2026年 · 第139卷第09期

Over the past decades, significant progress has been made in cancer treatment, including chemotherapy, targeted therapy, and more recently, immunotherapy. However, only a limited number of patients achieve cure with these therapies. A major challenge lies in acquired resistance to cancer treatments, where patients initially respond but eventually develop resistance and relapse. The underlying mechanisms of acquired resistance are still emerging, encompassing both tumor cell-intrinsic and extrinsic factors, such as the selection of pre-existing resistant clones, acquired genetic mutations, and alterations in the tumor microenvironment. In recent years, several new concepts and significant advances have emerged in this field, such as epigenetic alterations, lineage plasticity, metabolic reprogramming, and cellular crosstalk and signaling within the tumor microenvironment. This review systematically summarizes these advances, aiming to provide a comprehensive theoretical framework that integrates emerging concepts of resistance, while also offering a translational perspective focused on identifying actionable therapeutic targets and guiding the development of next-generation combination strategies to prevent or overcome acquired resistance in the clinic.

Over the past decade, research associated with organoids has entered a golden era, marking a significant shift in the biomedical landscape. Organoids have been widely applied in the industrial sector and have gained recognition from regulatory authorities. However, amid this rapid expansion, a comprehensive and precise overview of the field has been lacking. Our review aims to fill this gap by presenting a comprehensive overview of the regulations and prospects for the development of investigational new drugs (INDs) using organoids. Drawing on our extensive experience in academic research and industrial applications, we meticulously analyzed the organoid field from two distinct perspectives. We explored the synergies between organoids and cutting-edge technologies such as single-cell omics, which highlights their crucial role in customizing personalized medicines, improving high-throughput drug screening, and establishing physiologically relevant disease models. Organoids offer advantages over traditional animal models, including high throughput, rapid results, cost-effectiveness, and strong clinical relevance. Our analysis delves into supportive policies from regulatory bodies such as the European Medicines Agency (EMA), Food and Drug Administration (FDA), and Center for Drug Evaluation (CDE) for the use of organoids. Our comprehensive analysis and reflective discourse provide a deep dive into the current landscape of drugs derived from organoids that have obtained IND status and the subsequent progress in clinical trials. We cautiously anticipate challenges and future directions in organoid research, particularly in terms of its potential impact on personalized patient care, novel avenues for drug discovery, and clinical research. In summary, our review presents a comprehensive exploration of organoid technology and prospects for the development of INDs using organoids, thereby providing reflections, summaries, and projections that can be beneficial for current researchers.

Ferroptosis, an iron-dependent form of programmed cell death, has attracted significant attention in the field of immunometabolism. Macrophages, which are key immune cells, undergo metabolic reprogramming and polarization, influencing disease progression. This review investigates the interplay between ferroptosis signaling and macrophage glycometabolic reprogramming. To this end, it highlights the roles of iron, lipid, and amino acid metabolism in ferroptosis, alongside the distinct glycometabolic pathways in M1 and M2 macrophages. It also examines how gluconeogenesis, lactate, nicotinamide adenine dinucleotide phosphate, glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway regulate ferroptosis. Furthermore, the review investigates the feedback mechanisms between macrophage polarization and ferroptosis signaling and discusses the implications of these interactions in diseases such as cancer, metabolic disorders, infections, neurodegenerative conditions, and cardiovascular diseases. Finally, it proposes therapeutic strategies targeting ferroptosis to modulate macrophage polarization, offering new insights for disease treatment. Thus, this work provides a foundation for understanding ferroptosis-macrophage metabolism interactions and identifies potential therapeutic targets.

Atopic dermatitis (AD) is a prevalent and burdensome chronic skin disease, with profound effects on patient quality of life. Advancing its diagnosis and management remains a pressing clinical need. Artificial intelligence holds growing promise in addressing this challenge. This review outlines the current landscape of AD and explores the expanding role of AI in its care—from improving diagnostic accuracy and objective severity scoring to predicting therapeutic outcomes and personalizing treatment strategies. While these technologies are poised to transform dermatology practice, their successful integration will depend on overcoming technical and practical barriers through collaborative, interdisciplinary efforts. Further research and thoughtful implementation are essential to translate AI’s potential into better, more precise patient care.

