Oral squamous cell carcinoma (OSCC), a highly prevalent and poor-prognosis malignancy, is closely associated with tumor metabolic reprogramming, particularly the glutamine-dependent metabolic phenotype. This study systematically investigates the role of N6-methyladenosine (m6A) modification in OSCC through integrated bioinformatics analysis and functional experiments, focusing on the tumor-suppressive function of the m6A reader YTHDC2 and its regulation of glutaminolysis. Analysis based on The Cancer Genome Atlas (TCGA) datasets revealed that YTHDC2 expression was significantly inversely correlated with OSCC malignancy and patient survival. Functional validation showed that YTHDC2 depletion promoted OSCC cell proliferation and stem-like properties, whereas YTHDC2 overexpression markedly suppressed these malignant phenotypes. Mechanistic studies demonstrated that YTHDC2 stabilized VHL mRNA by recognizing m6A modification sites, enhancing VHL protein expression. This promoted VHL-mediated ubiquitin-dependent degradation of HIF-1α, leading to transcriptional repression of its downstream target GLS1. Consequently, this blocked glutaminolysis, tricarboxylic acid (TCA) cycle-driven energy production, and glutathione (GSH)-mediated antioxidant pathways. Additionally, low YTHDC2 expression in OSCC tissues was closely associated with DNA hypermethylation at CpG islands in its promoter, an epigenetic silencing mechanism that sustains the glutamine-addicted phenotype. This study first uncovers the core role of the YTHDC2/m6A/VHL/HIF-1α/GLS1 signaling axis in metabolic regulation of OSCC, providing new insights into the molecular basis of glutamine addiction. YTHDC2 not only serves as a prognostic biomarker for OSCC but also highlights its-mediated metabolic pathway as a theoretical basis for developing targeted therapies against glutaminolysis.

Information on siRNAs targeting ITGA5 and CD44

Background: Respiratory Syncytial Virus (RSV) is the primary cause of lower respiratory tract infections(LRTI ) in children. It is well-known that factors such as age, prematurity, and underlying comorbidities are associated with the severity of RSV, but whether the presence of co-detected pathogens is related to it remains unclear. In this study, we aimed to use targeted next-generation sequencing (tNGS) to describe the spectrum of co-detected pathogens in children with RSV-positive pneumonia admitted for LRTI, and risk factors for severe pneumoniain in children. Methods: This study included clinical data from children under 5 years of age who were hospitalized for LRTI and tested positive for RSV by tNGS between August 2024 and December 2025 at Guizhou Hospital, Shanghai Children's Medical Center, Guizhou Province.The children were divided into severe groups (n=173)and non-severe groups (n=79)based on disease severity. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for severe pneumonia, and results were reported as odds ratios (OR) and 95% confidence intervals (CI). Results: A total of 252 cases,152 boys（60.3%)were admitted with RSV-positive LRTI .Severe disease was documented for 173 cases (68.7%).Patients with severe disease were younger than those with non severe disease(median age, 7.8 months（IQR, 3.6~17.0 months）vs. 17 months（IQR, 8.8~26.5 months; P < 0.001). Multivar-iable analysis revealed that congenital heart disease(CHD) (OR = 2.76, 95% CI: 1.18~6.44, p = 0.019) and S. aureus (OR = 3.25, 95% CI: 1.23~8.55, p = 0.017) and P. jirovecii (OR = 2.59, 95% CI: 1.24~5.41, p = 0.011) were associated with severe disease, while RSVco-infected with other viral (OR = 0.30, 95% CI: 0.13~0.69, p = 0.005) and higher birth weight (OR = 0.52, 95% CI: 0.32~0.85, p = 0.008) showed a protective effect against severe RSV disease. Conclusion: In this cohort study reveal the diversity of co-detected pathogens in children with RSV-positive pneumonia. We identified that CHD, S. aureus , and P. jirovecii increase the risk of severe illness, while RSV co-infected with other viral and higher birth weight have a protective effect. These findings support prevention strategies for all younger children, including premature infants, with potential benefit for children aged 5years or younger in specific high-risk groups.

