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PubMed2026

Spatial Omics in High-Grade Gliomas: Mapping Immune-Tumor Niches for Precision Therapy.

High-grade gliomas (HGGs), particularly glioblastoma (GBM), remain among the most lethal human cancers despite decades of molecular profiling and therapeutic innovation. A primary reason for treatment failure is that HGG biology is spatial: malignant cell states, immune suppression, metabolic stress, and therapeutic resistance are organized into distinct anatomical and functional niches. Spatial omics technologies now enable high-dimensional mapping of gene expression, protein signaling, immune architecture, and metabolic activity within intact tumor tissue. These approaches reveal how proneural and mesenchymal transcriptional states coexist yet localize to distinct regions, alongside hypoxic, invasive, and stem-enriched niches. Spatial analyses show that key clinical determinants, including O6-methylguanine-DNA methyltransferase (MGMT)-associated temozolomide resistance, radiotherapy tolerance in hypoxic regions, and immunotherapy failure driven by myeloid-dominated immune exclusion, are influenced not only by molecular programs but also by cellular location. Beyond biological insight, spatial omics is reshaping clinical paradigms by enabling region-specific patient stratification, early assessment of treatment response, and identification of therapy-resistant reservoirs that seed recurrence. Prior bulk and single-cell studies defined HGG cell states and pathways but often treated resistance as tumor-wide. This review presents a spatially explicit framework that synthesizes spatial transcriptomic and immune-profiling studies to identify tumor-immune niches and spatial bottlenecks that drive therapeutic failure and recurrence.

Humans↗

PubMed2026

A novel lactylation-related gene signature deciphers the immunosuppressive microenvironment and stratifies precision therapy in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality, largely due to the heterogeneity of the tumor microenvironment (TME) and the limited efficacy of immunotherapy in microsatellite stable (MSS) tumors. Histone lactylation, a post-translational modification derived from the Warburg effect, serves as a critical bridge linking metabolic reprogramming to gene regulation and immune evasion; however, its specific prognostic value and clinical implications in CRC remain to be fully elucidated. METHODS: In this study, we systematically analyzed transcriptome profiling data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts, supplemented by single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) protein-level validation. By integrating univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox regression, we constructed a novel lactylation-related gene (LRG) risk signature. We extensively evaluated the association between this risk signature and patient prognosis, immune infiltration patterns, somatic mutations, and therapeutic sensitivity. RESULTS: A robust 9-gene prognostic signature (DHRS7, SPR, MBD2, RBM17, CSRP2, S100A4, TMSB4X, TKT, COPS4) was identified and corroborated at the protein level. Patients with high risk scores exhibited significantly worse overall survival (OS) across the training and two independent validation cohorts. Immunogenomic and scRNA-seq analyses revealed that high-risk tumors were characterized by an immunosuppressive and stromal-dense microenvironment-with stromal cells exhibiting the highest lactylation risk scores-enriched with regulatory T cells (Tregs), and frequently harbored PIK3CA mutations. Differential expression analysis indicated that this immune exclusion is structurally maintained by enriched extracellular matrix (ECM) organization and TGF-β signaling. Conversely, low-risk tumors displayed an inflamed phenotype with active antitumor immunity. Pharmacogenomic prediction identified distinct therapeutic stratifications: low-risk patients exhibited significant sensitivity to standard chemotherapeutics (fluorouracil, oxaliplatin) and EGFR/HER2 inhibitors (e.g., lapatinib, erlotinib). In contrast, high-risk patients showed specific vulnerabilities to novel targeted agents, including PI3K pathway inhibitors (TG-100-115, XL765), microenvironment-modulating agents (sildenafil, GANT-61), and epigenetic inhibitors (UNC0638). CONCLUSION: We established a novel lactylation-related risk signature that effectively stratifies CRC patients by prognosis and TME characteristics. By elucidating the crosstalk between metabolic dysregulation, stromal barriers, and immune exclusion, this study provides potential biomarkers and stratified therapeutic strategies-ranging from standard chemotherapy to targeted metabolic and stromal interventions-to optimize precision medicine for CRC patients.