Background: Substantial metabolic heterogeneity exists prior to the development of diabetes, creating opportunities for earlier and more precise intervention. This study aimed to analyze common clinical indicators in a diabetes-free population using innovative clustering methods to identify characteristic subgroups and evaluate their utility in stratified prediction of diabetes risk and related complications. Methods: This analysis included 13,829 adults without diabetes from the Kunshan Aging Research with E-health (KARE) cohort, a population-based longitudinal cohort of 51,400 community-dwelling residents from both urban and rural areas of Kunshan City, China, who have received annual health examinations between January 2014 and December 2023. A novel subtype classification method based on complication clustering and weighted naive Bayes classification was applied to select the most informative variables and categorize individuals into distinct diabetes subtypes. We then assessed 3-year risks of diabetes and complications, including cardiovascular disease (CVD), fatty liver disease (FLD), and stroke. To evaluate the influence of genetic factors, polygenic risk scores (PRS) were compared across all participants. External validation was performed using data from 6209 diabetes-free individuals in a cohort of 22,630 people who have been followed since 2014 at Beijing Jiuhua Hospital. Results: Thirteen clinically relevant variables were identified: sex, age, body mass index (BMI), waist circumference, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), uric acid (UA), blood urea nitrogen (BUN), fasting blood glucose (FBG), systolic blood pressure (SBP), and heart rate. Three clusters were identified in the Kunshan cohort. Cluster 1 (n = 6751) had favorable indicators and the lowest risks of diabetes (2.04%, 138/6751) and complications, including CVD (4.52%, 305/6751), FLD (15.30%, 1033/6751), and stroke (9.07%, 612/6751). Cluster 2 (n = 4622) had the poorest glucose and lipid control, with the highest 3-year cumulative incidence of diabetes (9.95%, 460/4622) and FLD (52.14%, 2410/4622). Cluster 3 (n = 2456) was characterized by the oldest age, highest SBP, BMI, and waist circumference, with intermediate diabetes risk (3.05%, 75/2456) and the highest risks of CVD (8.47%, 208/2456) and stroke (14.13%, 347/2456). In Cox survival analysis for FLD (adjusted), using Cluster 1 as reference, the hazard ratio (HR) was 2.357 (95% confidence interval [CI]: 2.161-2.571, P <0.001) for Cluster 2, and was 1.903 (95% CI: 1.718-2.108, P <0.001) for Cluster 3. In Cox survival analysis for CVD, HRs were 1.193 (95% CI: 0.975-1.459, P = 0.087) for Cluster 2 and 1.295 (95% CI: 1.041-1.611, P = 0.02) for Cluster 3. In stroke analysis, HRs were 1.058 (95% CI: 0.911-1.23, P = 0.46) for Cluster 2 and 1.212 (95% CI: 1.029-1.428, P = 0.021) for Cluster 3. The risks of diabetes and CVD predicted by PRS were consistent with those identified by clinical clustering. The findings were independently confirmed in the Beijing Jiuhua Hospital cohort. Conclusions: Phenotypes derived from clinical characteristic analysis using the new clustering method effectively identify and stratify the risk of diabetes and related complications, such as CVD, FLD, and stroke, in two large cohorts of diabetes-free Chinese adults, supporting the development of more precise and individualized prevention strategies.

