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PubMed2025

Identification of a prognostic signature consisting of three macrophage-related genes for glioblastoma based on bulk and single-cell transcriptomes analyses.

BACKGROUND: Tumor-associated macrophages have been implicated in the progression and treatment resistance of glioblastoma (GBM). This study aimed to identify macrophage-related genes associated with prognosis and therapeutic response in GBM. MATERIALS AND METHODS: Bulk RNA-seq data from 533 patients with GBM were downloaded from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Bioinformatic tools were used to detect the co-expression gene modules associated with the infiltration of immune cells, identify a prognostic macrophage-related gene signature, and explore their association with sensitivity to chemotherapeutic drugs and immune checkpoint blockade. Single-cell RNA-seq data and multiplexed immunofluorescence were used to validate ISG20 expression (a member of the identified gene signature) in macrophages. RESULTS: We detected gene modules associated with macrophages and identified a signature consisting of three macrophage-related genes (ISG20, PARP12 and IFIT5) in the discovery set (TCGA-GBM, n = 159), and validated its prognostic value in the validation set (CGGA-GBM, n = 374). This gene signature demonstrated favorable accuracy in predicting prognosis and resistance of immuno- and chemo-therapy. The co-expression of ISG20 and PD-1 in macrophages was verified by single-cell RNA-seq data and multiplex immunofluorescence. CONCLUSIONS: This study presents a macrophage-related gene signature to predict prognosis and therapeutic response in GBM. ISG20, PARP12 and IFIT5 are interferon-stimulated genes, and further investigations may provide new insights into the interplay between macrophages and interferon signaling in GBM.

Humans↗

PubMed2026

Bacterial Outer Membrane Vesicles in Colorectal Cancer: Interdomain Communication Hubs in Pathogenesis and Immunotherapy.

The complex interaction between the intestinal microbiota and host mucosal immunity plays a defining role in colorectal cancer (CRC) development and therapeutic outcomes. Recently, bacterial outer membrane vesicles (OMVs)-nano-sized, lipid-bilayered extracellular particulates released by both commensal and pathogenic microorganisms-have emerged as critical long-range signaling vehicles within the gut. This review provides a comprehensive synthesis of the dual functionalities of OMVs in CRC pathogenesis and oncology. Mechanistically, pathogenic OMVs cross compromised mucosal barriers to drive horizontal gene transfer (HGT) of chimeric episomes, such as SPHINX DNAs and Bovine Meat and Milk Factors (BMMFs), thereby promoting genomic instability and neoplastic transformation. Conversely, there is a paradigm shift toward exploiting next-generation probiotic and engineered OMVs as highly tunable therapeutic platforms. By combining cutting-edge bioengineering strategies-such as biomimetic mineralization to neutralize local tissue acidity and chemotherapeutic packaging-these nanovectors effectively reprogram the immunosuppressive tumor microenvironment (TME). Specifically, optimized OMVs modulate macrophage polarization from an M2 to an M1 phenotype and stimulate CXCL10-mediated CD8+ T-cell infiltration, effectively turning immunologically "cold" tumors "hot." Finally, the great translational challenges regarding systemic endotoxicity, scalability, and target delivery, providing a strategic approach for the integration of OMV-based platforms into synergistic immune checkpoint inhibition regimens.

Colon cancer↗

PubMed2026

Genomic profiling as an option for ovarian cancer diagnostics.

INTRODUCTION: Ovarian cancer (OC) is a highly heterogeneous and lethal gynecological malignancy. Precision oncology has shifted the management paradigm to comprehensive molecular profiling. Genomic-based diagnostics are now a clinical necessity for accurate prognostic stratification and the rational selection of targeted therapeutics, such as PARP and immune checkpoint inhibitors. AREAS COVERED: This review evaluates current literature regarding the distinct genomic landscapes defining OC histotypes to underlined the role of molecular profiling in the diagnostic field of OC. We discuss the practical implementation, technical aspect, and clinical validity of the main molecular diagnostic platforms, focusing on tissue-based Comprehensive Genomic Profiling (CGP) and Homologous Recombination Deficiency (HRD). Furthermore, we explore emerging translational data on liquid biopsy (LBx) applications. EXPERT OPINION: While current tissue-based methodologies provide critical baseline data, the OC diagnostic paradigm must pivot from static testing to proactive and longitudinal tracking. Integrating advanced LBx approaches enables a real-time monitoring of dynamic parameters as minimal residual disease (MRD) and acquired resistance. Integrating these dynamic blood-based assays with multi-omic profiling and artificial intelligence (AI)-driven tools allows a full understanding of the complex tumor behavior.