Colorectal cancer↗

PubMed2026

Endobronchial Ultrasound-Guided Biopsy-Derived Lung Cancer Models: A Platform for Precision Therapy.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration is used for clinical diagnosis and staging in patients with lung cancer. Nevertheless, establishing patient-derived preclinical models using needle biopsy samples remains challenging. This study describes the establishment and utility of patient-derived organoid (PDO) from endobronchial ultrasound-guided (EBUS) specimens and EBUS patient-derived xenograft (PDX). METHODS: A total of 175 EBUS specimens were used to establish PDO and PDX. "Stable establishment" organoids with passage numbers of 10 or greater were used for genomic, transcriptome, and pathologic assessment. Drug sensitivity of EBUS organoids and PDX tumors were compared with those of the matched patient. Drug screening was performed using stably established organoid models. RESULTS: We successfully established a total of 20 EBUS organoids: six EBUS-PDOs and 14 EBUS-xenograft derived organoids. These stable cancer organoid models were validated for cancer cell enrichment and pathologic assessment. Pathologic findings, exome, and transcriptome analysis found a high correlation between EBUS organoids and parental samples. EBUS organoids and PDX indicated consistent drug response patterns with their corresponding patients. A drug screening conducted on an EBUS organoid led to the discovery of potent activity of trametinib to a rare MAP2K1 K57N mutation. CONCLUSIONS: EBUS-PDO and -xenograft‒derived organoids are good options to generate stable organoids in patients with advanced stage lung cancer. The models were consistent with the genetic and pathologic features of patient tumors, and the patient's responses to treatment, supporting their utility for novel therapeutic research.

Humans↗

PubMed2026

A Multi-omics Regulated Cell Death Framework Defines Immune Phenotypes and Guides Precision Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is molecularly and immunologically heterogeneous, contributing to variable treatment response. Because regulated cell death (RCD) intersects with tumor metabolism, immune regulation, and therapeutic susceptibility, we built an RCD-centered framework for CRC stratification. Multi-cohort transcriptomic data were used to infer RCD subtypes with non-negative matrix factorization (NMF) and non-negative least squares (NNLS). Genomic, bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic datasets were integrated to characterize subtype-associated biology. Machine-learning models were developed for immunotherapy response and survival-risk estimation. Candidate compounds were screened by GDSC2-based drug-sensitivity modeling and molecular docking, and FSTL3 was functionally assessed in vitro. The framework separated CRC samples into two RCD-related phenotypes resembling immune-hot and immune-cold states. RCD1 showed immune activation and higher mutational burden, whereas RCD2 showed immune-suppressed features, intratumoral heterogeneity, and aggressive biology. RCD-associated signatures showed potential for predicting immunotherapy response and survival risk. Dasatinib was prioritized for immune-cold, high-risk tumors, with preliminary evidence supporting its activity in CRC cells, while functional assays suggested a role for FSTL3 in growth, invasion, epithelial-mesenchymal transition, and apoptosis regulation. These findings suggest that RCD-based multi-omics analysis may refine CRC stratification and help generate therapeutic hypotheses.

Colorectal cancer↗

PubMed2026

Advances in Precision Editing Therapies for Alpha-1 Antitrypsin Deficiency.

Genome and RNA editing modalities have revolutionized precision gene therapy, offering a safer alternative to traditional gene replacement approaches. Alpha-1 antitrypsin deficiency (AATD) is a compelling model for precision medicine because the disease mechanism is well defined-mutations in a single gene are responsible for both liver and lung pathology. In this review, we summarize the current preclinical and clinical efforts for AATD, with an emphasis on genome and RNA editing strategies.

Humans↗

PubMed2026

Advancing precision tacrolimus therapy: a systems genetics dissection in BXD platform.

