation in ccRCC and suggest that NPHS2 loss may contribute to immune-evasive features and reduced sunitinib sensitivity. Further multicohort and mechanistic studies are warranted.

Breast cancer (BC) continues to be a major cause of cancer-related mortality among women, and early diagnosis remains critical for improving survival outcomes. Conventional tissue biopsy and imaging techniques are constrained by invasiveness and limited sensitivity in early-stage disease, whereas routine serum tumor markers lack sufficient specificity for reliable early detection. Circular RNAs (circRNAs) have increasingly been recognized as promising non-invasive biomarkers, owing to their remarkable stability and detectability in plasma. Here, we summarize the current landscape of plasma circRNAs as diagnostic, prognostic, and chemoresistance-related biomarkers in BC, emphasizing their clinical relevance in therapy selection, subtype stratification, treatment monitoring, and recurrence prediction. Aberrant circRNA expression in the plasma of BC patients has been associated with tumor size, stage, and molecular subtype, and functionally linked to cell survival, metastasis, and drug resistance. Importantly, circRNAs may complement conventional approaches including imaging and serum markers, and their integration with other circulating analytes could enhance diagnostic precision and support individualized therapeutic decisions. Our work consolidates recent advances in circRNA research across preoperative, postoperative, drug resistance, and recurrence settings, providing a framework for non-invasive diagnosis, clinical decision-making, and outcome prediction in BC management. This review aims to bridge tissue-based discoveries and plasma-based applications for the clinical translation of circRNAs.

Gastric cancer (GC) remains a leading cause of global cancer mortality, with progression and therapy resistance heavily influenced by the dynamic tumor microenvironment (TME). Despite advances in surgical techniques, chemotherapy, targeted therapy, and immunotherapy, overall survival for advanced disease remains poor, underscoring the need for a deeper understanding of resistance mechanisms. A hallmark of the TME is metabolic reprogramming, which sustains tumor growth and actively shapes an immunosuppressive landscape. This review aims to detail the coordinated metabolic adaptations of GC cells, cancer-associated fibroblasts (CAFs), and immune cells within the TME, focusing on nutrient competition, immunosuppressive metabolite accumulation, and dysregulated lipid metabolism. We analyze how glucose depletion, lactate accumulation, and amino acid deprivation establish a hostile metabolic niche that impairs cytotoxic T lymphocyte (CTL) function while paradoxically supporting regulatory T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). We examine four major immunosuppressive metabolic pathways, lactate, adenosine, tryptophan-kynurenine, and arginine and demonstrate their convergence on immune checkpoint upregulation, forming an integrated metabolic-immune checkpoint axis. These pathways establish a self-reinforcing immunosuppressive circuit that drives T cell exhaustion and limits immune checkpoint blockade efficacy. We highlight emerging therapeutic strategies targeting this crosstalk, including inhibitors of glycolysis, glutaminolysis, indoleamine 2,3-dioxygenase 1 (IDO1), and adenosine signaling, often combined with immunotherapy. The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types. Finally, we discuss challenges and future directions, emphasizing the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve clinical outcomes in GC.