Humans↗

PubMed2025

The assembly of cancer-specific ribosomes by the lncRNA LISRR suppresses melanoma anti-tumor immunity.

Gains of chromosome 12p11.21, encoding for the cancer-specific lncRNA LISRR, correlate with poor survival across different cancers. In melanoma, LISRR is upregulated in immunotherapy-resistant patients to contribute to the generation of drug-tolerant cells by activating an immune-suppressive translational program, affecting the synthesis of PD-L1 and of the glycocalyx. Accordingly, downregulation of LISRR initiates robust immune responses and resensitizes to immunotherapy ex vivo and in vivo. The use of glycans to evade immunity exhibits shared characteristics with the testis, where defects in the glycocalyx cause infertility. Mechanistically, we showed that LISRR affects the ribosome core composition and recruits deleted in azoospermia-associated protein 1 to polysomes to prime the integrated stress response. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based strategy to overcome resistance to immune checkpoint blockade.

RNA, Long Noncoding↗

PubMed2025

Structural investigation of an RNA device that regulates PD-1 expression in mammalian cells.

Synthetic RNA devices are engineered to control gene expression and offer great potential in both biotechnology and clinical applications. Here, we present multidisciplinary structural and biochemical data for a tetracycline (Tc)-responsive RNA device (D43) in both ligand-free and bound states, providing a structure-dynamical basis for signal transmission. Activation of self-cleavage is achieved via ligand-induced conformational and dynamical changes that stabilize the elongated bridging helix harboring the communication module, which drives proper coordination of the catalytic residues. We then show the utility of CRISPR-integrated D43 in EL4 lymphocytes to regulate programmed cell death protein 1 (PD-1), a key receptor of immune checkpoints. Treatment of these cells with Tc showed a dose-dependent reduction in PD-1 by immunostaining and a decrease in messenger RNA levels by quantitative PCR as compared with wild type. PD-1 expression was recoverable upon removal of Tc. These results provide mechanistic insight into RNA devices with potential for cancer immunotherapy or other applications.

Programmed Cell Death 1 Receptor↗

PubMed2025

HDAC inhibition unlocks tumor plasticity and enhances immunotherapy response in Myc-Driven Small Cell Lung Cancer.

Small Cell Lung Cancer (SCLC) is a highly aggressive malignancy, accounting for approximately 15% of all lung cancer cases. Characterized by low immunogenicity, SCLC may utilize epigenetic mechanisms to evade immune detection. Here, we demonstrate that entinostat, a class I histone deacetylase inhibitor (HDACi) upregulates immune-related genes in human SCLC cells. In vivo, we confirmed entinostat treatment increased expression of immunecheckpoint ligands and antigen presentation machinery in Myc-driven tumors in a Rb1/Trp53/MycT58A (RPM) SCLC mouse model, while shifting tumors from a neuroendocrine(NE)-high to a NE-low phenotype. Notably, combining entinostat with anti-PD-1 immunotherapy significantly enhances T-cell infiltration, suppresses tumor growth, and prolongs survival in RPM allograft models. These findings underscore the potential of entinostat to reprogram the immunological landscape and NE status of SCLC, enhance immune checkpoint blockade efficacy, and improve therapeutic outcomes.

anti-PD-1 therapy↗

PubMed2025

Engineering TME-activated CD47-specific CAR macrophage via Arg1 promoter for safe and effective solid tumor immunotherapy.

