Weidong Han

Lung adenocarcinoma (LUAD) remains a leading cause of cancer‐related mortality, yet the stromal mechanisms driving rapid disease progression are incompletely understood. Here, we integrated single‐cell RNA sequencing with exploratory whole‐exome sequencing to characterize tumor microenvironment remodeling in a rapidly progressing LUAD patient. Tumor tissue exhibited marked stromal enrichment, with inflammatory cancer‐associated fibroblasts (CAFs) constituting a prominent fibroblast subset. Receptor–ligand and cell‐type‐specific expression analyses identified CAF‐derived insulin‐like growth factor 1 (IGF1) as a potential stromal mediator of LUAD progression. This fibroblast‐specific IGF1 pattern was corroborated by an external single‐cell dataset and by immunofluorescence validation in LUAD tissues with or without bone metastasis. Functionally, recombinant IGF1 enhanced LUAD cell proliferation, migration, and invasion, whereas IGF1 knockdown in CAF‐like cells attenuated these malignant phenotypes in co‐culture models. In vivo, IGF1 knockdown in CAF‐like cells reduced distant metastatic burden, accompanied by alterations in Wnt‐related signaling, extracellular matrix organization, and metastasis‐associated molecules. These findings indicate that CAF‐derived IGF1 contributes to LUAD progression and bone metastatic remodeling through paracrine stromal–tumor communication, highlighting the IGF1/IGF1R axis as a potential stromal‐directed therapeutic target in selected LUAD patients.

Hyperactivated M1 macrophages with excessive reactive oxygen species (ROS) exacerbate intestinal inflammation, driving the progression of inflammatory bowel diseases (IBDs), for instance, ulcerative colitis. Current standard treatments for IBDs show limited efficacy and off‐target side effects. Herein, we develop an oral, drug‐free hyaluronic acid (HA)‐based therapeutics that could self‐assemble in aqueous solution, accumulate in inflamed colons and attenuate M1‐like activation, thereby rebalancing the colonic immune landscape. Such drug‐free therapeutics are generated by the conjugation of unsaturated fatty acids to HA via dynamic covalent boronate‐catechol ester bonds. Mechanistically, the nano‐assemblies (termed uhNAs) effectively scavenge ROS, dampen NF‐κB signaling, and diminish pro‐inflammatory cytokines in M1‐like phenotypes. In DSS‐induced acute colitis, oral uhNAs treatment elicits significant decreases in M1‐like macrophages, CD8 ⁺ T cells, and neutrophils with concomitant increases in Tregs. In chronic and relapsing DSS colitis, uhNAs also confer robust protection, supporting sustained colonic immune remodeling during recurrent intestinal inflammation. Single‐cell RNA‐sequencing corroborates these shifts and maps the myeloid, B and T‐cell programs, highlighting the downregulated inflammatory responses following uhNAs treatment. Notably, uhNAs‐OA outperform physical HA (or HA‐PBA)/oleic‐acid mixtures, and two clinically established IBD drugs (5‐aminosalicylic acid and dexamethasone), protecting mice models against both acute and chronic colitis.

Glucose Transporter 1 (GLUT1) is the quintessential facilitator of basal glucose uptake, indispensable for maintaining cellular energy homeostasis, particularly across the blood–brain barrier. Beyond physiological necessity, GLUT1 dysregulation drives a broad pathological spectrum. While genetic haploinsufficiency precipitates severe neurological energy crises like Glut1 deficiency syndrome (Glut1DS), oncogenic networks hyperactivate GLUT1 as the central executor of the Warburg effect to fuel malignant proliferation. Despite its immense therapeutic potential, severe on‐target toxicity in normal tissues and adaptive metabolic plasticity remain critical roadblocks to systemic GLUT1 inhibition. This review comprehensively synthesizes GLUT1's multidimensional regulatory networks in health and disease, dissecting how its overexpression fundamentally remodels the tumor microenvironment (TME). We elucidate how GLUT1‐driven “metabolic competition” fosters metabolic immune exclusion and drives therapeutic resistance. Furthermore, we map the paradigm shift from traditional systemic blockades to emerging precision interventions. Specifically, we highlight “Trojan horse” glycan‐functionalized nanocarriers, targeted protein degradation technologies like PROTACs, and metabolically engineered CAR‐T cells. By conceptualizing GLUT1 as the linchpin of the immunosuppressive ecosystem, this work provides a strategic roadmap for precision metabolic immuno‐oncology, guiding the development of novel therapies that maximize durable efficacy while minimizing collateral physiological damage.

