BACKGROUND:Collision tumors, characterized by the coexistence of distinct histological tumor types in adjacent regions, are rare in neuro-oncology. While meningioma-glioma collisions are documented, sequential occurrence without a history of radiotherapy is exceptionally uncommon, posing diagnostic challenges and implying elusive pathogenic mechanisms. OBSERVATIONS:A 31-year-old female underwent resection of a left frontal WHO grade I-II astrocytoma (2000) without radiotherapy. Eighteen years later, she developed an atypical meningioma (WHO grade II) at the same site, confirmed histologically and immunohistochemically (epithelial membrane antigen positive/glial fibrillary acidic protein negative). Seven years thereafter, a high-grade glioma (WHO grade 3) with oligodendroglioma-like features and a 1p/19q co-deletion emerged. Molecular profiling revealed divergent alterations: the meningioma exhibited NCOR2/CHD4/ELP1 mutations and 22q deletion, while the glioma harbored IDH2 p.R172H, TERT promoter, NOTCH1, and CIC mutations, supporting metachronous primary tumors despite shared 1p/19q loss. LESSONS:This case underscores that metachronous collision tumors can arise without radiotherapy, necessitating histopathological and molecular integration for accurate diagnosis. Long-term vigilance is critical for detecting sequential tumors, and shared microenvironments or genetic pathways may underlie tumorigenesis. Comprehensive profiling aids in clarifying pathogenesis and guiding management. https://thejns.org/doi/10.3171/CASE26149.

Glioblastoma (GBM) recurrence features acquired treatment resistance and tumor microenvironment (TME) remodeling, yet conserved drivers remain elusive due to inter-cohort heterogeneity. To identify core mechanisms, we integrated multiple large-scale single-cell/single-nucleus datasets, high-resolution 6000-plex CosMx spatial transcriptomics, and an 890-sample bulk cohort, complemented by in vitro functional assays.Cross-cohort screening identified 11 recurrence-associated subpopulations and prioritized PLOD2 as a prominent hub gene associated with relapse. Clinically, elevated PLOD2 expression was associated with increased mortality risk (HR = 1.25, 95% CI: 1.15–1.35). Spatially, PLOD2 transcript enrichment within hypoxic peri-necrotic niches correlated with tumor stemness and CD8 + T-cell exhaustion signatures.Mechanistically, PLOD2 knockdown reduced LAMA4 secretion; spatial profiling confirmed their single-cell in situ co-localization within perivascular and myeloid-enriched niches. Pan-cancer analyses indicated that hypoxia may remodel tumor-stromal signaling via PLOD2 upregulation, potentially reinforcing cancer-associated fibroblast interactions.Collectively, within the limitations of our preclinical and computational models, these findings suggest that PLOD2 modulates the recurrent TME via a potential PLOD2 / LAMA4 axis, correlating with microvascular proliferation and mesenchymal niche evolution. Targeting this pathway represents a potential translational strategy to disrupt microenvironmental barriers and alleviate therapy resistance.

How diverse cancer lineages navigate the draconian central nervous system environment—whether constrained by ancestral ontogeny or driven by convergent adaptation—remains a fundamental biological paradox. To decode this, we integrated extensive in-house and public resources to construct the largest single-cell atlas of primary and secondary brain malignancies (>550,000 cells). We demonstrate that malignant cells balance strict lineage imprinting with shared brain-adaptive programs, powerfully converging upon a dominant pan-cancer mesenchymal (MES)-like state alongside a SYT1+ pioneer subpopulation exploiting neuronal mimicry. Concurrently, the microenvironment undergoes lineage-constrained divergence. The myeloid landscape shifts from a resident-dominated architecture in gliomas to extensive blood-borne infiltration in metastases. Lymphoid responses parallel this, crowning laryngocarcinoma as an ultra-hot subtype and revealing that massive T cell influx in highly infiltrated niches is paradoxically driven into terminal exhaustion, contrasting with severe immune exclusion in cold tumors. Furthermore, stromal-vascular adaptation couples pro-angiogenic tip-endothelial activation with a dynamic opposition between structural extracellular matrix (ECM) deposition and focal proteolytic degradation. Anchored by the pan-cancer MES adaptation, we leveraged subcellular spatial transcriptomics to redefine the microenvironment around four MES-like architectural niches, mapping an evolutionary trajectory from perivascular entry to immunosuppressive stromal remodeling. Finally, projecting these architectures onto independent clinical cohort establishes the MES-S2 proliferative niche as the primary driver of severe clinical deterioration across both transcriptomic and proteomic dimensions.