BACKGROUND: Chimeric antigen receptor macrophage (CAR-Mφ) therapy has promising therapeutic potential in solid tumors, yet challenges remain in target compatibility and systemic toxicity. METHODS: In this study, we screened the CD47-scFv sequence of CAR-Mφ as the extracellular structure. We then constructed a classical CD47 CAR-Mφ incorporated the costimulatory domain of the α1β1 integrin-mediated Fc-gamma receptor I (FcγRI) signaling component. Subsequently, we developed a tumor microenvironment (TME)-responsive CAR macrophage platform by the arginase 1 (Arg1) promoter to target CD47, a highly expressed but clinically challenging immune checkpoint in solid tumors. RESULTS: We found that anti-CD47-scFv-mediated macrophages can effectively kill tumor cells both in vivo and in vitro. Furthermore, by integrating an α1β1 integrin-mediated FcγRI signaling domain, CD47 CAR-Mφ exhibited superior antitumor activity in hCD47+4T1 and SGC-7901 cells in vitro, which demonstrated that the CD47 CAR-Mφ was effective against solid tumors. Subsequently, Arg1-mediated activated pArg1 CD47 CAR-Mφ exhibited strong cytotoxicity against target cancer cells. We further demonstrated TME-controllable CAR gene expression in situ and induced a significant regression of established tumors in vivo. Besides, TME-dependent activation of CD47 CAR Mφ reduced the cytotoxic killing effect on erythrocytes. CONCLUSIONS: Our findings confirmed that the TME-specific activation mechanism of pArg1 CD47 CAR-Mφ based on intrinsic Arg1 promoter reprogramming endowed CAR-Mφ to effectively mitigate erythrocyte toxicity while enabling safe multidose administration regimens. This Trojan horse-like CAR-Mφ system achieves tumor-specific activation while minimizing systemic toxicity, offering a novel strategy to expand CAR-Mφ applications for solid tumors.

Animals↗

PubMed2026

Overall survival of immunotherapy versus standard of care in chemorefractory microsatellite stable metastatic colorectal cancer: a propensity score matched analysis of 708 patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). However, selected patients with specific metastatic patterns may derive benefit. METHODS: Patients with chemorefractory pMMR/MSS mCRC treated with ICI-based regimens were retrospectively identified. A comparison cohort treated with trifluridine/tipiracil±bevacizumab, regorafenib, or fruquintinib as standard of care (SOC) was generated through 1:1 propensity score matching by age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), liver metastases (present/absent), and RAS/BRAF status. Overall survival (OS) was compared using Cox regression. RESULTS: A total of 354 patients treated with ICIs and 354 treated with SOC were matched. Median age was 55 years, 52% male, 32% ECOG PS 0, 30% right-sided, and 69% RAS mutated in both groups, while 61% and 60% had liver metastases, respectively. Median OS (mOS) was 10.8 months with ICIs and 9.0 months with SOC (HR 0.76, 95% CI 0.64 to 0.92, p=0.004). In patients without liver metastases, mOS was longer with ICIs than SOC (19.1 vs 13.2 months, HR 0.59, 95% CI 0.43 to 0.80, p<0.001), whereas outcomes were similar in patients with liver metastases (6.4 vs 6.5 months, p=0.303). In univariable analyses, age, sex, primary tumor site, and RAS/BRAF status were not associated with OS. Treatment with ICIs, absence of liver metastases, one prior line of therapy, less than three metastatic sites, and ECOG PS 0 were associated with the most favorable outcomes in univariable and multivariable models. CONCLUSIONS: In chemorefractory pMMR/MSS mCRC without liver metastases, ICI-based regimens yielded longer OS than SOC. Further investigation of ICIs in this patient population is warranted.

Humans↗

PubMed2026

Tumor microbial burden drives immune responses through regulation of Interferon signaling.

Tumor microbes are increasingly recognized for modulating tumor behavior and therapy responses. Intratumoral microbial burden (ITMB) analysis across cancers revealed regulation of immune pathways, and activated mast cells, mostly in colorectal (CRC) and gastric (STAD) cancers. High ITMB CRC leads to interferon regulation and is associated with improved outcomes in advanced disease. Single-cell sequencing revealed induction of interferon-related genes (IRGs) within microbes-containing human CRC. GI-luminal mismatch repair deficiency (MMRd) tumors had higher ITMB than proficient tumors (MMRp). In a rectal MMRd cohort with 100% remission after immune checkpoint blockade (ICB), tumor microbes and microbes-containing mast cells increased. In ICB-sensitive syngeneic murine MMRd tumor models, local tumor microbial depletion, impaired ICB efficacy while downregulating IFN signaling. Forced upregulation of IRGs in ADAR1-deficient cancer cells restored immunotherapy responses during microbial ablation. These data highlight dynamic interplay between ITMB, host defense, and immunogenicity which seems key to determine therapy responses.