The combined therapeutic approaches by unique biomaterial have great attention for gastric cancer therapy with peritoneal metastasis. In this research report, we designed NIR-responsive Fe3O4@MIL-100(Fe)-Upconversion nanoparticles (FMUNPs) functionalized injectable β-cyclodextrin/hyaluronic acid macromolecular hydrogel-encapsulated with HER-2 targeting trastuzumab (TZB) molecules to induce ROS against gastric cancer cells. The developed FMUNPs could provide effective ROS generation ability by photo-Fenton rection with NIR irradiation for toxicity and cell death against gastric cancer cells (NCI-N87). The ROS generation-induced apoptotic efficiency of the treated groups was confirmed by expressions of pro-apoptotic and anti-apoptotic markers. The TZB/FMUNPs-hydrogel with NIR prominently produced cell death by apoptotic pathway, which was confirmed by flow cytometry method. In-vivo study demonstrated that the significant reduction on tumor volume and size when tumor-induced mice treated with developed formulation with NIR irradiation. This investigation outcome demonstrates this novel formulation could be a new avenue for the gastric cancer treatment.

Information on siRNAs targeting SDC4

Spatial distribution of myeloid cells in high-grade serous ovarian carcinoma

Detailed information for the entire cohort, including patient characteristics, sample sites, sample groups, and data types

Vascular smooth muscle cell (VSMC) migration is the key event in the pathogenesis of atherosclerosis (AS) and plaque instability. Trimethylamine-N-oxide (TMAO) induces VSMC migration to promote the progression of AS. However, the effects of the N6-methyladenosine (m6A) modification on this process remain unclear. Here, TMAO increased total m6A levels in human aortic smooth muscle cells (HASMCs) and decreased fat mass and obesity-associated protein (FTO) and YTH domain-containing family protein 2 (YTHDF2) protein expression. FTO or YTHDF2 overexpression significantly inhibited HASMC migration induced by TMAO. Mechanistically, the COL3A1 gene was shown to be critical for the regulation of HASMC migration by FTO or YTHDF2. Furthermore, methylated RNA immunoprecipitation and RNA stability assays demonstrated that FTO bound to the COL3A1 mRNA and altered its m6A modification, resulting in its decay. In vivo, VSMC-specific FTO or YTHDF2 deletion aggravated AS and plaque instability, whereas adeno-associated virus serotype 9 (AAV9)-mediated VSMC-specific YTHDF2 overexpression or COL3A1 knockdown exerted protective effects on AS and/or plaque instability. Notably, VSMC-specific FTO deletion promoted VSMC migration in atherosclerotic lesions in ApoE−/− AS model mice, whereas VSMC-specific YTHDF2 overexpression had the opposite effect. Overall, the in vitro and in vivo evidence highlights the critical role of the FTO/YTHDF2/COL3A1 axis in VSMC migration, AS, and plaque instability, suggesting that targeting the FTO/YTHDF2/COL3A1 axis in VSMCs may be a novel and promising therapeutic strategy for the treatment and prevention of AS and plaque instability.

Validation of SDC4+ EPCAM+ epithelial cells in multiple metastatic samples

Information on the primary antibodies used for additional assays

Spatial distribution of T cells in high-grade serous ovarian carcinoma

Rationale: Despite available therapies, patients with advanced non-small cell lung cancer have a poor prognosis, highlighting the need for novel treatment strategies. The combination of immune checkpoint inhibitors and chemotherapy represents a promising approach. This case report describes the efficacy and safety of this combination in a patient with aggressive metastatic disease. Patient concerns: A 60-year-old male patient, who had undergone surgical resection for primary lung adenocarcinoma, presented with newly developed subcutaneous nodules and symptoms suggestive of adrenal involvement during routine follow-up. Diagnoses: Histopathological and imaging examinations confirmed recurrent lung adenocarcinoma with metastases to the subcutaneous soft tissues and the adrenal gland. Interventions: The patient received platinum-based doublet chemotherapy combined with pembrolizumab (an anti-programmed cell death protein 1inhibitor) as second-line systemic therapy. Outcomes: Following several treatment cycles, imaging revealed marked regression of metastatic lesions, with only minimal treatment-related adverse events reported. The patient achieved a durable clinical response. Lessons: This case suggests that combining chemotherapy with programmed cell death protein 1 inhibition may provide rapid and effective tumor control in advanced non-small cell lung cancer patients with bulky, symptomatic metastases, while maintaining a manageable safety profile. Further clinical trials are warranted to validate this approach.

