2026年 · 第139卷第12期

Small cell lung cancer (SCLC) is the most aggressive histological subtype of lung cancer and is characterized by rapid tumor proliferation, early dissemination, and poor prognosis. Currently, the standard first-line treatment for extensive-stage SCLC consists of platinum-based chemotherapy and immune checkpoint inhibitors. Although patients exhibit a high initial response rate to platinum-based chemotherapy, the majority develop acquired resistance within 6 months. Overcoming drug resistance and prolonging the duration of first-line therapy are critical for long-term survival in these patients. However, the definitive resistance mechanisms associated with chemotherapy and immunotherapy in SCLC remain unclear. In this context, we comprehensively review the diverse mechanisms contributing to therapeutic resistance in SCLC, including transcriptional subtype plasticity, the epithelial–mesenchymal transition, an enhanced DNA damage repair capacity, dysregulated autophagy and apoptosis, the presence of cancer stem cells, alterations in the tumor microenvironment, and the aberrant expression of cellular transporters. We particularly focus on the dynamic evolution of resistance from intrinsic to acquired states and the complex interplay among these mechanisms, aiming to provide an integrated theoretical framework to guide the development of rational combination strategies to overcome therapeutic resistance.

Gut microbiota can modulate antitumor immunity and influence immune checkpoint blockade (ICB) therapy efficacy and treatment-associated toxicity. Variations in the therapeutic effect of ICB among individuals are partially attributed to microbiota. This review summarizes current knowledge on how specific bacterial species enhance or hinder ICB outcomes by regulating immune cell activation, antigen presentation, and systemic inflammation. The review further outlines translational strategies to optimize ICB, including microbiota-targeted interventions (e.g., prebiotics, fecal microbiota transplantation, and metabolite therapies) to overcome resistance and mitigate treatment-related toxicities, focusing on immune-related colitis. Additionally, emerging microbial biomarkers in melanoma, lung cancer, and hepatobiliary cancers that predict ICB response are discussed, highlighting the gut microbiome as a potential target for personalized cancer immunotherapy. By integrating mechanistic insights with clinical evidence, this review underscores the potential of microbiota-centered approaches to improve patient outcomes in ICB-based treatments, emphasizing the pivotal role of the gut microbiota in modulating both therapeutic efficacy and immune-related adverse events.

Previous studies have confirmed that chondrocytes are derived from mesenchymal stem cells (MSCs) and mature into hypertrophic chondrocytes during endochondral ossification. This maturation is followed by apoptosis, which induces vascular invasion, cartilage matrix degradation, and osteoblast differentiation. In addition to this classical transdifferentiation pathway, recent studies have shown that chondrocytes can also be derived from periosteal stem cells (PSCs). Using lineage-tracing techniques to detect the transdifferentiated forms of chondrocytes during endochondral ossification, several new models of transdifferentiation have been discovered, such as a chondrocyte-to-osteoblast precursor transdifferentiation model, a chondrocyte dedifferentiation and redifferentiation model, and a chondrocyte-to-osteoblast direct transdifferentiation model. These findings expand current understanding of chondrocyte origins and their fate during endochondral ossification. In the endochondral ossification process of fracture healing, chondrocytes, as core cells, coexist with a variety of cell types and crosstalk with each other in the callus. This article comprehensively describes the endochondral ossification models in the process of bone development and fracture healing with chondrocytes as the core. The signal pathways and key factors regulating chondrocyte differentiation, maturation, hypertrophy, apoptosis, dedifferentiation, and transdifferentiation into osteoblasts in different models are summarized.