Journal Article↗

PubMed2026

The clinical landscape of POLE-mutant colorectal cancer: a retrospective analysis of real-world outcome.

BACKGROUND: Pathogenic mutations in the POLE gene disrupt its proofreading function during DNA replication, causing an accumulation of erroneous nucleotide incorporations. This defect leads to a significantly elevated tumor mutation burden (TMB) and increased generation of tumor neoantigens. These molecular characteristics suggest a potential association between POLE-mutant tumors and distinct prognostic outcomes in colorectal cancer (CRC); however, clinical evidence supporting this correlation remains limited. METHODS: We retrospectively collected a cohort of CRC patients harboring pathogenic POLE mutations. Comparative analyses were performed between POLE-mutant and POLE wild-type CRCs regarding their clinical characteristics, prognostic outcomes, and genomic profiles. Additionally, we evaluated the response to immunotherapy in metastatic POLE-mutant CRC cases. RESULTS: Among 35,108 CRC patients, pathogenic POLE mutations were identified in 261 individuals, accounting for 0.74% of the cohort. The median age at diagnosis for POLE-mutant patients was 48 years, with a male predominance (74.4%) and a substantial proportion (50.4%) of tumors localized in the right-sided colon. All patients with pathogenic POLE mutations exhibited hypermutated phenotypes, characterized by a median TMB of 235.26 mutations per megabase (range: 71.20-719.00 mutations/Mb). In stage II CRC, POLE mutations were significantly associated with a reduced risk of recurrence (hazard ratio [HR] 0.344, 95% confidence interval [CI] 0.157-0.754, p = 0.008) when compared to POLE wild-type, microsatellite stable CRC patients. However, this association was not evident in stage III patients (HR 1.004, 95% CI 0.490-2.057, p = 0.992). Importantly, the incorporation of immune checkpoint inhibitors in first-line treatment regimens significantly improved progression-free survival (HR = 0.247, 95% CI 0.117-0.552, p = 0.0002) and overall survival (HR = 0.317, 95% CI 0.103-1.143, p = 0.0832) in metastatic CRC patients with pathogenic POLE mutations. CONCLUSIONS: Pathogenic POLE-mutant CRC constitutes a relatively rare, yet clinically important, subtype. These cancers exhibit distinct clinicopathological and genomic features. Our results indicate that mutations in the POLE gene may serve as a valuable prognostic marker and a potential indicator of benefit to immunotherapy in CRC, offering promising avenues for personalized treatment strategies.

Humans↗

PubMed2026

Age-related genomic characterization and therapeutic targets in Chinese breast cancer: insights from prospective targeted sequencing and clinical data analysis.

BACKGROUND: In China, breast cancer occurs at a much younger age and has a higher recurrence and mortality rate. However, with changes in lifestyle, there has been a trend towards an older age of breast cancer incidence in Chinese women. There is a paucity of large-scale next-generation sequencing cohorts for the analysis of genomic characterization in these populations and the identification of potential therapeutic targets. METHODS: To address this gap, we performed prospective targeted sequencing of tumor and blood samples from Chinese patients and collected detailed clinical information. We then categorized patients into two groups based on age (< 40 years, n = 637; ≥ 40 years, n = 3442) and proceeded to provide comprehensive descriptions of somatic and germline mutations in both groups. RESULTS: The somatic mutation analysis revealed that PIK3CA, FOXA1, and TBX3 mutations were more prevalent in elderly patients. By leveraging the aforementioned mutational characteristics, we employed our institution's FUTURE-SUPER clinical trial, an umbrella study targeting metastatic breast cancer, to confirm the potential benefits of PI3K-AKT-mTOR pathway inhibitors among elderly patients with breast cancer. Furthermore, TP53 and ERBB2 were more likely to be co-mutated in young women. Patients with TP53 and ERBB2 co-mutation tend to have a poorer prognosis, but through investigation of the SPARK cohort, patients carrying the TP53 and ERBB2 co-mutation are more likely to benefit from immune checkpoint inhibitor combination with tyrosine kinase inhibitor therapy. In our study, we observed a higher frequency of mutations in the DNA homology-dependent recombination pathway in young patients with breast cancer, which was associated with an elevated Ki67 index. Additionally, we confirmed a significant prevalence of germline breast cancer susceptibility gene 1 (gBRCA1) mutations in young patients, whereas germline checkpoint kinase 2 (gCHEK2) mutations are more common in elderly patients. CONCLUSIONS: Our study, which makes use of the largest Chinese breast cancer sequencing cohort, sought to characterize the age-related genomic profile of breast cancer patients and identify novel therapeutic opportunities for individuals with breast cancer.