Therapeutic resistance in IDH-wildtype glioblastoma (GBM) is driven by an intricate interplay between cellular plasticity and protective microenvironmental niches. By constructing the GRIT-Atlas—a massive transcriptomic compendium encompassing nearly one million high-quality single cells across 17 cohorts—and cross-analyzing it with 48 independent Visium spatial transcriptomics sections, we discover a recurrent "Spatial Resistance Triad" comprising mesenchymal-like (MES-like) malignant cells, myeloid-derived suppressor cells (MDSCs), and collagen-secreting cancer-associated fibroblasts (CAFs). This large-scale spatial integration reveals that the triad physically fortifies microvascular proliferation (MVP) and pseudopalisading necrosis (PAN) niches. To substantiate these findings at true single-cell resolution, we deploy high-plex spatial molecular imaging (CosMx SMI) to map over 400,000 single cells across a clinical validation cohort. This high-resolution architecture firmly validates the triad's geography and, critically, provides structural gradient evidence unmasking a spatiotemporal continuum wherein PAN emerges as a direct functional consequence of MVP advancement and subsequent vascular collapse. Mechanistically, stromal CAF-derived COL6A1 engages CD44 receptors on MES-like cells to accelerate a potent neural stemness cascade within these protective domains. Utilizing a blood-brain barrier (BBB)-penetrant multi-library compound screen, we identify Lacidipine as a multi-modal stromal disruptor that successfully silences CAF activation and halts matrix secretion. Incorporating Lacidipine into the standard chemo-immunotherapy backbone (TMZ + anti-CSF1R) completely dismantles the protective desmoplastic matrix niche, forcing a profound collapse of intracranial tumor burden and dramatically extending overall survival in orthotopic models. Collectively, our study leverages unprecedented single-cell and spatial scale to provide a definitive blueprint of GBM therapeutic evasion, establishing matrix-targeted intervention as a mandatory prerequisite for successful glioblastoma eradication.

Background and aimsDifferentiating neoplastic proliferation from inflammatory fibrosis in peripheral nerve hypertrophy is critical. We report a patient with a neurofibromatosis type 1 (NF1) deletion exhibiting extreme diffuse nerve enlargement and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like autoimmunity. This study aims to elucidate the underlying endoneurial fibrotic mechanism, specifically focusing on the signaling networks between Schwann cells (SCs) and fibroblasts.MethodsSingle-cell RNA sequencing was performed on a biopsied sural nerve to profile the cellular and transcriptomic landscape. Intercellular interactome and pseudotime trajectory analyses were utilized to map molecular evolution and signaling crosstalk.ResultsTranscriptomic profiling revealed that SCs—which normally maintain myelin around axons and support peripheral nerve function—were pathologically entrapped in a dedifferentiated state. Serving as a genetic primer, the NF1 deletion lowered the threshold for SC reprogramming, a vulnerability that was subsequently unleashed by a severe autoimmune infiltrate consisting of macrophages and T cells. These reprogrammed SCs abandoned myelin-maintaining genes, such as MPZ, to acquire a pro-fibrotic phenotype. Through a coordinated platelet-derived growth factor (PDGF) dual-axis network involving PDGFC-PDGFRA and PDGFD-PDGFRB, the entrapped SCs exclusively secreted PDGF ligands that potently activated endoneurial fibroblasts and vascular mural cells. This persistent paracrine signaling orchestrated excessive extracellular matrix deposition, driving a massive expansion of the endoneurial interstitium and the formation of classic “onion bulbs”.InterpretationOur data suggest that the macroscopic hypertrophic changes observed in this specific clinical presentation may reflect an aberrant, immune-triggered fibrotic cascade—where autoimmune leukocyte infiltration continuously drives stromal overgrowth—complementing rather than entirely precluding the classical RAS/MAPK-driven neoplastic SC hyperproliferation. Furthermore, within the limitations of this pilot evaluation, characterizing this potential SC-fibroblast crosstalk indicates that the PDGF signaling pathway may warrant further investigation as a candidate translational therapeutic target for refractory hypertrophic neuropathies.