BACKGROUND: Tacrolimus is a core immunosuppressant in organ transplantation, but its narrow therapeutic window and significant pharmacokinetic variability hinder precision dosing. Although CYP3A5-guided strategies have established clinical relevance for tacrolimus initial dose adjustment, they do not fully account for the marked interindividual variability in tacrolimus exposure, highlighting the need for complementary models to decode more complex genetic regulation. This study aimed to identify candidate genetic modulators of tacrolimus metabolism and develop an integrated predictive framework for individualized therapy. METHODS: Using 46 BXD recombinant inbred mouse strains, we characterized transcriptomics and machine learning, and validated key genes. We then constructed a clinical model using data from 168 renal transplant recipients. RESULTS: We identified 19 genomic loci associated with tacrolimus pharmacokinetic traits and supported DBP/CYP2A6 as candidate modulators associated with tacrolimus disposition. The clinical prediction model, incorporating these genes and clinical variables, achieved robust AUROC. CONCLUSIONS: These findings support a polygenic contribution to tacrolimus metabolism and provide an experimental and computational framework for identifying candidate modulators relevant to individualized dosing. The BXD mouse platform offers a systems-genetics approach for mechanistic discovery that may inform future translational studies on tacrolimus precision dosing.

Animals↗

PubMed2025

Tunable, proteolytic dosage control of CRISPR-Cas systems enables precise gene therapy for dosage sensitive disorders.

The ability to modulate gene expression through modular and universal genetic tools like CRISPR-Cas has greatly advanced gene therapy for therapeutics and basic science. Yet, the inherent stochasticity of delivery methods cause variation in target gene expression at the single-cell level, limiting their applicability in systems that require more precise expression. Thus, we implement a modular incoherent feedforward loop based on proteolytic cleavage of Cas to reduce gene expression variability against the variability of vector delivery. We target a genome-integrated marker and demonstrate dosage control of gene activation and repression, post-delivery tuning, and RNA-based compatibility of the system. To illustrate therapeutic relevance, we target the gene RAI1, the haploinsufficiency and triplosensitivity of which cause two autism-related syndromes. We demonstrate dosage-controlled gene activation for both human and mouse Rai1 via viral delivery to patient-derived cell lines and mouse cortical neurons. Overall, we established a robust dosage control circuit for uniform gene expression, beneficial for basic and translational research.

Journal Article↗

PubMed2026

Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.

Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.

Humans↗

PubMed2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Humans↗

PubMed2024

LRP4 mutations promote tumor progression and resistance to anti-PD-1 therapy in recurrent hepatocellular carcinoma.

BACKGROUND AND AIMS: HCC recurrence is a major factor limiting long-term survival and the cause of most deaths in patients with HCC. However, molecular characterization and potential therapeutic targets of recurrent HCC remain mostly unknown. APPROACH AND RESULTS: We performed whole-exome sequencing in 63 matched primary and recurrent HCC tumors and combined the data with whole-genome sequencing results in 43 paired samples from our previous study. Sanger sequencing was used to identify all low-density lipoprotein receptor-related protein 4 ( LRP4 ) coding exons in 203 additional patients with recurrent HCC. We identified LRP4 somatic mutations in 7.8% (24/309) of recurrent tumors and only 0.97% (3/309) of primary tumors ( p <0.001). Prognosis after the second liver resection was poorer in patients with an LRP4 mutation. Biofunctional investigations demonstrated that inactivating LRP4 mutations promoted tumor progression and immunosuppression. Mechanistically, mutated LRP4 reduced intratumoral conventional type 1 dendritic cell and CD8 + T cell infiltration by repressing C-C motif chemokine ligand 4 expression and secretion through activation of β-catenin signaling, resulting in resistance to anti-programmed cell death protein-1 therapy. Patients with recurrent HCC carrying an LRP4 mutation did not benefit from anti-programmed cell death protein-1 treatment after their second resection surgery. A β-catenin inhibitor-reversed LRP4-induced resistance to anti-programmed cell death protein-1 therapy in humanized tumor-bearing mice. CONCLUSIONS: Our results identified novel LRP4 mutations important in recurrent HCC. Inactivating LRP4 mutations were associated with resistance to anti-programmed cell death protein-1 therapy and could be useful biomarkers for precision therapy in patients with recurrent HCC.

