Yaohui Chen

Despite significant advancements in microsurgical techniques in recent years, the treatment and prognosis of craniopharyngiomas remain unsatisfactory. As a central nervous system tumor located adjacent to important brain structures such as the hypothalamus-pituitary axis and accompanied by a highly inflammatory microenvironment, the tumor heterogeneity and tumor microenvironment characteristics of papillary craniopharyngiomas (PCPs) remain unclear. In this study, we integrated multimodal single-cell and spatial profiling from PCP tissue and peripheral blood mononuclear cells (PBMCs) to elucidate the tumor heterogeneity and microenvironment characteristics of PCP. Our single-cell and spatial analyses defined four specific tumor cell states in PCP, representing specific transcriptional regulatory programs and spatial heterogeneity characteristics during tumor progression. By constructing a spatial niche composed of tumor, immune, and stromal cells, we analyzed the cellular and spatial ecosystem of PCP at multiple levels to further assess the communication relationships between different tumor cell states and microenvironment cells. This study established a multidimensional molecular atlas of PCP from the perspectives of cell state, spatial structure, and microenvironment interactions, providing a foundation for understanding its biological behavior and exploring new intervention strategies.

Traditional inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have long been characterized as classical antiproliferative agents that induce G1 cell cycle arrest by blocking the phosphorylation of the retinoblastoma protein (Rb). However, recent studies in lung cancer have expanded this paradigm, revealing a functional transition from exclusive tumor suppression to the profound remodeling of the tumor microenvironment (TME) to enhance antitumor immunity. This review systematically outlines the genomic aberrations of the CDK4/6-Rb axis across lung cancer subtypes and dissects its immunomodulatory networks. These encompass the activation of effector T cells, the alleviation of immunosuppression mediated by regulatory T cells (Tregs), and the enhancement of antigen presentation via the Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Furthermore, we analyze acquired resistance mechanisms, primarily focusing on p21-CDK2 bypass activation mediated by Cyclin E1 gene (CCNE1) amplification and tumor protein 53 gene (TP53) mutations. We also review clinical investigations combining CDK4/6 inhibitors with targeted therapies against driver genes, as well as immune checkpoint inhibitors in lung cancer. Notably, in the context of lung cancer, these combinatorial strategies have been primarily investigated in the second-line or subsequent settings following progression on standard platinum-based chemotherapy or immunotherapy. Finally, we propose individualized, stratified treatment strategies based on genomic and immunological biomarkers, providing a translational framework for overcoming multidrug resistance and optimizing next-generation combinatorial regimens in lung cancer.

SMARCA4-deficient thoracic undifferentiated tumor is a rare and highly aggressive subtype of lung cancer defined in the 2021 World Health Organization classification. Its scarcity and highly undifferentiated histology limit the availability of representative in vitro models and hinder therapeutic development. In this study, we established a novel cell line, TRI-LC21, from the primary tumor of a patient with lung cancer showing pathological features consistent with this entity. TRI-LC21 exhibited stable proliferation, strong colony-forming ability, and robust tumorigenicity in subcutaneous xenograft models. Xenograft tumors recapitulated the histological features and immunophenotype of the original tumor. Cell line authenticity was confirmed by short tandem repeat profiling, and mycoplasma contamination was excluded. Whole-exome sequencing revealed SMARCA4 loss accompanied by co-mutations in TP53 , STK11 , RBM10 , and ARHGAP35 . Transcriptome analysis demonstrated decreased expression of epithelial-associated genes and increased expression of stemness- and plasticity-related programs, consistent with an undifferentiated phenotype. Collectively, TRI-LC21 faithfully recapitulates the histological, immunophenotypic, and molecular characteristics of this tumor type and provides a valuable in vitro model for mechanistic investigation and preclinical studies.