Background: Colony-stimulating factor-1 receptor (CSF1R) signaling is crucial for the ability of tumor-associated macrophages (TAMs) to establish an immunosuppressive tumor microenvironment (TME), highlighting the potential of CSF1R signaling as a therapeutic target. Noninvasive preoperative prediction of CSF1R levels in gliomas using magnetic resonance imaging (MRI) holds clinical potential for guiding immunotherapy. Methods: This study enrolled 477 patients with glioma from three datasets. We retrospectively collected CSF1R staining data and paired MR images from center 1 between January 2020 and December 2022 (training cohort, n = 65) and extracted conventional radiomics (CR) and deep learning (DL) features, which were then integrated (CR+DL) to construct CSF1R prediction models using 12 classic machine learning classifiers, followed by five-fold cross-validation. We subsequently tested the model’s performance using CSF1R staining data from prospective patients with glioblastoma (GBM) collected between April 2024 and September 2024 (internal test cohort, n = 38). External validation of the model, including its correlation with CSF1R gene expression, was performed using MRI-transcriptomic-prognostic paired data (n = 101) from center 2, along with immune infiltration and survival analyses. Finally, the models were assessed from multiple perspectives using data from different cohorts at center 3: survival efficacy (n = 255), correlation with macrophage immunohistochemical (IHC) staining in patients with GBM (n = 16), and single-cell sequencing (scRNA-seq) (n = 2, lesions = 4) data from patients with multifocal GBM. Results: We successfully developed CSF1R prediction models leveraging CR, DL, and CR+DL features. In the internal test cohort, the CR+DL model achieved the highest accuracy (0.76, support vector machine (SVM) classifier) and sensitivity (0.86, SVM classifier), whereas the DL model yielded the best specificity (0.88, random forest classifier) and the CR model yielded the best area under the curve (0.77, naive Bayes classifier). A significant correlation was identified between CSF1R prediction and CSF1R gene expression in patients with GBM (P = 0.017). Further analysis of immune infiltration in samples from patients with GBM revealed higher immune scores and increased M2 macrophage infiltration in the groups with high CSF1R expression (P = 0.0038). Finally, results from the IHC staining of macrophages (P = 0.0003) and scRNA-seq data corroborated these findings. Conclusion: We successfully developed a CSF1R prediction model based on CR and DL features, elucidating its association with macrophage infiltration and its potential to guide preoperative immunotherapy strategies.

Background: Time-in-target range (TTR) of systolic blood pressure (SBP) is determined by the proportion of time during which the SBP remains within a defined optimal range. The study aims to explore the association between SBP TTR and the occurrence of chronic kidney disease (CKD) in hypertensive patients. Methods: A post hoc analysis of data from the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial was performed. The STEP trial compared intensive (110 to <130 mmHg) and standard (130 to <150 mmHg) SBP interventions in hypertensive individuals. The SBP TTR was calculated from baseline to 6 months using 110–130 mmHg and 130–150 mmHg as the target ranges for the intensive and standard groups, respectively. The primary outcome for this study was the first occurrence of CKD (estimated glomerular filtration rate <60 mL·min-1·1.73m-2). Cox proportional regression models were used to assess the association between SBP TTR and renal outcomes. Results: Overall, 4924 participants were included in this study. Participants with a higher SBP TTR were likely to have a higher baseline diastolic blood pressure. In fully adjusted models, a 1-standard deviation increase in SBP TTR was associated with a 10% lower risk of poor kidney outcomes (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.83–0.98). Compared with participants in the lowest TTR group (T1: 0 to <38%), those in the highest TTR tertile (T3: 81% to <100%) had a lower risk of renal outcomes (HR: 0.76; 95% CI: 0.61–0.94). Sensitivity analysis showed consistent results when considering the competing risk of death and a combined target range of 110–140 mmHg for SBP. Conclusions: A higher SBP TTR was associated with a lower risk of kidney events in adults with hypertension. Therefore, the SBP TTR may be considered a potential therapeutic target and quality metric.