Prognostic stratification for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with brain metastases (BM) varies widely, and identifying drivers of early mortality remains challenging. This study systematically evaluated the impact of clinical and molecular factors on short-term survival (≤6 months) and treatment-related outcomes using a comprehensive real-world dataset, and characterized the leptomeningeal metastasis (LM) subgroup with its distinct clinical features and exceptionally poor prognosis. We retrospectively analyzed 261 consecutive EGFR‑mutated NSCLC patients with BM diagnosed at a single center between 2014 and 2024. Data on Eastern Cooperative Oncology Group (ECOG) performance status, timing of BM (synchronous initial vs. metachronous), presence of LM, generation of EGFR-tyrosine kinase inhibitor (TKI) administered, and other relevant covariates were extracted. Overall survival (OS) was defined from the date of BM diagnosis to death or last follow‑up; short‑term survival was defined as OS ≤6 months. Independent risk factors were identified by multivariable logistic regression with backward selection. Survival curves were generated using the Kaplan-Meier method and compared with the log‑rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Of the 261 patients, 79 (30.3%) had short‑term survival. Independent risk factors were ECOG ≥1 [odds ratio (OR) =4.11, 95% CI: 1.82-9.30, Pvs. third‑generation (OR =5.88, 95% CI: 2.19-15.81, Pvs. first‑generation TKIs (34.0 vs. 17.0 months; HR =0.424, 95% CI: 0.31-0.58, PEGFR‑mutated NSCLC patients with BM, poor performance status, synchronous initial BM, and first‑generation EGFR‑TKIs independently predicted short‑term survival. Third‑generation EGFR‑TKIs demonstrated significantly longer OS, suggesting a potential survival benefit that warrants consideration in clinical decision‑making, including for patients with LM. However, given the retrospective design and single‑center setting, these findings should be validated in prospective studies. Our results reinforce the importance of early molecular testing and upfront central nervous system (CNS)‑penetrant therapy in this high‑risk population.

Colorectal cancer (CRC) is one of the most frequently diagnosed malignant tumors. However, clear evidence explaining the regulatory mechanisms of programmed death ligand 1 (PD-L1) in CRC has been limited. To illustrate the function of YTH N ⁶ -methyladenosine (m ⁶ A) RNA binding protein F2 (YTHDF2), we conducted a comprehensive evaluation of expression profiling datasets from online databases and clinical samples. We used a subcutaneous immunodeficient mouse model to investigate the impact of YTHDF2 on CRC. Western blots, flow cytometry, PD-1/PD-L1 binding assay, and cell killing assay were used to assess the relationship between YTHDF2 and PD-L1. We used RNA sequencing, along with methylated RNA immunoprecipitation (MeRIP) and RNA binding protein immunoprecipitation (RIP) sequencing to analyze mRNA expression, m ⁶ A methylation levels, and YTHDF2 target transcripts. The m ⁶ A methylation locations of mRNAs were verified using sequence-based RNA adenosine methylation site predictor (SRAMP), MeRIP-qRT-PCR, RIP-qRT-PCR, and a dual-luciferase reporter system. YTHDF2 was upregulated in CRC tissues, and patients with higher YTHDF2 expression had a worse prognosis. The in vivo model showed that YTHDF2 promoted CRC growth, whereas in vitro experiments showed that inhibiting YTHDF2 expression did not affect cell proliferation, migration, or invasion. Mechanistically, interference with YTHDF2 reduced PD-L1 expression and the binding ability between PD-1 and PD-L1. The use of RNA-seq, MeRIP-seq, RIP-seq, and bioinformatics tools confirmed that the speckle type BTB/POZ protein ( SPOP ) mRNA was a YTHDF2 target and validated its m ⁶ A methylation sites. After YTHDF2 knockdown, SPOP mRNA stability increased, causing an increase in SPOP expression and a decrease in PD-L1 expression. This study demonstrated that YTHDF2 might upregulate PD-L1 expression by destabilizing m ⁶ A-containing SPOP mRNA and promote CRC development. The biological effect of the YTHDF2-SPOP-PD-L1 axis presented a promising target for CRC treatment and provided an approach to enhance the efficacy of anti-PD-1/PD-L1 therapy.

Colorectal cancer (CRC) is one of the most frequently diagnosed malignant tumors. However, clear evidence explaining the regulatory mechanisms of programmed death ligand 1 (PD-L1) in CRC has been limited. To illustrate the function of YTH N ⁶ -methyladenosine (m ⁶ A) RNA binding protein F2 (YTHDF2), we conducted a comprehensive evaluation of the expression profiling datasets from online databases and clinical samples. A subcutaneous immunodeficient mouse model was utilized to investigate the impact of YTHDF2 on CRC. Western blots, flow cytometry, PD-1/PD-L1 binding and cell killing assays were employed to detect the relationship between YTHDF2 and PD-L1. We utilized RNA sequencing, along with methylated RNA immunoprecipitation (MeRIP) and RNA binding protein immunoprecipitation (RIP) sequencing to analyze mRNA expression, m ⁶ A methylation level, and target transcripts of YTHDF2. The m ⁶ A methylation locations of mRNAs were verified using sequence-based RNA adenosine methylation site predictor (SRAMP), MeRIP-qRT-PCR, RIP-qRT-PCR, and a dual-luciferase reporter system. It was found that YTHDF2 was upregulated in CRC tissues, and patients with higher YTHDF2 expression had a worse prognosis. The in vivo model illustrated that YTHDF2 promoted CRC growth, while in vitro experiments showed that the inhibition of YTHDF2 expression did not affect cell proliferation, migration or invasion. Mechanistically, interference with YTHDF2 reduced PD-L1 expression and the binding ability between PD-1 and PD-L1. The use of RNA-seq, MeRIP-seq, RIP-seq, and bioinformatics tools confirmed speckle type BTB/POZ protein (SPOP) mRNA as a YTHDF2 target and validated its m ⁶ A methylation sites. After YTHDF2 knockdown, SPOP mRNA stability increased, causing an increase in SPOP expression and a decrease in PD-L1 expression. This study demonstrated that YTHDF2 might upregulate PD-L1 expression by destabilizing m ⁶ A-containing SPOP mRNA and promote CRC development. The biological effect of the YTHDF2-SPOP-PD-L1 axis presented a promising target for CRC treatment and provided an approach to enhance the efficacy of anti-PD-1/PD-L1 therapy.