Background: Despite increased response and long-term benefit of anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) harboring ALK-fusion, the role of induction ALK-TKIs in locally advanced NSCLC remained poorly investigated. This study aimed to demonstrate the short-term and long-term efficacy of ALK-targeted induction therapy in stage III lung cancer. Methods: We consecutively collected data of patients from Guangdong Lung Cancer Institute since 2016, and those who were pathologically confirmed stages IIIA-IIIB NSCLC treated with induction ALK-TKIs initially were eligible for subsequent analysis. Patients’ clinicopathological features as well as therapeutic management were fully reviewed. Analysis of longitudinal single-cell RNA sequencing from patients treated with alectinib were performed. Fisher’s exact test was used to compare two categorical variable and Kaplan-Meier was applied for survival curve with estimation for median and 95% confidence interval (CI) value if available. Results: Forty stage III NSCLC patients treated with either alectinib or crizotinib were enrolled. Among those who had surgery, all patients had R0 resection without postoperative radiotherapy. Only two patients suffered grade 2 postoperative complications in terms of Clavien-Dindo score. Induction alectinib showed numerically superior pathological response compared with crizotinib with both major pathological response (MPR) (11/17, 64.7% vs. 6/13, 46.2%, P = 0.46) and complete pathological response (pCR) (6/17, 35% vs. 2/13, 15%, P = 0.41). Patients who received induction alectinib had significantly longer PFS (not reached [NR] vs. 17.9 months, P <0.001) and numerically improved overall survival (NR vs. NR, P = 0.092) compared with crizotinib. Brain metastasis remained the most common recurrent pattern after induction ALK-TKIs. Longitudinal single-cell RNA sequencing revealed increased tumor stemness and induced a more suppressive immune microenvironment in the residual tumor while highly inflamed microenvironment along with low infiltrating regulatory T cell and exhausted T cell was observed in resected specimens which achieved pCR. Conclusion: Induction ALK-TKIs provided a clinically efficient and well-tolerated therapeutic strategy in locally advanced ALK-positive NSCLC.

Background: Most anti-CD19 chimeric antigen receptor (CAR) T-cell products have the single-chain variable fragment (scFv) derived from the FMC63 monoclonal antibody. We developed a new hybridoma clone, HI19α, which binds to distinct epitopes on CD19. CNCT19 is a second-generation CAR T-cell with a scFv derived from clone HI19α and a 4-1BB costimulatory domain. A pilot clinical trial was conducted to assess the safety and preliminary efficacy of CNCT19 cells (CNCT19s) in patients with relapsed or refractory (R/R) aggressive B-cell lymphoma. Methods: From June 2017 to March 2019, 16 patients with R/R CD19-positive aggressive B-cell lymphoma from the Institute of Hematology and Blood Disease Hospital were enrolled. All patients received lymphodepleting chemotherapy with fludarabine (25-30 mg/m2/per day on days 4, 3, and 2) and cyclophosphamide (350 mg/m2/per day on days 4 and 2) before CNCT19s infusion. The primary objective was the safety profiles. Kaplan-Meier survival analysis was used to compare the cumulative incidence rate. Results: The study cohort comprised 14 patients diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), one patient with follicular lymphoma grade 3B (FL3B), and one patient with Richter’s transformation. The patients had received a median of 3 (range 1-7) lines of prior therapy. Thirteen patients (81.3%) had disease resistant to the last-line therapy, and TP53 mutation and/or deletion were detected in 5 of 12 patients (41.7%). The median dose of CNCT19s infusion was 3.6 × 106 (range 1.8-6.5 × 106)/kg. Cytokine release syndrome occurred in 11 (68.8%) patients, all classified as grade 1. One patient (6.3%) experienced CAR T-cell-related encephalopathy syndrome. The overall response rate and the complete response rate were 75% (12/16) and 43.8% (7/16), respectively. After a median follow-up of 54.0 months, the estimated 5-year progression-free survival and overall survival rates were 25.0% and 37.5%, respectively. Conclusions: CNCT19s exhibited favorable safety profiles and efficacy in patients with R/R DLBCL and FL3B. Long-term follow-up confirmed the curative potential of CNCT19s in R/R aggressive B-cell lymphoma.