Background: The prognostic value of germline BRCA1/2 mutations (gBRCA1/2m) in ovarian cancer is controversial, and the clinical implications of specific mutation domains within BRCA1/2 remain underexplored. This study aimed to investigate the impact of distinct gBRCA1/2m domains on survival outcomes in patients with ovarian cancer. Methods: This multicenter retrospective study, conducted between 2010 and 2022 at three major academic centers in China, analyzed 313 patients with epithelial ovarian cancer with pathogenic gBRCA1/2m. We evaluated associations between gBRCA1/2m domains and clinical outcomes including progression-free survival (PFS) and platinum-free interval. Results: Patients who received platinum-based chemotherapy without maintenance therapy with BRCA1 C-terminal domain 1 (BRCT1) mutations showed significantly prolonged PFS (37.8 vs. 22.6 months; hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19–0.99; P = 0.042), whereas those with Really Interesting New Gene (RING) mutations had shorter PFS (13.1 vs. 23.2 months; HR, 1.82; 95% CI, 0.89–3.72; P = 0.097). In the subgroup of gross residual disease, RING mutations were significantly associated with reduced PFS (12.9 vs. 21.8 months; HR, 3.25; 95% CI, 1.29–8.18; P = 0.008). A higher likelihood of primary platinum-refractory disease (odds ratio, 7.78; 95% CI, 1.25–48.31; P = 0.028) was observed. Across all mutation locations, poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy demonstrated benefits, notably for patients with BRCA1 RING mutations (HR, 0.10; 95% CI, 0.01–0.84; P = 0.010) and BRCA2 RAD51-binding domain (RAD51-BD) mutations (HR, 0.29; 95% CI, 0.11–0.79; P = 0.010). Conclusions: BRCA1 BRCT1 mutations are associated with improved prognosis following platinum-based chemotherapy, whereas BRCA1 RING domain mutations are linked to a heightened risk of primary platinum-refractory disease. Our findings underscore the need for complete resection with no gross residual disease in patients harboring RING mutations. Furthermore, PARPi maintenance therapy exhibits variable efficacy based on mutation location, with BRCA1 RING and BRCA2 RAD51-BD mutations conferring significant benefits.

Background: Lung cancer remains a significant medical problem in Asia, and improved treatments are needed for patients diagnosed with non-small cell lung cancer (NSCLC), who are frail with poor performance status or substantial comorbidities. This study aimed to investigate the efficacy and safety of first-line atezolizumab vs. single-agent chemotherapy in the Asian subpopulation in IPSOS trial. Methods: This exploratory analysis of the Asian subpopulation from the phase 3, global, open-label, randomized controlled IPSOS trial evaluated the efficacy and safety of atezolizumab (1200 mg intravenously every 3 weeks) vs. single-agent chemotherapy (investigator’s choice of vinorelbine or gemcitabine) as first-line treatment in patients with locally advanced or metastatic NSCLC, who were ineligible for platinum-based chemotherapy. The primary outcome was overall survival (OS); other outcomes were progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety. Results: Seventy patients from China and Vietnam were included. Median OS was 15.8 months in the atezolizumab group vs. 12.5 months in the chemotherapy group; unstratified hazard ratio, 0.74 (95% confidence interval 0.41, 1.35). Median PFS was 8.1 months vs. 5.4 months, ORR was 27.9% vs. 7.4%, and median DOR was 18.7 months vs. 9.3 months, in the atezolizumab group vs. in the chemotherapy group, respectively. All-grade and grade 3–4 treatment-related adverse events (AEs) were less frequent with atezolizumab compared with chemotherapy. Two patients in the atezolizumab group had grade 5 AEs, namely pneumonia and acute left ventricular failure, with the latter considered treatment-related. Conclusions: Atezolizumab showed encouraging efficacy results and was well tolerated in an Asian subpopulation of patients with NSCLC who were deemed ineligible for standard platinum-based chemotherapy. The findings of this exploratory subpopulation analysis were consistent with those for the global IPSOS population.