Lung cancer remains one of the leading causes of mortality among cancer patients. Chromatin remodeling is a crucial epigenetic process in cancer, primarily regulated by alterations in genes encoding subunits of the switch/sucrose non-fermentable (SWI/SNF) complex. SMARCA4 and SMARCA2 are two mutually exclusive catalytic subunits within the SWI/SNF complex responsible for utilizing ATP hydrolysis to provide energy for chromatin remodeling. In lung cancer, SMARCA4 is one of the most common mutated subunits of the SWI/SNF complex. Patients with SMARCA4-deficient lung cancer typically experience poorer clinical outcomes. At present, there is no established targeted therapy designed specifically for this type of cancer. Here, we mainly discuss the mechanisms of SMARCA4 in lung cancer development and progression, its co-mutations and mutually exclusive mutations, cellular origin, clinical pathological characteristics, diagnosis and treatment of SMARCA4-deficient lung cancer. We also investigate the concept of synthetic lethality between SMARCA4 and SMARCA2, along with susceptibility to SMARCA4-deficient lung cancer and potential applications of immunotherapy.

Chest X-ray report generation has attracted increasing research attention. However, most existing methods neglect the temporal information and typically generate reports conditioned on a fixed number of images. In this paper, we propose STREAM: Spatio-Temporal and REtrieval-Augmented Modelling for automatic chest X-ray report generation. It mimics clinical diagnosis by integrating current and historical studies to interpret the present condition (temporal), with each study containing images from multi-views (spatial). Concretely, our STREAM is built upon an encoder-decoder architecture, utilizing a large language model (LLM) as the decoder. Overall, spatio-temporal visual dynamics are packed as visual prompts and regional semantic entities are retrieved as textual prompts. First, a token packer is proposed to capture condensed spatio-temporal visual dynamics, enabling the flexible fusion of images from current and historical studies. Second, to augment the generation with existing knowledge and regional details, a progressive semantic retriever is proposed to retrieve semantic entities from a preconstructed knowledge bank as heuristic text prompts. The knowledge bank is constructed to encapsulate anatomical chest X-ray knowledge into structured entities, each linked to a specific chest region. Extensive experiments on public datasets have shown the state-of-the-art performance of our method. Related codes and the knowledge bank are available at https://github.com/yangyan22/STREAM.

Automatic medical report generation is an emerging field that aims to transform medical images into descriptive, clinically relevant narratives, potentially reducing the workload for radiologists significantly. Despite substantial progress, the increasing model parameter size and corresponding marginal performance gains have limited further development and application. To address this challenge, we introduce an Adapter-enhanced Hierarchical cross-modal Pre-training (AHP) strategy for lightweight medical report generation. This approach significantly reduces the pre-trained model's parameter size while maintaining superior report generation performance through our proposed spatial adapters. To further address the issue of inadequate representation of visual space details, we employ a convolutional stem combined with hierarchical injectors and extractors, fully integrating with traditional Vision Transformers to achieve more comprehensive visual representations. Additionally, our cross-modal pre-training model effectively handles the inherent complex visual-textual relationships in medical imaging. Extensive experiments on multiple datasets, including IU X-Ray, MIMIC-CXR, and bladder pathology, demonstrate our model's exceptional generalization and transfer performance in downstream medical report generation tasks, highlighting AHP's potential in significantly reducing model parameters while enhancing report generation accuracy and efficiency. Our code is available on the project page: https://github.com/OpenMICG/AHP.

Aberrant activation of tropomyosin receptor kinases (TRKs) is a well-defined oncogenic driver for neurotrophic tropomyosin receptor kinase (NTRK)-fusion cancers, and acquired resistant mutations have emerged with clinical use of the first-generation TRK inhibitors. Here we present BPI-28592, a novel second-generation TRK inhibitor with efficacy against TRK fusion-positive cancers, including those with resistant mutations. Docking simulations indicated no steric hindrance between BPI-28592 and TRK mutants, suggesting its potential to overcome drug resistance. Biochemical assays showed strong inhibition and high selectivity against TRKA, TRKB, and TRKC. The inhibitor significantly reduced cell proliferation and blocked TRK signaling. In vivo studies demonstrated effective tumor suppression in xenograft models harboring TRK fusions with or without resistant mutations. Clinically, BPI-28592 achieved a complete response in a patient with malignant melanoma carrying an AP3S2-NTRK3 fusion (Clinicaltrials. gov identifier: NCT05302843).