Adult↗

PubMed2024

Integrated bioinformatics analysis and experimental validation reveal the relationship between ALOX5AP and the prognosis and immune microenvironment in glioma.

BACKGROUND: Treatment of gliomas, the most prevalent primary malignant neoplasm of the central nervous system, is challenging. Arachidonate 5-lipoxygenase activating protein (ALOX5AP) is crucial for converting arachidonic acid into leukotrienes and is associated with poor prognosis in multiple cancers. Nevertheless, its relationship with the prognosis and the immune microenvironment of gliomas remains incompletely understood. METHODS: The differential expression of ALOX5AP was evaluated based on public Databases. Kaplan-Meier, multivariate Cox proportional hazards regression analysis, time-dependent receiver operating characteristic, and nomogram were used to estimate the prognostic value of ALOX5AP. The relationship between ALOX5AP and immune infiltration was calculated using ESTIMATE and CIBERSORT algorithms. Relationships between ALOX5AP and human leukocyte antigen molecules, immune checkpoints, tumor mutation burden, TIDE score, and immunophenoscore were calculated to evaluate glioma immunotherapy response. Single gene GSEA and co-expression network-based GO and KEGG enrichment analysis were performed to explore the potential function of ALOX5AP. ALOX5AP expression was verified using multiplex immunofluorescence staining and its prognostic effects were confirmed using a glioma tissue microarray. RESULT: ALOX5AP was highly expressed in gliomas, and the expression level was related to World Health Organization (WHO) grade, age, sex, IDH mutation status, 1p19q co-deletion status, MGMTp methylation status, and poor prognosis. Single-cell RNA sequencing showed that ALOX5AP was expressed in macrophages, monocytes, and T cells but not in tumor cells. ALOX5AP expression positively correlated with M2 macrophage infiltration and poor immunotherapy response. Immunofluorescence staining demonstrated that ALOX5AP was upregulated in WHO higher-grade gliomas, localizing to M2 macrophages. Glioma tissue microarray confirmed the adverse effect of ALOX5AP in the prognosis of glioma. CONCLUSION: ALOX5AP is highly expressed in M2 macrophages and may act as a potential biomarker for predicting prognosis and immunotherapy response in patients with glioma.

Humans↗

PubMed2025

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

Humans↗

PubMed2026

Integrating molecular subtypes, genomics and functional dependencies to identify context-specific therapeutic vulnerabilities in small cell lung cancer.

Small cell lung cancer is one of the most aggressive malignancies, characterized by rapid tumor growth, early metastatic spread and extremely poor survival. Although most patients initially respond to platinum-based chemotherapy, relapse is almost inevitable and treatment options at recurrence remain limited. The recent introduction of immune checkpoint inhibitors has provided only modest clinical benefit, largely due to the fact that these tumors are immunologically cold. These limitations highlight the urgent need to better understand the molecular features of small cell lung cancer in order to identify more effective therapeutic strategies. In this review, we summarize current knowledge of the molecular landscape of small cell lung cancer, with particular emphasis on transcriptome-based classifications that have identified four major molecular subtypes defined by distinct transcriptional regulators and gene expression programs. We discuss how these classifications have improved the biological understanding of the disease and stimulated efforts to develop subtype-specific therapeutic strategies. At the same time, we highlight important limitations of this framework, including the remarkable transcriptional plasticity of tumor cells, which allows dynamic transitions between subtypes and may contribute to therapeutic resistance. To address these challenges, we examine additional molecular features that may represent more stable vulnerabilities, including recurrent genomic alterations, such as the widespread loss of tumor suppressor genes or oncogene amplifications through extrachromosomal DNA. We also discuss emerging approaches aimed at identifying novel context-specific cancer dependencies, including genome-scale functional screens in vitro and in vivo and genetic restraint analyses. Finally, we consider the growing potential of liquid biopsy strategies, which exploit the high level of circulating tumor DNA in patients with this disease to detect clinically relevant genomic alterations and monitor tumor evolution. Overall, this review highlights both the opportunities and challenges associated with molecular stratification in small cell lung cancer. The integration of transcriptional classifications with genomic and functional approaches may help identify more robust therapeutic vulnerabilities and guide the development of more effective treatments for this highly aggressive disease.

