Abstract. 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.

Background: The malignant progression of lung adenocarcinoma (LUAD) is not only a hallmark of this prevalent cancer but is also closely linked to epigenetic regulation, particularly N6-methyladenosine (m6A) methylation. Disruption of the m6A regulatory machinery results in the uncontrolled upregulation of multiple oncogenic drivers, thereby fueling tumor development. Our study investigated the mechanism by which G Protein Subunit Gamma 4 (GNG4), a gene upregulated via m6A modification, promoted LUAD by enhancing its mRNA stability and subsequently inhibiting the cGAS-STING pathway. This provides novel mechanistic insight for clinical LUAD research. Methods: Based on transcriptomic and m6A sequencing data from The Cancer Genome Atlas Program (TCGA) database, the candidate gene GNG4, associated with m6A regulation, was identified. Correlations of GNG4 expression with two m6A regulators-the writer Vir Like M6A Methyltransferase Associated (VIRMA) and reader Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3)-were statistically evaluated. Prediction of the biological functions pertaining to GNG4 was performed using Single-gene Gene Set Enrichment Analysis (Single-gene GSEA). Cellular experiments, including gene knockdown/overexpression, Western blot, flow cytometry, m6A-related assays, and cellular senescence detection, as well as animal models were employed to investigate the regulatory effects of m6A-modified GNG4 on the cGAS-STING pathway and its impact on cell cycle progression and cellular senescence. Results: TCGA data combined with functional experiments demonstrated that GNG4 was highly expressed in LUAD (p < 0.05). Knockdown of GNG4 activated the cGAS-STING pathway, upregulated p21, induced G1/S cell cycle arrest (p <0.05) and cellular senescence (p < 0.05), thereby inhibiting LUAD cell proliferation (p < 0.05) and tumor growth (p < 0.05). Mechanistically, increased GNG4 mRNA expression was associated with elevated m6A modification in LUAD. GNG4 expression was positively correlated with the m6A writer VIRMA and the m6A reader IGF2BP3. Knockdown of VIRMA or IGF2BP3 significantly reduced both m6A modification and mRNA expression of GNG4 (p < 0.05), thereby alleviating its suppressive effect on the cGAS-STING pathway, promoting cellular senescence (p < 0.05), and inhibiting proliferation in LUAD cells (p < 0.05). Conclusion: The upregulation of m6A modification of GNG4 in LUAD enhances its mRNA stability, which in turn suppresses the cGAS-STING signaling pathway, ultimately inhibiting cellular senescence and promoting LUAD cell proliferation, thereby driving disease progression.

OBJECTIVES:To develop an individualized nomogram for predicting disease progression risk in systemic anaplastic large cell lymphoma (sALCL). METHODS:Independent predictors of progression-free survival (PFS) were identified using Cox regression in a multicenter retrospective cohort of 109 sALCL patients (2010-2022). These were incorporated into a three-factor nomogram, evaluated via bootstrapped internal validation (1000 resamples), ROC analysis, C-index, decision curve analysis (DCA), and clinical impact curve (CIC). RESULTS:A total of 29 PFS events occurred during a median follow-up of 31 months. Multivariable modelling selected serum β2-microglobulin elevation, extranodal disease, and front-line chemotherapy choice (CHOP versus CHOPE or BV+CHP) as autonomous progression drivers. Upon internal bootstrap validation, the nomogram yielded strong prognostic accuracy, achieving AUCs of 0.81, 0.85 and 0.87 for 1-, 3- and 5-year progression-free survival, alongside a corrected C-index of 0.779 (95% CI: 0.699 - 0.861). Calibration plots showed close agreement between predicted and observed outcomes, while DCA confirmed superior net clinical benefit versus conventional IPI or Ann Arbor stratification across multiple decision thresholds. CONCLUSION:This first sALCL-specific nomogram integrates clinical and treatment variables to provide personalized PFS risk estimation. While internally validated, this exploratory, observation-based tool requires external validation and recalibration in prospective cohorts before clinical implementation.