Ischemic heart disease, as one of the major causes of morbidity worldwide, there is no effective therapy for preventing myocardial ischemia–reperfusion injury (MIRI). Baicalin, a flavonoid glycoside extracted from the Scutellaria baicalensis Georgi, yet its effects in MIRI remain unclear. In the study, pretreatment with Baicalin (100 mg/kg, i.p.) markedly alleviated I/R-induced cardiac dysfunction, as shown by reduced serum lactate dehydrogenase (LDH), creatine kinase (CK), and myocardial infarction. Baicalin also improved cardiomyocyte survival by increasing Bcl-2 and decreasing Bax and caspase-3/9 levels. In addition, Baicalin suppressed oxidative stress by reducing malondialdehyde (MDA) while elevating glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, Baicalin inhibited the STING, NLRP3, cleaved caspase-1, IL-18, and IL-1β expression in vivo and in vitro. Crucially, amidobenzimidazole (ABZI), a STING agonist, reversed the cardioprotective effects of Baicalin. Collectively, these findings demonstrated that Baicalin exerted cardioprotective effects by attenuating apoptosis and oxidative stress through suppression of STING/NLRP3 activation.

Glioblastoma (GBM) is a deadly brain cancer with a poor prognosis. Here, we developed DepMeta, a specialized pipeline designed to identify essential genes with stable prognostic value across various cancer types. Applying DepMeta in conjunction with Weighted Gene Co-expression Network Analysis (WGCNA) to GBM resulted in the establishment of the DepMetaPath signature, a set of 12 genes critical for GBM progression. Multi-omics analysis subsequently revealed significant alterations within the DepMetaPath signature in GBM, which were associated with antigen presentation and processing pathway activity, as evidenced by immune infiltration profiling. Furthermore, pan-cancer analysis extended the signature's significance, linking it to immunotherapy response prediction and drug sensitivity, thereby highlighting its therapeutic target potential. Among the signature, minichromosome maintenance complex component 3 (MCM3) was identified as a novel regulator in GBM. Single-cell analysis demonstrated that MCM3 was selectively upregulated in oligodendrocyte precursor cell (OPC)-like malignant cells, a finding corroborated by clinical sample data showing that MCM3 expression was elevated in higher-grade gliomas. In vitro experiments further confirmed that MCM3 plays an essential role in glioma proliferation. Proteome sequencing and subsequent Western blot analysis identified the Wnt pathway as a key downstream target suppressed by MCM3 knockdown. Finally, the adaptability of DepMeta was demonstrated through its successful application in identifying analogous targets in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). This research proposes DepMeta as a promising tool for identifying essential pan-cancer genes with stable prognostic value, suggesting a foundation for future development of targeted therapies and personalized treatment strategies.

Background:Protease serine 1 (PRSS1) has been implicated in various pathological processes. This study utilized bioinformatics analyses to evaluate PRSS1 expression in gastric cancer (GC) and explore its role in tumor invasion and metastasis. Methods:GC-related differentially expressed genes were identified using Gene Expression Omnibus (GEO) datasets. A combination of bioinformatics analysis and literature review identified PRSS1 as a hub gene, and its putative functions were inferred by functional enrichment analyses. PRSS1 expression levels were verified in GC tissues, cell lines, and serum samples from patients with metastatic lesions using Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assays (ELISAs), and their association with clinicopathological characteristics was analyzed. A stable PRSS1-knockdown cell line was generated to evaluate the effects of the gene on cell migration and invasion, using wound-healing and Transwell migration/invasion assays, as well as in a mouse model of peritoneal metastasis. Altered expression of epithelial-mesenchymal transition (EMT)-related and MAPK/ERK pathway proteins was examined using Western blotting and immunofluorescence. Results:PRSS1 expression was markedly upregulated in HGC-27 and MKN-45 GC cells relative to that in normal gastric mucosal cells. Serum levels of PRSS1 were significantly elevated in patients with GC, particularly those with advanced-stage disease, and were strongly correlated with unfavorable clinicopathology: vascular invasion, Tumor Node Metastasis (TNM) staging, and lymph node metastasis. Functional enrichment analyses indicated involvement of PRSS1 in multiple biological processes associated with tumor progression. Silencing of PRSS1 suppressed migration and invasion of GC cells in vitro and in vivo peritoneal dissemination. Mechanistically, PRSS1 knockdown reduced the expression of MMP2 and MMP9, increased expression of E-cadherin, reduced that of vimentin, and also modulated MAPK/ERK signaling activity. Conclusions:These findings indicate that PRSS1 is overexpressed in GC and may contribute to invasion and metastasis, possibly through induction of EMT and activation of MAPK/ERK signaling, highlighting its potential as a therapeutic target.