Background: Acquired resistance to tyrosine kinase inhibitors (TKIs), e.g., osimertinib for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) and alectinib for anaplastic lymphoma kinase (ALK)-fusion NSCLC is a critical clinical barrier, with most patients progressing within 1 year of treatment. Previous studies on TKI resistance have mainly focused on target-dependent and target-independent mechanisms. Among target-independent mechanisms, the main research directions have centered on the activation of bypass signaling pathways, tumor microenvironment (TME) remodeling, cell phenotypic transition and metabolic reprogramming. The role of triglyceride (TG) synthesis—a key branch of metabolic reprogramming—in this process remains unclear. Methods: Osimertinib-resistant (PC-9 OR) and alectinib-resistant (NCI-H3122 ALR) cell lines were established via a dose-escalation strategy. The resistant cells were then compared with their original sensitive cells under both drug-present and drug-withdrawn conditions. Metabolomic liquid chromatography-mass spectrometry (LC-MS) and transcriptomic analyses revealed shared differential features, which were selected as candidate key metabolic enzymes in TKI resistance. From this pathway, LPIN2 was selected as a consistently upregulated key enzyme for validation. The LPIN2 gene was knocked out using CRISPR/Cas9 technology; a series of functional assays (e.g., drug sensitivity, colony formation), complemented by lipid supplementation, pathway inhibition (PI3K/mTOR), and a mouse xenograft model to verify the underlying mechanism. Results: LPIN2 was identified as a key driver of TKI resistance in NSCLC, with its mRNA and protein levels significantly upregulated (~2-fold) in osimertinib-resistant (PC-9 OR) and alectinib-resistant (NCI-H3122 ALR) cells. CRISPR/Cas9-mediated LPIN2 knockout restored TKI sensitivity, displaying oncogene-specific magnitudes of reduction in the half-maximal inhibitory concentration (IC₅₀): decreasing from 3,585 nM to 229–477 nM in EGFR-mutant PC-9 OR cells, and exhibiting a more moderate reduction from 2,264 nM to 325–488 nM in ALK-fusion NCI-H3122 ALR cells, while suppressing tumor growth in vivo (Ki67 downregulation). Mechanistically, LPIN2 promoted TG accumulation and lipid droplet deposition; exogenous TG supplementation (1,2-dioleoyl-3-arachidoyl-sn-glycerol) induced TKI resistance in parental cells and rescued drug tolerance in LPIN2-knockout cells, whereas inhibition of downstream TG synthesis enzymes [diacylglycerol O-acyltransferase1/2 (DGAT1/2)] recapitulated the knockout phenotype. Furthermore, perturbation of the LPIN2-TG axis was associated with modulation of the PI3K-AKT-mTOR survival pathway, regulating apoptosis-related proteins (BCL-XL/BCL2 downregulation, BAX upregulation). Combined treatment with osimertinib and a PI3K inhibitor (Wortmannin) synergistically suppressed tumor growth and prolonged survival in xenograft models. Conclusions: LPIN2 contributes to TKI resistance in NSCLC through a novel LPIN2-TG metabolic node that is functionally associated with PI3K-AKT signaling: it enhances TG biosynthesis and lipid droplet accumulation, thereby indirectly modulating the PI3K-AKT pathway to inhibit apoptosis. Targeting this axis reverses TKI resistance in vitro and in vivo, identifying LPIN2 as a drug stress-independent resistance driver and potential biomarker for metabolic-targeted combination therapy.

The strategic integration of micro/nano-engineering with controlled optical responses is pivotal for advancing solid tumor therapy. We have constructed a biomimetic nanosystem via the precise encapsulation of a flexible-chain iridium complex (IrC8) within giant plasma membrane vesicles (GPMVs) derived from tumor cells. This micro/nano-scale design leverages the endogenous structure of GPMVs to achieve superior biocompatibility and enhance homologous targeting, resulting in a 4.7% increase in cellular uptake compared to the free complex. The encapsulated IrC8 complex serves as a highly efficient photosensitizer, exhibiting a strong optical response characterized by an aggregation-induced emission enhancement factor (I/I₀) > 10 and a high singlet-oxygen quantum yield (ΦΔ = 0.18). Upon photoactivation, this system generates reactive oxygen species (ROS) with an 18-fold increase in yield, leading to potent phototoxicity with over 90% tumor cell apoptosis. Furthermore, the systematic integration of the vesicular carrier and the photosensitizer initiates a cascade reaction: the photodynamic effect not only directly eradicates tumor cells but also triggers immunogenic cell death (ICD), leading to potent immune activation. This synergistic combination of targeted delivery, photodynamic therapy, and immune stimulation within a single nanosystem demonstrates a remarkable synergistic therapeutic effect against solid tumors.