Fusobacterium nucleatum (Fn) is frequently detected at increased abundance in colorectal cancer (CRC) tissues and has been associated with tumor progression, reduced treatment responsiveness, immune escape, and poor clinical outcomes. However, whether Fn functionally contributes to colorectal cancer liver metastasis (CRLM) and can be therapeutically exploited in this context remains incompletely understood. Here, we found that Fn was enriched in CRC tissues and that higher intratumoral Fn abundance was associated with unfavorable patient outcomes. Functional experiments showed that Fn enhanced CRC cell migration, proliferation, clonogenic growth, and hepatic colonization, suggesting that Fn may participate directly in tumor progression and metastatic seeding. To integrate antitumor and intratumoral antibacterial treatment, we developed MM@IRI-MTZ, a biomimetic nanodrug consisting of a self-assembled irinotecan-metronidazole conjugated prodrug nanocore (IRI-MTZ) coated with membranes derived from matrix metalloproteinase-14 (MMP14)-overexpressing tumor cells. This design integrates chemotherapeutic and antibacterial activities within a single platform while enhancing tumor homing and stromal penetration through biomimetic membrane engineering. In vitro, MM@IRI-MTZ displayed stable physicochemical characteristics, efficient cellular uptake, cytotoxic and proapoptotic effects against CRC cells, and sustained antibacterial activity against Fn. In vivo, MM@IRI-MTZ accumulated more efficiently in tumor tissues and reduced both subcutaneous tumor growth and Fn-associated liver metastatic burden. These therapeutic effects were accompanied by decreased intratumoral Fn signals, reduced stromal collagen deposition, increased tumor cell death, and enhanced CD8+ T-cell infiltration. Transcriptomic analysis suggested that MM@IRI-MTZ attenuated inflammatory amplification, cytokine signaling, and programs involved in stromal adhesion and invasion, while increasing transcriptional features associated with antitumor immunity. No obvious histological injury was observed in major organs after MM@IRI-MTZ treatment, and overall gut microbial homeostasis was not markedly disrupted. These results support Fn as a therapeutically relevant contributor to CRC progression and liver metastasis and suggest that MM@IRI-MTZ may provide an integrated antibacterial and antitumor strategy for reducing intratumoral Fn burden within the CRC tumor microenvironment.

Primary gastro-intestinal lymphomas (PGIL) are the most common extra-nodal lymphomas. Currently, existing prognostic models for gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) like the HLAMA model is lack of rigorous external validation. In this study, we conducted a multi-center retrospective investigation to establish a prognostic model for PGI-DLBCL. A total of 1 023 consecutive newly-diagnosed patients with PGIL were recruited from 9 medical centers in China. Among them, data of 462 patients with diffuse large B-cell lymphoma (DLBCL) who received R-CHOP treatment were analyzed, which was used as the training cohort. Additionally, data of 192 PGl-DLBCL patients from the other 3 medical centers were collected and used as the external validation cohort. A risk prediction model was constructed using the coefficients of weighted independent prognostic co-variates from the multi-variate analysis. It was found that patients with PGI-DLBCL receiving R-CHOP had better survival than those receiving CHOP (P < 0.001). In multi-variate analysis of the training cohort with PGI-DLBCL receiving R-CHOP, Age (P = 0.03), Lugano stage (P < 0.001), Hemoglobin (P = 0.04) and Lactic dehydrogenase (LDH) concentrations at diagnosis (P < 0.001) were significantly-associated with survival. Using these co-variates we constructed a survival prognosis nomogram model, resulting in C-statistics of 0.83 (0.79, 0.88) and 0.81 (0.73, 0.88) in the training cohort and the validation cohort, respectively. Our model, which includes 4 variables (Age, Lugano stage, LDH and Hemoglobin), is efficient in predicting survival of patients with PGI-DLBCL.

Chronic obstructive pulmonary disease (COPD), a disease responsible for early mortality worldwide, is well accepted to be associated with periodontitis epidemiologically. Although both of the diseases are the multi-microbial inflammatory disease, the precise underlying mechanisms by which periodontitis influences the progression of COPD remains largely unknown. Here, we established COPD accompanied with periodontitis mouse models and observed the pronounced progress in pulmonary symptoms and histopathology, characterized by poorer respiratory function, thickened bronchial walls, and increased neutrophils infiltration in lung tissue. Mechanistically, periodontitis pathogen Porphyromonas gingivalis (P. gingivalis) relocated in the lung through the respiratory tract and LPS from P. gingivalis promoted the secretion of chemokines CXCL2 and G-CSF of alveolar epithelial cells through NF-κB and p38 MAPK pathways to recruit neutrophils. Furthermore, exposure to P. gingivalis of infiltrated neutrophils released matrix metallopeptidase-8 (MMP-8) and neutrophil elastase (NE), which aggravated airway inflammation and tissue damage. These findings indicated that periodontitis could exacerbate COPD via its pathogen P. gingivalis, which translocated in the lung and stimulated neutrophil chemotaxis and activation in the lung.