Cancer vulnerabilities↗

PubMed2025

What is on the Horizon Beyond Platinum and Immunotherapy for Patients With Advanced Non-Small Cell Lung Cancer Without Actionable Genomic Aberrations?

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. While targeted therapy and immunotherapy have transformed first-line management, most patients without actionable genomic alterations (AGAs) will experience disease progression within the first year of their initial treatment. Here, we review pivotal trials, emerging strategies, challenges, and unmet needs for patients with advanced NSCLC without AGAs. Docetaxel with or without ramucirumab is the standard second-line therapy for patients who have progressed after platinum-based chemotherapy and immunotherapy. Targeted therapy is only suitable for patients with specific AGAs. Understanding the hallmarks of cancer immune evasion is key to developing new strategies beyond chemoimmunotherapy. The combination of antiangiogenic agents with immune checkpoint inhibitors (ICIs) has shown mixed results after progression on platinum and ICI. Bispecific antibodies, particularly ivonescimab, have shown encouraging early efficacy in this space. Artificial intelligence-driven pathomics and radiomics tools may help to refine treatment selection in the future. Chimeric antigen receptor T-cell therapy remains investigational. Patients with advanced NSCLC without AGAs who progressed after chemoimmunotherapy have limited treatment options. Novel therapies such as specific antibodies have shown promising results. Future progress will depend on the development of predictive biomarkers and understanding the mechanisms of resistance to ICIs to guide drug development.

Humans↗

PubMed2024

A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer.

BACKGROUND: Although there is evidence that ribonucleotide reductase subunit M2 (RRM2) is associated with numerous cancers, pan-cancer analysis has seldom been conducted. This study aimed to explore the potential carcinogenesis of RRM2 in pan-cancer using datasets from The Cancer Genome Atlas (TCGA). METHODS: Data from the UCSC Xena database were analyzed to investigate the differential expression of RRM2 across multiple cancer types. Clinical data such as age, race, sex, tumor stage, and status were acquired to analyze the influence of RRM2 on the clinical characteristics of the patients. The role of RRM2 in the onset and progression of multiple cancers has been examined in terms of genetic changes at the molecular level, including tumor mutational burden (TMB), microsatellite instability (MSI), biological pathway changes, and the immune microenvironment. RESULTS: RRM2 was highly expressed in most cancers, and there was an obvious correlation between RRM2 expression and patient prognosis. RRM2 expression is associated with the infiltration of diverse immune and endothelial cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). Moreover, the cell cycle is involved in the functional mechanisms of RRM2. CONCLUSIONS: Our pan-cancer study provides a comprehensive understanding of the carcinogenesis of RRM2 in various tumors.

Humans↗

PubMed2026

A cuproptosis-related lncRNAs-based risk signature for predicting prognosis and immune status in glioma.