The efficacy of photodynamic therapy is greatly compromised by the low drug delivery efficiency and the hypoxic tumor microenvironment (TME). Here, we report the rational design of near-infrared (NIR)-enzyme dual-driven asymmetric NMs for enhanced tumor-targeted photodynamic therapy (PDT). These NMs comprise a biodegradable poly(lactic-co-glycolic acid) (PLGA) core loaded with indocyanine green (ICG), partially coated with a gold nanoshell, and functionalized with glucose oxidase (GOx), catalase (CAT), polyethylene glycol (PEG), and cancer cell membranes. The Janus-like asymmetric structure enables directional motion, facilitating efficient navigation through the complex tumor microenvironment. The GOx/CAT enzymatic cascade consumes tumor glucose and endogenous H2O2 to generate oxygen, simultaneously propelling the NMs and alleviating tumor hypoxia. Under Near Infrared (NIR) irradiation, the gold nanoshell produces localized heating, further driving propulsion and accelerating ICG release. This design, combining enzymatic and photothermal driving forces, overcomes biological barriers, ensures precise tumor targeting, and greatly improves the accumulation and penetration of NMs in tumor tissue. Additionally, PEG enhances biocompatibility and prolongs circulation time, while the homologous cancer cell membrane coating promotes active tumor targeting and cellular uptake. This dual-driven system jointly addresses key limitations of conventional PDT and demonstrating superior therapeutic efficacy against tumors.

Therapeutic resistance in IDH-wildtype glioblastoma (GBM) is driven by profound cellular plasticity and a structured immunosuppressive tumor microenvironment (TME). Here, we present the Glioblastoma Resistance Insights from Treatment Atlas (GRIT-Atlas), the most comprehensive single-cell resource to date, encompassing nearly one million cells from 296 samples across primary and recurrent cohorts, including those treated with immune checkpoint blockade (ICB) and anti-angiogenic combination therapy. We identify a convergent evolutionary trajectory where therapeutic pressure selects for a specific malignant state, cNMF7 (MES-like), characterized by a synergy of hypoxia, stemness, and inflammatory signaling. Integrating spatial transcriptomics across 48 patient sections, we define a "Spatial Resistance Triad", a core functional unit composed of cNMF7 cells, differentiation-arrested E-MDSCs, and Type VI Collagen-secreting myCAFs. This triad specifically colonizes the hypoxic microvascular proliferation (MVP) and pseudopalisading necrosis (PAN) niches. Mechanistically, we show that myCAFs act as stromal architects, constructing a fibrotic scaffold through a Collagen/Fibronectin-CD44 signaling axis. This spatial infrastructure not only physically excludes cytotoxic T cells but also provides essential cues to sustain malignant plasticity and myeloid-mediated immunosuppression. Our findings across seven independent cohorts and pan-cancer validation underscore the clinical significance of this axis in driving immunotherapy failure. Collectively, the GRIT-Atlas provides a blueprint for dismantling the "immunosuppressive sanctuaries" of GBM to overcome therapeutic resistance. ### Competing Interest Statement The authors have declared no competing interest. the Innovative Technology Class A grant of the First Affiliated Hospital of Soochow University, 0499980301001 National Natural Science Foundation of China, 82571477 National Natural Science Foundation of China, 82201445