11526 Background: Clinical studies show overexpression of multiple tyrosine kinase receptors in osteosarcoma, supporting targeted therapy as a promising direction. Anlotinib, a multi-targeted tyrosine kinase inhibitor, exerts anti-tumor angiogenesis effects. Combining anti-angiogenic agents with chemotherapy may yield synergistic tumor control, particularly as perioperative therapy. We present updated long-term efficacy and safety data, including key secondary endpoints, to validate this regimen’s clinical value. Methods: This was an open-label, single-arm, multicenter phase II trial. Eligible patients (12-40 years) had histologically confirmed primary localized stage IIB classic extremity osteosarcoma and were operable. Patients received anlotinib (10mg, po, d1-14, q3w), doxorubicin (A, 20-25 mg/m², iv, d1-3, q3w) and cisplatin (P, 70-90 mg/m², iv, d1, q3w) for 9 weeks. Radical surgery was performed at week 10 (no contraindications). Postoperatively, A+P was given at weeks 12-14, followed by anlotinib+A+P (same doses) at weeks 15-20. From week 21, anlotinib monotherapy (12mg, po, d1-14, q3w) continued until week 104 or an event-free survival (EFS) event. Primary endpoint: 24-month EFS rate. Secondary endpoints: 36-month EFS rate, local recurrence rate, lung metastasis rate, 3-year overall survival (OS) rate, and safety. Results: From May 2020 to April 2022, 52 patients were enrolled, treated, and included in full analysis set (FAS) and safety set (SS). Of these, 84.6% (44/52) were Han and 55.8% (29/52) male. Median follow-up was 42.7 months (IQR 30.4-52.7). The 24-month and 36-month EFS rates were 73.7% (95% CI 59.0-83.9) and 46.6% (95% CI 27.4-63.7), respectively. Median OS was not reached; 36-month and post-hoc 60-month OS rates were 74.6% (95% CI 59.6-84.7) and 71.4% (95% CI 55.5-82.4). Twenty-five percent (13/52) of patients died, mostly due to lung metastasis (13%). Among 51 surgical patients, local recurrence, lung metastasis, and other-site metastasis occurred in 23.5%, 17.6%, and 9.8%, respectively. Median recurrence-free survival (RFS) was 32.4 months (95% CI 25.7-not estimable). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 84.6% (44/52) of patients, with neutropenia most common (28/52 [53.8%]). No grade 5 TRAEs were observed. Serious TRAEs occurred in 40.4% (21/52), mainly myelosuppression (14/52 [26.9%]). None of the 13 on-study deaths were TRAE-related. Conclusions: Perioperative anlotinib plus cisplatin and doxorubicin shows promising efficacy in treatment-naïve stage IIB classic extremity osteosarcoma, with manageable safety. It achieves favorable long-term OS, and clinically acceptable local recurrence and lung metastasis rates, serving as a potential new perioperative option for this population. Clinical trial information: ChiCTR 2000033298.

NK cells demonstrate potent antitumor activity but show limited efficacy in gastric cancer (GC) due to poor tumor infiltration and dysfunction. To overcome this, we investigated the therapeutic potential of combining NK cell (expanded from healthy donor PBMCs) with chemotherapy (oxaliplatin + fluorouracil). In vitro, low-dose chemotherapy significantly upregulated activating ligands, particularly death receptors, on GC cells, enhancing NK cell cytotoxicity. In vivo, chemotherapy promoted NK cell proliferation, persistence, and tumor infiltration while modulating the immunosuppressive microenvironment. The combination therapy significantly improved therapeutic efficacy across GC models without increasing chemotherapy-related toxicity, instead alleviating weight loss and leukopenia. These findings support chemo-NK cell combination as a promising GC treatment strategy.