Background: Among primary malignant brain tumors in adults, glioblastoma is the most common and the most aggressive, characterized by profound metabolic reprogramming. This metabolic shift is essential for sustaining relentless proliferation and adapting to the challenging tumor microenvironment (TME). Central to this adaptation in glioma is the Warburg effect, which leads to excessive lactate production and accumulation, even in the presence of oxygen. This metabolic divergence significantly impacts the tumor immune microenvironment, promoting the recruitment of immunosuppressive cells and weakening the anti-tumor immune response. Core Content: This review provides a comprehensive analysis of the multifaceted roles of lactate in IDHwt glioma pathogenesis. It explores how lactate serves as a critical nexus connecting aberrant metabolism, epigenetic reprogramming (notably via histone lactylation), and immune evasion. The review delves into the molecular mechanisms by which lactate, particularly through the post-translational modification known as lactylation, directly modulates the epigenetic landscape to promote oncogene expression. Furthermore, it examines lactate’s role in acidifying the TME, promoting the immunosuppressive M2 polarization of glioma-associated macrophages (GAMs), and inhibiting the cytotoxic activity of T lymphocytes. Conclusions: This “lactate-centric” framework provides a unifying model that links metabolic dysregulation directly to malignant progression and therapeutic resistance (e.g., to TMZ). By elucidating this metabolic–epigenetic–immune axis, the review highlights a critical dependency that fuels glioma aggression. Finally, it discusses emerging therapeutic strategies aimed at targeting lactate production (LDHAi), transport (MCTi), and downstream epigenetic signaling (HDACi/p300i), offering novel avenues for integrative immunometabolic therapy.

Lung cancer is one of the most prevalent malignant tumors with high morbidity and mortality rates worldwide. Extensive multi-omics analyses have revealed significant intratumoral heterogeneity even within the same histopathological subtype. However, a database that systematically integrates multi-omics data for lung cancer research has long been lacking. Here, we developed LOSTdb, a molecular subtype annotation system for lung cancer that integrates multi-omics data and metadata. LOSTdb comprises 295 multi-omics datasets, including bulk RNA-seq, genomic, proteomic, methylation, and scRNA-seq data, with over 10,000 manually curated metadata entries. This resource encompasses high-quality clinical specimens, mouse models, and cell lines, totaling 34,393 samples and more than 1.2 million single cells. Each omics sample was annotated with both literature-based classical subtypes and NMF-derived meta-program (MP) subtypes. The platform supports cross-searching of omics and metadata at the gene and dataset levels, offers multiple visualization and analysis methods, and includes five tool modules, enabling functions such as integrated analysis, significance analysis between metadata as well as between genes and metadata, and target prediction for lung cancer molecular subtypes, serving as an essential tool for lung cancer precision medicine. LOSTdb is a user-friendly interactive database freely accessible at http://lostdbcancer.com:8080 .

Abnormal lipid metabolism is a hallmark of cancer and represents a potential target for anti-cancer strategies. β-lactamase-like protein (LACTB) is a novel tumor suppressor; however, its biological functions and underlying mechanisms in glioma remain poorly understood. In this study, we demonstrate that LACTB suppresses glioma growth independent of its enzymatic activity. Through RNA sequencing and untargeted lipidomics analysis, we reveal that LACTB inhibits lipid synthesis in glioma cells. Mechanistically, LACTB downregulates ERBB3 and suppresses the PI3K/AKT/mTOR signaling pathway, thereby restraining tumor cell lipogenesis. Furthermore, we show that LACTB reduces ERBB3 protein stability by promoting its lysosomal degradation. Specifically, LACTB or S164I enhances the interaction between ERBB3 and Hsc70, facilitating ERBB3 degradation in the lysosome. Finally, we demonstrate that targeting the LACTB/ERBB3 axis significantly inhibits glioma growth in the mouse model. Our findings highlight the anti-tumor role of LACTB in glioma and identify the LACTB/ERBB3 axis as a potential therapeutic target for this malignancy.

Background: Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Methods: Here, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. Results: We uncovered that LC-BrMs exhibited a significantly greater intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic, and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry, and multiplexed immunofluorescence staining of patients’ paired tumor specimens. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids of LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Conclusions: In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.