Humans↗

PubMed2026

Synergistic HMGN1 and VP64 Fusions Potentiate High-Precision and PAM-Flexible Base Editing.

RNA-guided CRISPR-derived base editors (BEs) have revolutionized genome editing by enabling targeted base substitutions. However, their application is frequently constrained by the stringent requirement for PAM sequences and low editing precision (bystander editing). Here, we present a robust strategy to overcome these limitations by coupling SpRY, a near-PAM-less Cas9 variant, with truncated CDA1 cytidine deaminases. While this combination enables precise editing of virtually any cytosine in the genome, it initially exhibited suboptimal efficiency. To address this, we systematically screened a diverse panel of candidate DNA-binding proteins and identified that the synergistic fusion of HMGN1 and VP64 substantially enhances editing activity without compromising precision. Importantly, this enhanced editing efficiency was achieved without markedly increasing off-target effects. Our new BEs demonstrated robust performance not only in yeast but also in rice, suggesting broad applicability in gene therapy, precision breeding, and fundamental research.

Gene Editing↗

PubMed2025

Phosphoproteomics delineates hepatocellular carcinoma subtypes and pinpoints therapeutic targets.

BACKGROUND AND AIMS: Only a minority of patients could benefit from systemic therapy owing to the high heterogeneity of HCC. Therefore, a deeper understanding of the pathogenesis of HCC is essential for precision therapy. Genomic and proteomic studies of HCC have enhanced our understanding of HCC. However, the phosphoproteomic characterization of HCC remains poorly understood. APPROACH AND RESULTS: We conducted an in-depth analysis of a clinical cohort of HCC using high-coverage phosphoproteomic. Effective therapeutic targets were validated using liver cancer cell lines and HCC patient-derived xenograft mouse models that correspond to the phosphoproteomic subtypes of HCC. Phosphoproteomic analysis classified HCC into 3 subtypes, A, B, and C, with increasing malignancy and correlation with clinical features, including patient prognosis, tumor staging, serum alpha-fetoprotein levels, tumor thrombus, and tumor size. Phosphoproteomic subtyping deeply reflected the biological characteristics and clinical features of patients with HCC. The profiles of HCC-dysregulated kinase activities inferred from the different phosphoproteomic subtypes consistently identify increased kinase activity related to cell proliferation. Subtype-C HCC patients showed the most significant dysregulation, indicating a potential therapeutic target. The corresponding drug, bosutinib, demonstrated efficacy in inhibiting the growth of subtype C tumors in liver cancer cell lines and HCC patient-derived xenograft mouse models representative of the phosphoproteomic HCC subtypes. CONCLUSIONS: Our study provides a comprehensive exploration of the phosphoproteomic landscape of HCC, establishing new subtypes that match clinical features and identifying potential therapeutic targets for the most malignant C subtype.

Carcinoma, Hepatocellular↗

PubMed2026

MET Exon 14 Skipping Mutation in NSCLC: From Genomic Discovery to Biomarker-Guided Therapeutic Innovation.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the MET exon 14 skipping mutation is a key oncogenic driver, which promotes tumor progression and provides a new direction for precision therapy. METHODS: A systematic search of English-language literature and clinical trial data related to the MET exon 14 skipping mutation from 2020-2025 was performed to summarize the role of the mutation and therapeutic advances. RESULTS: DNA-based next-generation sequencing (NGS), RNA-based NGS, and RT-qPCR were employed as the main detection methods. Preclinical models confirmed that mutations promote tumor progression by activating the RAS/MAPK pathway. Clinical trials have reported objective remission rates (ORR) of 46-68% for first-line treatment with MET inhibitors in NSCLC patients harboring MET exon 14 skipping mutations. DISCUSSION: MET exon 14 skipping mutation as a therapeutic target for NSCLC has made significant progress, and MET inhibitors are more advantageous than chemotherapy and immunotherapy, and have been recommended by national and international guidelines as a first-line treatment option. Additionally, NGS technology has the potential to dynamically monitor tumor evolution and drugresistant mutations, thereby helping to realize precision medicine. CONCLUSION: The MET exon 14 skipping mutation is an important target for the precision treatment of NSCLC, and MET-TKIs have remarkable efficacy but a prominent problem with drug resistance. The construction of a precision medicine system encompassing diagnosis, treatment, and drug resistance management through multi-omics research, technological innovation, and international collaboration is a key direction for improving prognosis.