ADGRL3 is an important protein mediating neural activities, which is closely associated with various physiological processes including synaptic regulation, motor function, attention, and cognitive behaviors. However, its role in cerebral ischemia has not been investigated to date. In this work, we used CZ-7 which is a pyrano[3,2-a]carbazole alkaloid as hit compound and synthesized 25 nitrone/oxime-bearing derivatives. Pharmacological evaluations showed that 14a and its nano formulation (14a-NPs) mitigated multiple indices of cerebral ischemic injury, outperformed Edaravone-Dexborneol and dl-3-n-butylphthalide (dl-NBP), and displayed a favorable safety profile. Pharmacokinetic results showed that 14a-NPs was highly enriched in the brain compared with plasma. Meanwhile, transcriptomic analysis identified ADGRL3 as its therapeutic target, and the synaptic protective effect of 14a was verified. Collectively, we report for the first time that ADGRL3 is a novel therapeutic target for stroke, and that 14a exerts protective effects against cerebral ischemic injury by targeting ADGRL3 to preserve synaptic function.

Five undescribed neolignans (1-5), and three known compounds (6-8) were isolated from the root bark of Magnolia officinalis Rehd. et Wils. Compounds 3 and 4 were obtained as racemates and separated completely using a chiral column. Their structures were elucidated through extensive analyses of 1D and 2D NMR, HRESIMS, and electronic circular dichroism (ECD) calculations. The hepatoprotective activities of all isolates were assessed. Results indicated that compounds 1 and 8 exhibited significant hepatoprotective activity in both APAP- and H2O2-induced liver injury models. Further in vitro experiments demonstrated that compound 1 attenuated apoptosis by reducing reactive oxygen species production and modulating the expression of key apoptotic proteins.

4118 Background: China bears a high biliary tract cancer (BTC) burden, with cholangiocarcinoma rising incidence ( > 6/100,000 vs 0.3–6/100,000 globally) and high mortality ( > 4/100,000). Over 60% of BTC patients are diagnosed at advanced stage (stage III/IV), and nearly two-thirds are unresectable. GEMOX regimen is a widely recognized standard of care in China, favored for its reduced renal toxicity and better tolerability compared with GemCis. Envafolimab is the world's first subcutaneously (SC) injectable anti-PD-L1 monoclonal antibody approved by China's NMPA. We report the final analysis of this pivotal trial, the first global phase III study initiated to evaluate immunotherapy plus chemotherapy in this setting. Methods: In this multicenter, open-label, phase III study in China, eligible patients (pts) with previously untreated, unresectable locally advanced/metastatic BTC were randomized 1:1 to envafolimab (2.5 mg/kg SC weekly) + GEMOX (gemcitabine 1000 mg/m² d1, 8; oxaliplatin 85 mg/m² d1, Q3W) or GEMOX chemotherapy alone. Chemotherapy was limited to 6 cycles in both arms. Stratification factors: primary site, disease stage, prior therapy, and ECOG PS. Primary endpoint: OS. Secondary endpoints: PFS, ORR (RECIST v1.1 by BICR), and safety. Results: 472 pts were randomized; 462 treated (envafolimab+GEMOX n = 232; GEMOX n = 230). At the final analysis, the primary endpoint was met well. Envafolimab+GEMOX significantly improved OS vs GEMOX (HR 0.723; 95% CI 0.585–0.880; P = 0.0016). Median OS was 10.9 months vs 8.6 months; 36-mo OS rates were 12.5% vs 7.7%. OS benefit was observed across subgroups, notably in intrahepatic cholangiocarcinoma (HR 0.705) and metastatic disease (HR 0.704). Median PFS (BICR) was 4.8 vs 4.6 months (HR 0.899; 95% CI 0.713–1.132); notably, the gallbladder cancer subgroup showed more favorable PFS benefit (HR 0.628). ORR was 27.6% vs 20.9%. Grade 3–4 TEAEs occurred in 69.4% (combination) vs 56.1% (chemo). irAEs occurred in 20.7%. Conclusions: This study demonstrates that adding subcutaneously administered envafolimab to GEMOX significantly improves OS with a manageable safety profile in advanced BTC. Compared with other regimens, the combination showed robust efficacy with a low rate of irAEs. Those findings establish envafolimab, the world's first SC PD-L1 inhibitor, combined with GEMOX as a new, effective, and convenient standard of care for this population. Clinical trial information: NCT03478488 .

BackgroundHepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) carries a poor prognosis. Although SBRT combined with cadonilimab and lenvatinib has shown encouraging antitumor activity in a prior prospective phase II trial, marked interpatient heterogeneity remains. Gut microbiota may influence antitumor immunity and could help identify patients more or less likely to benefit from this regimen.ObjectiveTo characterize baseline and longitudinal gut microbiota features in treatment-naïve HCC patients with PVTT receiving SBRT plus cadonilimab and lenvatinib, and to explore microbial signatures associated with therapeutic response.MethodsThis is a complementary exploratory study nested within the aforementioned phase II trial. In this prospective multicenter exploratory cohort, 23 patients from the parent trial provided 46 paired fecal samples collected before treatment (Phase A) and after 3 cycles of cadonilimab (Phase B). Patients were categorized by best mRECIST response as responders (group C, CR/PR; n = 10) or non-responders (group D, SD/PD; n = 13), consistent with the parent trial’s grouping strategy. 16S rRNA amplicon sequencing and downstream bioinformatic analyses were performed to assess microbial diversity, differential taxa, predicted KEGG functional profiles, and exploratory discriminatory performance.ResultsA total of 1,410,203 high-quality non-chimeric reads were retained and rarefied to 5,459 reads per sample. Baseline α-diversity indices were largely comparable between groups, although Faith’s phylogenetic diversity was higher in responders (P = 0.0178). β-diversity did not show clear between-group separation at baseline or marked restructuring after treatment. Genus-level DESeq2 analysis identified 7 baseline differential genera. Extibacter was absent in responders but detectable in 6/13 non-responders and showed the strongest discriminatory signal (P = 0.0179). Predicted functional analysis suggested differences in KEGG level 2 modules, and [Ruminococcus]_gnavus_group was positively correlated with “immune diseases” and “carbohydrate metabolism” after BH correction (q = 0.042). In exploratory ROC analysis, baseline Extibacter yielded an AUC of 0.731, increasing to 0.777 when combined with AFP.ConclusionsIn HCC patients with PVTT treated with SBRT plus cadonilimab and lenvatinib, the overall gut microbiota architecture remained relatively stable, whereas selected baseline genus-level features were associated with therapeutic response. Extibacter showed an exploratory non-response-associated signal that requires validation in larger independent studies.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT06040177.

BACKGROUND:SHR-A2102 is a new antibody-drug conjugate consisting of a fully human nectin-4-directed monoclonal antibody bound to a topoisomerase I inhibitor payload via a cleavable linker. We did a phase 1 trial to evaluate the safety, preliminary activity, and pharmacokinetics of SHR-A2102 in advanced solid tumours. METHODS:This multicentre, single-arm, phase 1 trial was done at 39 hospitals in China and included dose-escalation (Bayesian Optimal Interval design), pharmacokinetic-expansion, and efficacy-expansion stages. Eligible patients were aged at least 18 years, had unresectable, locally advanced or metastatic solid tumours that had progressed after, were intolerant to, or had no available standard therapy, and had an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received SHR-A2102 intravenously at doses of 2-10 mg/kg once every 3 weeks. The primary endpoints were safety, dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. All patients who received at least one dose of SHR-A2102 were included in the safety and activity analyses. This trial is registered at ClinicalTrials.gov (NCT05701709) and is ongoing. FINDINGS:Between April 17, 2023 and Feb 20, 2025, 395 patients (median age 59 years [IQR 53-66]; 239 [61%] male and 156 [39%] female; 395 [100%] Chinese) were enrolled and treated across study stages, including 197 with non-small cell lung cancer, 32 with hormone receptor-positive, HER2-negative breast cancer, 36 with triple-negative breast cancer, 77 with oesophageal squamous cell carcinoma, 26 with head-and-neck squamous-cell carcinoma, and 27 with other solid tumours. As of data cutoff (June 20, 2025), the median follow-up was 7·2 months (IQR 4·7-9·7). Based on data from the dose-escalation stage, 6 mg/kg (n=10) and 8 mg/kg (n=11) were selected for pharmacokinetic expansion. During dose escalation, one dose-limiting toxicity was reported at 10 mg/kg (grade 4 decreased platelet count); maximum tolerated dose was not reached. Grade 3-4 treatment-related adverse events were reported in 212 (54%) of 395 patients, with the most common being decreased neutrophil count (118 [30%]), decreased white-blood-cell count (75 [19%]), and anaemia (69 [17%]). Treatment-related serious adverse events were reported in 98 (25%) patients with the most common being pneumonia (21 [5%]). Treatment-related deaths occurred in two (<1%) patients (pulmonary embolism and pneumonia). INTERPRETATION:SHR-A2102 demonstrated a safety profile consistent with its topoisomerase I inhibitor payload and showed promising activity in patients with various advanced solid tumours who had previously received anti-cancer treatment. A range of active dose was identified in various tumour types. Several trials are ongoing to evaluate SHR-A2102, either as monotherapy or in combination, in advanced solid tumours. FUNDING:Jiangsu Hengrui Pharmaceuticals.