Background: Neuroinflammation driven by microglial activation is a key contributor to secondary brain injury after intracerebral hemorrhage (ICH). This study aimed to determine whether transcranial photobiomodulation (tPBM) modulates microglial activation and improves neurological outcomes following ICH. Methods: In this study, we used a mouse model of ICH induced by collagenase to investigate the effects of tPBM at three different power levels (25, 50, and 100 mW) on neurological function, hematoma volume, brain edema, and blood–brain barrier (BBB) integrity. We conducted neurobehavioral assessments and analyzed the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway through quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. In addition, we used the STING-specific inhibitor H151 and agonist diABZI to elucidate the role of the cGAS-STING pathway in neuroinflammation. Results: tPBM treatment significantly improved neurological recovery, with optimal effects observed at 50 mW. This treatment reduced hematoma volume, alleviated brain edema, and preserved BBB integrity. Importantly, tPBM inhibited microglial polarization toward a neurotoxic phenotype by suppressing the activation of the cGAS-STING pathway. The use of H151 resulted in decreased neuronal apoptosis and inflammatory cytokine expression, whereas diABZI reinstated inflammatory processes, highlighting the detrimental role of cGAS-STING overactivation in ICH. Conclusions: tPBM effectively mitigates neuroinflammation and enhances functional recovery after ICH by modulating the cGAS-STING signaling pathway and suppressing neurotoxic microglial activation. This study underscores the potential of tPBM as a novel therapeutic intervention for improving outcomes in patients with ICH, warranting further exploration in clinical settings.

Background: Intestinal ischemia/reperfusion (I/R) injury is a prevalent pathophysiological occurrence that results in significant morbidity and mortality. Growth arrest and DNA damage-inducible β (GADD45B) mediates various cellular responses and is engaged in apoptosis, DNA demethylation and repair, and cell survival. Nonetheless, the role of GADD45B in intestinal I/R injury remains inadequately defined. This study aimed to elucidate whether GADD45B contributes to intestinal I/R injury through the regulation of apoptosis and DNA demethylation. Methods: In this study, we established a mouse intestinal I/R model using mesenteric artery occlusion, and Caco-2 cells were used to create the in vitro hypoxia/reoxygenation (H/R) model. Using these models, the function of GADD45B in intestinal I/R injury was investigated by knockdown and overexpression approaches, combined with histological staining, immunohistochemistry, and Western blotting. Transcriptomic analyses were performed to identify downstream signaling pathways and molecular targets of GADD45B. The specific molecular mechanisms by which GADD45B regulates intestinal I/R injury were further elucidated using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), methylation-specific polymerase chain reaction (MSP), co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP) assays. Results: Our research revealed a notable increase in GADD45B in both H/R-induced Caco-2 cells and mouse models of intestinal I/R. GADD45B knockdown significantly mitigated intestinal barrier dysfunction and apoptosis resulting from H/R, whereas its overexpression had the opposite effect in vitro. GADD45B-knockdown mice were generated via the adeno-associated virus (AAV)-short hairpin (sh)-GADD45B and subjected to I/R. These findings indicated that GADD45B knockdown alleviated intestinal injury and reduced apoptosis triggered by intestinal I/R. Transcriptomic Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that GADD45B regulated apoptosis during intestinal I/R by activating the Hippo pathway, with mammalian sterile 20-like kinase 1 (MST1) recognized as a downstream target gene of GADD45B. ChIP confirmed that GADD45B bound to the MST1 promoter and that ten-eleven-translocation 1 (TET1) occupied the MST1 promoter region following GADD45B overexpression. Co-IP confirmed that GADD45B interacts with TET1. MSP confirmed that TET1 knockdown impaired GADD45B-induced MST1 promoter DNA demethylation. Mechanistically, GADD45B interacted with TET1 to enhance MST1 expression through DNA demethylation, which subsequently activated the Hippo pathway and exacerbated apoptosis following intestinal I/R. Conclusion: GADD45B represents a pivotal regulatory factor in intestinal I/R injury, and targeting the GADD45B/TET1/MST1 axis might serve as a feasible treatment strategy.