Humans↗

PubMed2026

Duchenne muscular dystrophy: from gene to gene-ius therapies.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional dystrophin, leading to progressive muscle degeneration, loss of ambulation, respiratory failure, cardiomyopathy, and premature mortality. Despite advances in multidisciplinary supportive care, DMD remains an incurable disease associated with substantial physical, psychosocial, and economic burdens. The monogenic nature of DMD and its well-defined molecular pathogenesis have made it a prime target for the development of precision therapies aimed at restoring dystrophin expression or modifying disease progression. This review provides an overview of the genetic and molecular mechanisms underlying DMD, summarizes its clinical manifestations and natural history, and discusses current standards of care. It further examines recent advances in disease-modifying therapeutic strategies, including exon-skipping antisense oligonucleotides, nonsense mutation readthrough agents, adeno-associated virus (AAV)-mediated micro-dystrophin gene replacement, and emerging genome-editing technologies such as CRISPR/Cas9. The review also highlights the limitations of existing treatments, including mutation specificity, variable efficacy, immune-related challenges, and uncertainties regarding long-term durability and safety. Finally, it considers future directions in therapeutic development, emphasizing the need for combination approaches, improved delivery systems, and next-generation gene-editing platforms to achieve more effective and lasting clinical outcomes. Collectively, these advances represent a paradigm shift in DMD management and offer renewed hope for improving survival and quality of life for affected individuals.

Humans↗

PubMed2026

Longitudinal analysis of genomic and immune differences between primary and metastatic nasopharyngeal carcinoma for precision oncology.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) is a common malignancy with a high incidence in Southern China and Southeast Asia. Distant metastasis remains a major cause of poor prognosis. This study aims to explore the genomic and immune microenvironmental changes in primary and metastatic NPC through longitudinal analysis, to provide insights for guiding precision treatment strategies. METHODS: We analyzed tumor samples from 11 male NPC patients with distant metastasis. Paired primary and metastatic samples underwent targeted whole-exome sequencing (551 genes) and RNA sequencing (289 genes). Multiplex immunohistochemistry was performed to assess immune cell composition and immune response markers. Genomic alterations and immune features were compared between primary and metastatic tumors, and their associations with clinical outcomes were evaluated. RESULTS: Metastatic tumors exhibited distinct chromosomal changes, including frequent 1q gain, while 6p gain showed a trend toward prolonged survival. Primary tumors showed stronger immune suppression characterized by increased B-cell and Treg infiltration and elevated CTLA4 and IDO1 expression, whereas metastatic lesions displayed more active immune responses. Liver metastases presented a distinct immune landscape with lower CD8+ T-cell density compared to non-liver metastases. In locoregionally advanced NPC, high expression of oncogenic genes such as EGFR and MYC correlated with shorter disease-free survival, while elevated PANCK expression and enhanced cytotoxicity were linked to better outcomes. These results delineate the molecular and immune evolution of NPC and provide a foundation for developing precision therapeutic strategies. CONCLUSION: This study identifies key molecular and immune features associated with NPC survival. Primary tumors show an immunosuppressive phenotype, suggesting potential benefits from combining CTLA4 or IDO1 inhibitors with PD-1 blockade. Liver metastases exhibit distinct immune features, supporting the need for site-specific precision therapies. These findings contribute to personalized management strategies in NPC, guiding treatment based on molecular and immune profiles.

distant metastasis↗

PubMed2025

Advances in tumor subclone formation and mechanisms of growth and invasion.