Insufficient T cell infiltration into solid tumors represents a major barrier to effective immunotherapy, particularly in the context of CAR-T therapy. Identifying key molecules capable of promoting T cell migration to tumor sites is therefore critical. GPR183 (EBI2), a receptor for oxidized sterols, has not yet been fully characterized in terms of its role in antitumor T cell immunity or its potential for application in CAR-T cell engineering. Public single-cell transcriptomic data from breast cancer and ovarian cancer were analyzed to identify distinct expression patterns of GPR183 across T cell subsets, which were validated using flow cytometry. Functional assays, including in vitro Transwell migration experiments, as well as GPR183 knockout and overexpression models, demonstrated that GPR183 regulates T cell migration. To investigate the underlying molecular mechanisms, we employed ligand stimulation, co-culture systems, and transcriptome sequencing. Furthermore, we generated HER2-targeted CAR-T cell models with either GPR183 knockdown or overexpression, and systematically evaluated the impact of GPR183 on CAR-T cell function through in vitro cytotoxicity assays, IFN-γ secretion measurements, and in vivo tumor xenograft models in mice. Single-cell analysis revealed that GPR183high T cells exhibit a central memory phenotype and are enriched in migration-related signaling pathways. Functional experiments confirmed that GPR183 acts as a key positive regulator of T cell migration. Mechanistically, direct contact between T cells and tumor cells induced upregulation of CH25H and CYP7B1 in tumor cells, leading to increased production of 7α,25-OHC, which activated GPR183 and further enhanced its expression, establishing a positive feedback loop. In the HER2-CAR-T model, GPR183 overexpression significantly enhanced tumor infiltration, IFN-γ secretion, and tumor cell killing, and resulted in an additively improved antitumor efficacy in vivo. This study reveals, for the first time, that the GPR183-mediated positive feedback loop is a critical novel mechanism governing T cell tumor infiltration. Enhancing GPR183 expression through genetic engineering represents a promising strategy that significantly improves the migratory capacity and antitumor functionality of CAR-T cells, thereby providing a new therapeutic target and theoretical foundation for overcoming current limitations in the treatment of solid tumors.

Gastric cancer (GC) remains a leading cancer-related cause of death globally, with limited effective therapies due to drug resistance and heterogeneity. Triptolidenol (TPO), a diterpenoid derived from Tripterygium wilfordii Hook. f., exhibits enhanced water solubility and safety compared with triptolide (TPL), albeit with reduced antitumor activity. To address this trade-off, nitric oxide (NO)-releasing TPO derivatives were synthesized by conjugating TPO to furoxan, and compound A9 was identified as the most potent candidate. A9 exhibited sub-micromolar inhibitory activity against GC cells (HGC27 cells: IC50 = 0.10 ± 0.01 μM; AGS cells: IC50 = 0.02 ± 0.01 μM) in vitro, outperforming TPO. Mechanistically, A9 exerts synergistic antitumor effects through two distinct pathways. First, it releases NO to induce a mitochondrial ROS (Mito-ROS) burst, which in turn triggers mitochondrial dysfunction and activates the Bax/Bcl-2-Cyt c-Caspase-9/Caspase-3 apoptotic pathway. Second, A9 targets the folate one-carbon metabolism (FOCM) enzymes SHMT2 and MTHFD2, leading to decreased NADPH/NADP+ and GSH/GSSG ratios, which disrupts redox homeostasis and further amplifies intracellular ROS accumulation. In the HGC27 xenograft model, 15 mg/kg A9 achieved 98.78% tumor growth inhibition (TGI). Collectively, A9 integrates NO-mediated ROS induction and FOCM inhibition, emerging as a promising lead compound for the preclinical development of gastric cancer therapeutics.