Diffuse glioma, the most prevalent and malignant intracranial tumor, presents a formidable challenge due to its immunosuppressive microenvironment, which complicates conventional therapeutic approaches. This study conducted a comprehensive prognostic meta-analysis involving 2,968 patients with diffuse glioma and established a comprehensive machine learning framework with nested resampling of 18 machine learning algorithms, and developed the Immune Glioma Survival Signature (IGLoS). This signature, comprising CCL19, ICOSLG, IL11, PTGES, TNFAIP3, and TRAF3IP3, has been demonstrated to predict survival outcomes across a range of cancers and to correlate with tumor progression at the level of multi-omics. It is noteworthy that the IGLoS score enables precise patient stratification for personalized cancer treatments and elucidates pivotal resistance mechanisms to immunotherapy. Furthermore, siRNA screening has underscored the critical role of TRAF3IP3 in modulating PDL1 expression and immune pathways, with implications on the ERK pathway and NFATC2 involvement. Through single-cell analysis of published and in-house datasets, TRAF3IP3 exhibited selective enrichment in NPC-like and MES-like tumor cells, and showed a dual functionality in mediating T-Cell Exhaustion. Targeting TRAF3IP3 emerges as a promising avenue to combat immunotherapy resistance, particularly in glioma, thus paving the way for precision medicine.

Background:Proteinase 3 (PRTN3) has been linked to the progression of different cancer types. In this study, the expression and cell biological function of PRTN3 were investigated in gastric cancer (GC) to assess its role in GC progression. Methods:The PRTN3 levels in 20 pairs of GC tissues were detected via quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting, while immunohistochemical staining was used to assess the PRTN3 levels in 47 GC tissue samples. The effects of stable lentivirus-mediated PRTN3 knockdown on GC cell proliferative, cell cycle, and apoptotic activity were evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays, nude mouse models, and flow cytometry. Results:Elevated levels of PRTN3 messenger RNA (mRNA) and protein were noted in GC tissues, mostly in the cytosol. High PRTN3 levels were positively correlated with GC tumor N staging. in vitro knockdown of PRTN3 suppressed cell cycle progression, promoted apoptotic induction, and decreased the concentrations of cell cycle-associated proteins (cyclin D1, CDK4, and CDK6) and apoptosis-related Bcl-2 while inducing the upregulation of Bax. Downregulation of PRTN3 inhibited GC cell growth both in vitro and in mouse models. Conclusions:Our study found that high expression of PRTN3 is associated with GC tumor N staging. And PRTN3 silencing could regulate GC progression by inhibiting the cell cycle and promoting apoptosis in GC cells, which could be a potential target for GC diagnosis and treatment.

Liver cancer ranks among the most prevalent and lethal malignancies globally, with most patients presenting at an advanced stage at initial diagnosis. Although multiple treatment modalities exist—including surgical resection, interventional therapy, targeted therapy, and immunotherapy—outcomes for patients with advanced liver cancer often remain suboptimal. To broaden the scope of cancer treatment, drug repurposing has emerged as a promising strategy. In this study, we systematically evaluated the potential of the third-generation EGFR-TKI Almonertinib to inhibit liver cancer progression in vivo and in vitro. First, functional assays confirmed that Almonertinib effectively suppressed the proliferation, migration, and invasive capabilities of HepG2 and MHCC-97H cells. Subsequently, by investigating the precise type of cell death induced by Almonertinib, we discovered that it activates autophagy-dependent cell death in HepG2 and MHCC-97H cells via the PI3K/Akt1/mTOR pathway. Additionally, Almonertinib induces ferroptosis in liver cancer cells by suppressing the expression of the antioxidant pathway SLC7A11/GSH/GPX4. Interestingly, we demonstrated that Almonertinib-activated autophagy directly participates in ferroptosis activation by promoting Fe2+ release upstream and influencing lipid peroxidation, elucidating the occurrence of autophagy-dependent ferroptosis. In summary, these findings indicate that Almonertinib suppresses liver cancer progression by inducing autophagy-dependent ferroptosis in HepG2 and MHCC-97H cells, potentially providing insights for positioning Almonertinib as a novel therapeutic candidate for future liver cancer treatment.