Background: Sphingosine-1-phosphate (S1P), a metabolite of sphingosine, is associated with the proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aims to address the mechanisms by which S1P induces PASMC proliferation, contributing to pulmonary arterial remodeling. Methods: Primary cultured rat PASMCs were incubated with S1P. Cyclopamine was used to inhibit Smoothened (SMO) function, while siRNA transfection selectively knocked down the expression of signal transducer and activator of transcription 3 (STAT3), glioma-associated oncogene homolog 1 (GLI1), and forkhead box M1 (FOXM1). Cell proliferation was measured by 5-bromo-2′-deoxyuridine (BrdU) and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay. Subcellular localization of Gli1 was determined using immunofluorescence staining. In a monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model, PF543 (the inhibitor of S1P synthetase), NSC74859 (the inhibitor of STAT3), and cyclopamine (the inhibitor of sonic hedgehog [Shh] receptor) were administered to evaluate their effects on disease progression. Hemodynamic changes and histological examination were performed to evaluate the development of PAH. The protein levels of sphingosine kinase 1 (SphK1), phosphorylated/total STAT3 (p-/t-STAT3), Shh, Gli1 and FoxM1 were determined using immunoblotting. Results: S1P increased Shh expression by STAT3 activation, which further caused Gli1 upregulation and nuclear translocation in PASMCs. Activation of Gli1 raised FoxM1 expression and then triggered PASMCs proliferation and migration. In MCT-induced PAH rat models, S1P levels were elevated in lung tissues and serum, triggering STAT3 activation and subsequent upregulation of Shh, Gli1, and FoxM1 in lung. Targeting these molecules alleviated pulmonary arterial remodeling and prevented the development of PAH. Conclusions: S1P/STAT3/Shh/Gli1/FoxM1 pathway plays an important role in PASMCs proliferation and pulmonary arterial remodeling. Targeting this cascade may have potential value for the management of PAH.

Background: Pancreatic cancer (PC) is among the deadliest digestive malignancies, with over half of patients showing liver metastases at diagnosis. Understanding the molecular mechanisms underlying PC liver metastasis is crucial for improving patient prognosis and extending survival. This study aimed to elucidate the role of integrin subunit beta 6 (ITGB6), a downstream target of transforming growth factor-β (TGFβ) signaling, in PC progression and metastasis, particularly focusing on its involvement in liver metastasis. Methods: First, ITGB6 was identified as a key TGFβ-pathway gene linked to liver metastasis in PC, with its enrichment further confirmed by SMAD family member 4 (SMAD4)-based subgroup analysis. A total of 37 paired clinical PC and adjacent normal tissue samples were obtained from patients who underwent surgical resection at Peking Union Medical College Hospital, and immunohistochemistry (IHC) was performed to evaluate ITGB6 expression and its correlation with clinicopathological features. In vitro assays, including cell proliferation, apoptosis detection, and cell migration and invasion assays, were conducted to evaluate the role of ITGB6 in PC cell behavior. A SMAD4 wild-type (WT) PC cell line stably overexpressing ITGB6 was established, and its in vivo role was assessed using subcutaneous and liver metastasis xenograft models. To explore the transcriptional regulation of ITGB6 by TGFβ, chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and dual-luciferase reporter assays were performed. The effect of ITGB6-expressing PC cells on hepatic stellate cell (HSC) activation was evaluated using enzyme-linked immunosorbent assay (ELISA), Western blotting, and IHC. Finally, the therapeutic potential of targeting ITGB6 was preliminarily assessed using a monoclonal antibody intervention strategy. Results: TGFβ upregulates ITGB6 expression through a SMAD4-dependent pathway. Elevated ITGB6 expression not only promotes the migration and invasion of PC cells but also activates HSCs, thereby establishing a fibrotic microenvironment favorable for metastatic colonization. In mouse models, administration of an ITGB6 monoclonal antibody significantly attenuated HSC activation and suppressed the formation of liver metastases. Therefore, ITGB6 serves as a key downstream effector of TGFβ-mediated metastasis and represents a promising therapeutic target for liver metastasis in PC. Conclusions: The TGFβ-ITGB6 positive feedback axis plays a critical role in liver metastasis of SMAD4 WT PC, highlighting ITGB6 as a potential therapeutic target, especially for patients with intact SMAD4 function.