The recent rise of piezoelectronic technology has revitalized ultrasound-mediated tumor therapy through sonopiezoelectric therapy (SPT). However, piezoelectric semiconductor nanomaterials used as sonocatalysts still face challenges. On the one hand, its sonocatalytic efficiency requires improvement; on the other hand, its catalytic selectivity remains poor. Therefore, enhancing the yield of highly cytotoxic catalytic products is of significant importance. Chiral-Induced Spin Selectivity (CISS) provides a robust foundation for controlling catalytic reaction processes, thereby boosting the yield of highly cytotoxic products. This study pioneers the integration of the CISS effect into sonodynamic tumor therapy, significantly boosting the therapeutic efficacy. Employing R-MBA_MoS2/S-MBA_MoS2/rac-MBA_MoS2 as sonocatalysts, we investigated the enhancement of SPT by chiral molecules. The results demonstrate a significant increase in the yield of ·OH and O2, exhibiting outstanding antitumor efficacy. This phenomenon is attributed to the CISS effect. This study aims to achieve chirality-enhanced sonocatalytic antitumor therapy, opening new avenues for simple and efficient cancer treatment.

Background:Emerging observational and clinical studies have highlighted the role of gut microbiota in hematologic malignancies, including malignant lymphoma. However, conflicting findings persist regarding the causal direction of this relationship, as traditional studies are susceptible to confounding factors and reverse causality. Mendelian randomization (MR) analysis, leveraging genetic variants as instrumental variables (IVs), offers a robust approach to infer causality by minimizing these biases. Here, we investigate the bidirectional causal links between gut microbiota and malignant lymphoma, addressing controversies in existing population-based studies. Methods:Bidirectional two-sample MR analysis was used to examine the causal relationship between malignant lymphoma and gut microbiota. The summary-level data of gut microbiota was obtained from the MiBioGen Consortium, a large-scale genome-wide study, involving 18,340 participants from a multiethnic cohort. Summary statistics for malignant lymphoma were sourced from the OpenGWAS website, which contains data from 490,803 participants. Using the standard quality-controlled single-nucleotide polymorphism (SNP) as an IV, we examined the potential causative link between gut microbiota and malignant lymphoma via the inverse variance weighting, MR Egger, weighted median, weighted model, and simple mode. Reverse MR analysis was further conducted on bacterial taxa identified as causally associated with malignant lymphoma in the forward MR analysis. Results:Seven causal relationships between gut microbiota and malignant lymphoma were found, including the phylum Bacteroidetes [odds ratio (OR) =1.31; 95% confidence interval (CI): 1.02-1.68; P=0.03], the class Bacilli (OR =1.22; 95% CI: 1.00-1.49; P=0.048), the family Rikenellaceae (OR =1.27; 95% CI: 1.04-1.55; P=0.02), the genus Eubacterium nodatum group (OR =1.13; 95% CI: 1.00-1.27; P=0.046), the genus Oxalobacter (OR =1.23; 95% CI: 1.06-1.43; P=0.006), the genus Parabacteroides (OR =1.41; 95% CI: 1.00-1.99; P=0.049), and the genus Sellimonas (OR =1.18; 95% CI: 1.03-1.35; P=0.02). No significant level pleiotropy or heterogeneity was detected in the IV, and there was no reverse causality between gut microbiota and malignant lymphoma. Conclusions:We investigated the potential causal relationship between gut microbiota and malignant lymphoma. Our findings provide a theoretical foundation for future research on the relationship between gut microbiota and lymphoma, and may facilitate the development of diagnostic, therapeutic, and preventive strategies for lymphoma in clinical practice.