BACKGROUND: Glioma is one of the most prevalent primary malignant brain tumors, characterized by poor prognosis and limited treatment options. Recent studies have identified cuproptosis, a novel copper-dependent form of regulated cell death, as a critical mechanism involved in tumor progression. However, the role of cuproptosis-related long non-coding RNAs (lncRNAs) in glioma remains not fully clarified. This study aimed to develop and validate a prognostic model based on cuproptosis-associated lncRNAs to predict patient outcomes and guide individualizing therapeutic strategies. METHODS: Transcriptomic profiles and clinical data were obtained from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Cuproptosis -related prognostic lncRNAs were filtered via univariate and multivariate Cox and Least absolute shrinkage and selection operator (LASSO) regression analyses, which were selected to establish a prognostic model for glioma. Samples were divided into high- and low-risk groups, and the predictive performance of the prognostic model was evaluated based on receiver operating characteristic (ROC) curves, Kaplan-Meier (K-M) survival curves, and a nomogram. In addition, immune cell infiltration, tumor mutational burden (TMB), immunophenoscore (IPS), Tumor Immune Dysfunction and Exclusion (TIDE) and drug sensitivity were analyzed. Expression levels of selected lncRNAs and proteins were validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS: An 11-lncRNA signature associated with cuproptosis was established, and the risk score derived from this model was identified as an independent prognostic factor for glioma. The model exhibited excellent predictive ability, with area under the curve (AUC) values of 0.880, 0.913, and 0.866 for 1-, 3-, and 5-year survival, respectively. Higher TMB, immune checkpoint expression, and IPS were observed in the high-risk group and no significant difference was observed in TIDE between risk groups. Drug sensitivity analysis identified TPCA-1, KIN001-135, and ispinesib mesylate as potential therapeutic agents. Expression validation in glioma cells further supported the biological relevance of the selected lncRNAs. CONCLUSIONS: This cuproptosis-related lncRNA-based signature demonstrates strong prognostic value and may serve as a promising tool for glioma risk stratification and personalized treatment selection.

Glioma↗

PubMed2026

Development of m6A-related prognostic models for survival in lung squamous cell carcinoma with different PD-L1 expression levels.

BACKGROUND: Programmed death-ligand 1 (PD-L1) is widely used in the clinical context of immune checkpoint inhibitor therapy, but its relationship with N6-methyladenosine (m6A) RNA methylation in lung squamous cell carcinoma (LUSC) has not been well defined. This study aimed to investigate the association between PD-L1 messenger RNA (mRNA) expression and m6A regulator expression patterns and to develop exploratory m6A-based prognostic models in LUSC. METHODS: Transcriptome data from 502 patients with LUSC were obtained from The Cancer Genome Atlas (TCGA). Patients were divided into PD-L1 high-expression (PHE) and PD-L1 low-expression (PLE) groups according to the median PD-L1 mRNA level. Differential expression and correlation analyses were performed for 30 m6A regulators. Transcriptome sequencing data from surgical specimens from 28 Asian patients with LUSC were used for expression-pattern comparison. Principal component analysis (PCA), univariate Cox regression, and least absolute shrinkage and selection operator (LASSO)-Cox regression were used to construct prognostic models in the TCGA cohort. RESULTS: In the TCGA cohort, the main differentially expressed m6A regulators between the two PD-L1 groups were YTHDF2 (P<0.001), IGF2BP3 (P<0.001), and YTHDC2 (P<0.001). In the Asian cohort, ALKBH5 (P=0.008) and ZC3H13 (P=0.03) showed significant differences. LASSO-Cox models were constructed for the overall LUSC cohort and for the PHE and PLE subgroups. The overall model included METTL3, HNRNPC, and CBLL1, with a 5-year time-dependent area under the receiver operating characteristic curve (AUC) of 0.579. The 5-year AUCs were 0.742 in the PHE subgroup and 0.652 in the PLE subgroup. The risk score remained independently associated with prognosis in multivariate Cox analysis. CONCLUSIONS: In LUSC, PD-L1 mRNA status was associated with distinct m6A regulator expression profiles. In the TCGA cohort, the PHE subgroup showed higher expression of CBLL1, G3BP1, IGF2BP3, FMR1, and YTHDC2, but lower expression of VIRMA, YTHDF2, and PRRC2A compared with the PLE subgroup. In the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CICAMS) cohort, ALKBH5 and ZC3H13 were more highly expressed in the PHE subgroup. Moreover, m6A-based risk models were associated with survival outcomes, with significant prognostic separation in the overall TCGA cohort and the PHE subgroup, whereas the PLE subgroup showed a weaker survival separation.

Lung squamous cell carcinoma (LUSC)↗