Tumor subclones refer to distinct cell populations within the same tumor that possess different genetic characteristics. They play a crucial role in understanding tumor heterogeneity, evolution, and therapeutic resistance. The formation of tumor subclones is driven by several key mechanisms, including the inherent genetic instability of tumor cells, which facilitates the accumulation of novel mutations; selective pressures from the tumor microenvironment and therapeutic interventions, which promote the expansion of certain subclones; and epigenetic modifications, such as DNA methylation and histone modifications, which alter gene expression patterns. Major methodologies for studying tumor subclones include single-cell sequencing, liquid biopsy, and spatial transcriptomics, which provide insights into clonal architecture and dynamic evolution. Beyond their direct involvement in tumor growth and invasion, subclones significantly contribute to tumor heterogeneity, immune evasion, and treatment resistance. Thus, an in-depth investigation of tumor subclones not only aids in guiding personalized precision therapy, overcoming drug resistance, and identifying novel therapeutic targets, but also enhances our ability to predict recurrence and metastasis risks while elucidating the mechanisms underlying tumor heterogeneity. The integration of artificial intelligence, big data analytics, and multi-omics technologies is expected to further advance research in tumor subclones, paving the way for novel strategies in cancer diagnosis and treatment. This review aims to provide a comprehensive overview of tumor subclone formation mechanisms, evolutionary models, analytical methods, and clinical implications, offering insights into precision oncology and future translational research.

Humans↗

PubMed2026

A single-cell atlas of multiple myeloma defines malignant archetypes and proliferative states.

Multiple myeloma (MM) is a plasma-cell malignancy with extensive genomic and transcriptional heterogeneity, limiting disease classification and precision therapy. Here we generated a clinically annotated, population-scale, single-cell atlas of MM from 341 individuals spanning the disease and treatment continuum. We identified five recurrent malignant transcriptional archetypes and an orthogonal proliferative program associated with genomic features, therapeutic resistance and clinical outcomes. Validation in the independent CoMMpass cohort demonstrated robustness, prognostic relevance and portability across platforms. We developed a single-cell, target-discovery pipeline prioritizing malignant enrichment, cell-type specificity and tissue restriction, identifying FCRL2 as a plasma-restricted or B cell-lineage-restricted surface target expressed by malignant plasma cells. FCRL2-targeted chimeric antigen receptor T cells demonstrated antigen-specific activity in vitro and survival benefit in vivo. Together, these data provide a clinically actionable blueprint for patient stratification and precision target nomination in plasma-cell malignancies.

Multiple Myeloma↗

PubMed2026

Metabolic-cell-death gene trio predicts survival and cuproptosis sensitivity in colorectal cancer.

BACKGROUND: Metabolic cell death (MCD) modulates colorectal cancer (CRC) progression, yet its prognostic value remains unexplored. We aimed to build an MCD-centred gene signature for outcome prediction and precision therapy. METHODS: Transcriptomes of 1,174 CRC patients were integrated. Weighted gene co-expression network analysis, differential expressions and least absolute shrinkage and selection operator (LASSO) + random survival forest were successively applied to derive a three-gene (CDKN2A/MPC1/AHCY) risk model. Functional, immune-infiltration, drug-sensitivity and genomic analyses were performed, followed by validation in fresh clinical specimens and cell lines. RESULTS: Integrative metabolic-death transcriptomics identified CDKN2A, MPC1 and AHCY as the hub drivers of CRC. Their three-gene signature robustly stratified patients into high- and low-risk subsets [3-year area under the curve (AUC) 0.83-0.85, P<0.001]. High-risk tumors were enriched for extracellular matrix (ECM)-receptor-interaction pathways, displayed abundant myeloid-derived suppressor cell (MDSC) infiltration and were more vulnerable to AZD8186, AZ960 and JAK inhibitors. Guided by these in-silico findings, we functionally confirmed that CDKN2A silencing markedly repressed proliferation, invasion and migration of SW480/HCT116 cells and potentiated cuproptosis via up-regulation of lipoylated DLAT/DLST and CTR1. CONCLUSIONS: We report the first MCD-derived prognostic platform for CRC that simultaneously predicts survival and therapeutic response. Targeting CDKN2A-enhanced cuproptosis represents a promising metabolic-precision strategy for high-risk patients.

Colorectal cancer (CRC)↗