4139 Background: The recurrence rate of hepatocellular carcinoma (HCC) remains high, with multinodular HCC being a well-defined high-risk factor for recurrence. However, standardized neoadjuvant or adjuvant therapies for HCC have yet to be definitively established to effectively improve survival outcomes. Methods: In this ongoing single-center, phase 2, open-label, prospective cohort clinical trial, eligible pts were randomly assigned (1:1:1) to three arms (15 pts per arm). Neoadjuvant therapies included: (A) 2 cycles cadonilimab (6mg/kg Q2W); (B) once FOLFOX- HAIC and 2 cycles cadonilimab; (C) once FOLFOX-HAIC. Pts receive scheduled surgery on day 21-28 and postoperative adjuvant HAIC one month after surgery. The primary endpoints were major pathologic response (MPR, defined as ≤50% residual living tumor) and the 1-year recurrence-free survival (RFS) rate. Secondary endpoints included overall response rate (ORR, assessed per RECIST 1.1) and treatment-related adverse events (TRAEs). Additionally, a direct hepatectomy cohort was retrospectively collected as reference data. Results: A total of 42 pts were enrolled. Among them, 2 pts withdrew due to their desire to pursue conversion therapy. 38 pts underwent hepatectomy and were included in the efficacy analyses (A: 14pts, B: 14pts, C: 12pts). The median age was 55 years (range: 32-72), with 90.5% being male and 90.5% infected with hepatitis B virus. Arm B had the highest MPR rate of 78.6%, significantly higher than Arms A (35.7%) and C (20.0%) ( P = 0.011). Additionally, Arm B had the highest ORR (A: 14.3%; B: 40.0%; C: 8.3%), and lowest MVI detection rate (A: 50.0%; B: 21.4%; C: 40.0%). Focal heterogeneity was partially observed. The DCR was 100%. The most common TRAEs were elevated aspartate transaminase (64.3%) and alanine aminotransferase (59.5%). Grade 3-4 TRAEs occurred in 3 pts(hepatic dysfunction and erythema annulare). In Arms A and B, 4 pts experienced a delay in scheduled surgery by 2-4 weeks. The combination of HAIC and cadonilimab did not lead to a significant increase in TRAEs. After propensity score matching, the direct hepatectomy cohort was screened. Kaplan-Meier analysis revealed that the neoadjuvant cohort had a longer recurrence-free survival (RFS) time compared to the direct hepatectomy cohort (median RFS not reached vs. 24.7 months; P = 0.0048) and a lower MVI detection rate (36.8% vs. 52.6%). Conclusions: Neoadjuvant FOLFOX-HAIC combined with cadonilimab had a considerable antitumor activity, and a manageable safety for the resectable multinodular HCC. It brought the fewer MVIs of tumor and a better RFS. Clinical trial information: ChiCTR3000033692 .

Hepatitis B virus (HBV) infection remains a severe global public health challenge, with hepatocellular carcinoma being a primary cause of HBV-related mortality. Occult HBV infection (OBI) represents a distinct type of HBV infection that has been increasingly linked to hepatocellular carcinoma development, yet the precise molecular mechanisms underlying this association remain poorly elucidated. Although HBV pre-S deletion mutations have been shown to enhance cell proliferation and contribute to hepatocarcinogenesis, the biological functions of other types of pre-S mutations, particularly point mutations, are still mostly unexplored. In our prior studies, we identified several high-frequency pre-S point mutations from OBI blood donors. Within this research, we systematically explored the effects of these OBI-associated pre-S mutations on host cell proliferation and assessed their potential oncogenic properties. Cell proliferation assays revealed that several pre-S mutations significantly enhanced the proliferative capacity of host cells. Mechanistically, five pre-S mutations (E39K, D44N, N98T, H128R, and I161T) activated the Akt/mTOR signaling cascade, up-regulated Cyclin D1 expression, and induced G1-to-S phase cell cycle progression. Further analyses suggested that the large HBV surface protein (LHBs) likely acts as the key mediator linking pre-S mutations to signaling activation and cellular proliferation. These findings provide novel mechanistic understandings of the oncogenic potential of pre-S point mutations in hepatocarcinogenesis and may facilitate the identification of high-risk individuals within OBI populations as well as the development of treatment strategies for hepatocellular carcinoma linked to HBV.