[This corrects the article DOI: 10.1016/j.omtn.2017.12.010.].

BACKGROUND:This study aimed to use artificial intelligence (AI) to integrate various radiological and clinical pathological data to identify effective predictors of contralateral central lymph node metastasis (CCLNM) in patients with papillary thyroid carcinoma (PTC) and to establish a clinically applicable model to guide the extent of surgery. METHODS:This prospective cohort study included 603 patients with PTC from three centers. Clinical, pathological, and ultrasonographic data were collected and utilized to develop a machine learning (ML) model for predicting CCLNM. Model development at the internal center utilized logistic regression along with other ML algorithms. Diagnostic efficacy was compared among these methods, leading to the adoption of the final model (random forest). This model was subject to AI interpretation and externally validated at other centers. RESULTS:CCLNM was associated with multiple pathological factors. The Delphian lymph node metastasis ratio, ipsilateral central lymph node metastasis number, and presence of ipsilateral central lymph node metastasis were independent risk factors for CCLNM. Following feature selection, a Delphian lymph node-CCLNM (D-CCLNM) model was established using the Random forest algorithm based on five attributes. The D-CCLNM model demonstrated the highest area under the curve (AUC; 0.9273) in the training cohort and exhibited high predictive accuracy, with AUCs of 0.8907 and 0.9247 in the external and validation cohorts, respectively. CONCLUSIONS:The authors developed a new, effective method that uses ML to predict CCLNM in patients with PTC. This approach integrates data from Delphian lymph nodes and clinical characteristics, offering a foundation for guiding surgical decisions, and is conveniently applicable in clinical settings.

PurposeCardiac inflammation is a basic pathological process of diabetic cardiomyopathy (DCM). Inflammatory response is closely related to pyroptosis, which is a recently identified programmed cell death type. Curcumin (CUR) is a polyphenol extracted from turmeric and has been reported to be crucial in alleviating pyroptosis in DCM. However, the exact mechanism by which CUR improves pyroptosis remains unclear. Therefore, we aimed to investigate the effect of CUR on pyroptosis in DCM and explore the potential mechanisms.MethodsThe molecular docking (MOD) analysis was performed using AutoDock Tools to evaluate the binding patterns and affinities between CUR and tripartite motif containing 21 (TRIM21), as well as between TRIM21 and gasdermin D (GSDMD). Subsequently, DCM models were established in Sprague-Dawley (SD) rats (in vivo) by administering streptozotocin (STZ) and feeding them a high-fat diet. In addition, H9C2 cells were cultured in a high glucose and palmitate environment to construct in vitro models of DCM. Rats or cells were treated by CUR directly. Subsequently, body weight (BW), heart weight (HW)/BW ratio, fasting blood glucose level, and lipid metabolism were measured. Pathological changes were analyzed using hematoxylin and eosin (H&E) and Masson staining. Small interfering RNA (si-RNA) was used to knockdown TRIM21 expression, and the pyroptosis protein expression and cellular activity were evaluated in different groups.ResultsMOD analysis revealed that CUR had a strong binding affinity with TRIM21, and TRIM21 showed a robust interaction with GSDMD. STZ-induced diabetic SD rats showed metabolic abnormalities, structural changes in the ventricle, and the expression of TRIM21 and pyroptosis markers, including nod-like receptor protein-3 (NLRP3), Caspase-1, and GSDMD, were upregulated. CUR reduced cardiac remodeling and improved cardiac function in vivo. CUR inhibited pyroptosis by regulating TRIM21 through in vivo and in vitro studies.ConclusionCUR improves DCM by regulating TRIM21 expression to inhibit pyroptosis. Furthermore, this study provides novel approaches and experimental evidence for the research and treatment of DCM and presents new insights into its potential mechanisms.

Background:This study explores the factors related to the expression levels of carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA) and their association with poor postoperative prognosis in patients with esophageal squamous cell carcinoma (ESCC) who underwent minimally invasive resection. Methods:Eighty patients with ESCC who underwent minimally invasive surgery were divided into two groups: 40 with poor prognosis (recurrence) and 40 with good prognosis (no recurrence). Additionally, 80 healthy subjects were selected as a control group. Serum CA199 and CEA levels were measured before surgery and 3 and 6 months postoperatively. Results:The serum CA199 and CEA levels in the experimental group were significantly higher than in the control group (P < 0.05). Patients with poor prognoses within the experimental group had higher CA199 and CEA levels than those with good prognoses (P < 0.05). In the poor prognosis group, CA199 and CEA levels at 6 months were significantly higher than at 3 months post-surgery (P < 0.05). Conclusion:Poor prognosis in ESCC patients after minimally invasive resection may be influenced by factors such as lymph node metastasis, lesion length, and tumor location. Elevated CA199 and CEA levels postoperatively can serve as predictors of poor prognosis in patients with ESCC.

OBJECTIVE Gliomas are the most common intracranial tumors with the highest degree of malignancy. Disturbed cholesterol metabolism is one of the key features of many malignant tumors, including gliomas. This study aimed to investigate the significance of cholesterol metabolism-related genes in prognostic prediction and in guiding individualized treatment of patients with gliomas. METHODS Transcriptional data and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Intraoperative glioma samples retained in our unit and the corresponding clinicopathological information were also collected with the patients' knowledge. Firstly, cholesterol metabolism-related gene signatures (CMRGS) were identified and constructed based on difference analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and univariate/multivariate COX analysis. Then, the role of CMRGS in predicting the prognosis of gliomas and distinguishing immune landscapes was evaluated by using nomograms, survival analysis, enrichment analysis, and immune-infiltration analysis. Finally, the drug sensitivity of gliomas in different risk groups was evaluated using the oncoPredict algorithm, and potentially sensitive chemotherapeutic and molecular-targeted drugs were identified. RESULTS The prognostic CMRGS contained seven genes: APOE, SCD, CXCL16, FABP5, S100A11, TNFRSF12A, and ELOVL2. Patients were divided into high- and low-risk groups based on the median cholesterol metabolic index (CMI). There were significant differences in clinicopathological characteristics and overall survival between groups. COX analysis suggested that CMRGS was an independent risk factor for glioma prognosis and had a better predictive performance than several classical indicators. In addition, GSEA, immune infiltration analysis showed that CMRGS could differentiate the immune landscapes of patients in groups. The reliability of CMRGS was validated in the CGGA cohort and our Gusu cohort. Finally, 14 drugs sensitive to high-risk patients and 16 drugs sensitive to low-risk patients were identified. CONCLUSION The CMRGS reliably predicts glioma prognosis in multiple cohorts and may be useful in guiding individualized treatment.

Cancer-associated fibroblasts (CAFs) are a critical component of the glioma microenvi-ronment and play essential roles in tumor progression and resistance to immunotherapy. To comprehensively characterize CAF heterogeneity and their interactions with immune cells, we conducted an integrative multi-omics analysis incorporating single-cell and bulk RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence. This approach identified nine distinct CAF subtypes with phenotypic and functional diversity, including tumor-like CAFs (tCAFs), myofibroblast-like CAFs (myCAFs), vascular CAFs (vCAFs), metabolic CAFs (meCAFs), proliferative CAFs (pCAFs), antigen-presenting CAFs (apCAFs), interferon-responsive CAFs (infCAFs), inflammatory CAFs (iCAFs), and a group of CAFs with unknown identity. Several subtypes were significantly associated with poor clinical outcomes. Notably, apCAFs engaged in extensive crosstalk with M2-polarized macrophages via TGF-β signaling pathways. Spatial transcriptomic pro-filing and immunofluorescence imaging revealed the co-localization of apCAFs and M2 macrophages at the tumor periphery, indicating the formation of an immunosuppressive niche. Moreover, AQP4 was identified as a specific marker of apCAFs, and its expression was significantly correlated with poor prognosis and resistance to immunotherapy. These findings offer a comprehensive atlas of CAF heterogeneity in glioma and highlight the therapeutic promise of targeting apCAF–M2 macrophage interactions or AQP4 to over-come immune resistance and improve clinical outcomes.