8512 Background: HLX43 (a PD-L1 ADC) has demonstrated encouraging efficacy with a manageable safety in a phase 1 study. Here, we present the pooled findings from patients with NSCLC in a phase 1 study (HLX43-FIH101) as well as a global phase 2 study investigating HLX43 in NSCLC (HLX43-NSCLC201). Methods: The phase 1 study included a dose-escalation phase in patients with advanced solid tumors (0.5–4.0 mg/kg Q3W), followed by a dose-expansion phase in patients with advanced or metastatic NSCLC at doses of 2.0, 2.5, and 3.0 mg/kg Q3W. The phase 2 study was conducted in NSCLC and comprised two parts: Part A was dose-exploration for patients who had failed prior first-line therapy and had no actionable genomic alterations, to receive HLX43 at 2.0 or 2.5 mg/kg Q3W; Part B was dose-expansion in which patients received HLX43 at the recommended dose determined from Part A. This analysis integrated data from heavily pretreated NSCLC patients enrolled across both studies. Efficacy and safety outcomes were evaluated in the pooled population. Results: As of December 31, 2025, 205 patients were enrolled and received HLX43 at 1 mg/kg (n = 3), 2 mg/kg (n = 89), 2.5 mg/kg (n = 85), 3 mg/kg (n = 23), and 4 mg/kg (n = 5). Patients received a median of 2 lines of prior antitumor therapy (range, 1–9). Among the 161 response-evaluable patients (2, 69, 64, 21, and 5 in the 1, 2, 2.5, 3, and 4 mg/kg groups, respectively), the investigator-assessed ORR was 31.1%. In the 2.0 mg/kg group, investigator-assessed ORR was 36.4% for squamous NSCLC (n = 33); among these patients, ORR was 40.0% for those who previously failed docetaxel (n = 15). ORR was 47.4%, and 50.0% for patients with EGFR-wildtype (n = 19), and EGFR-mutant (n = 16) nonsquamous NSCLC receiving HLX43 at 2.5 mg/kg. Biomarker exploratory analyses showed that efficacy was not associated with PD-L1 expression, with ORRs of 30.1% and 32.1% in patients with PD-L1-positive (n = 83) and PD-L1-negative tumors (n = 78), respectively. Overall, 199 (97.1%) patients experienced treatment-related adverse events (TRAEs), of whom 88 (42.9%) had grade ≥3 in severity. Most common Grade ≥3 TRAEs (incidence ≥10%) included lymphocyte count decreased (n = 47, 22.9%), white blood cell count decreased (n = 27, 13.2%), anemia (n = 25, 12.2%), and neutrophil count decreased (n = 23, 11.2%). TRAEs led to treatment discontinuation in 17 (8.3%) patients. Conclusions: HLX43 exhibited promising efficacy in patients with heavily pretreated advanced NSCLC, regardless of histology subtypes, and PD-L1 expression, along with manageable tolerability. Further investigation is warranted. Clinical trial information: NCT06115642 (HLX43-FIH101-phase 1 study), NCT06907615 (HLX43-NSCLC201- phase 2 study).

Spatial distribution and co-localization of molecular subtypes across 16 public HGSOC slices

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by profound intratumoral heterogeneity and immune evasion. Although previous research has identified 4 molecular subtypes of HGSOC, defining their spatial distribution across anatomic sites could help identify functional mediators of progression and immune evasion. In this study, we performed single-cell and spatial transcriptomic sequencing on 66 anatomically paired samples across 5 sites from 8 patients and conducted an integrated analysis on the generated datasets. Five distinct gene programs (GP) with specific spatial distributions and functional roles were identified: GP1 (differentiated-invasive), GP2 (differentiated-proliferative), GP3 (immunoreactive), GP4 (mesenchymal), and GP5 (proliferative). Interestingly, molecular subtypes exhibited dynamic spatial transitions that promote HGSOC progression. The differentiated-proliferative subtype dominated tumor cores, whereas the differentiated-invasive subtype localized to the invasive front driven by SDC4-expressing epithelial cells (c40) that were functionally validated to promote migration/invasion. Concurrently, immune evasion operated through distinct mechanisms. Differentiated-invasive and immunoreactive subtype co-localization established immunosuppression via the TNFα-SAA1/2-APOE signaling axis that recruits immunosuppressive myeloid cells across primary and metastatic sites, whereas fibroblast-derived collagen barriers were constructed at the interfaces between mesenchymal and immunoreactive subtypes in omental metastases along with dysregulated chemokines to exclude immune infiltration. This spatially resolved atlas directly links subtype spatial transitions to tumor progression and subtype co-localization to immune evasion, providing a mechanistic framework for targeting spatially organized tumor-immune interactions in HGSOC. SIGNIFICANCE:Spatially resolved transcriptomic analysis reveals tumor subtype transitions and niche-specific immune evasion mechanisms in ovarian cancer.

Validation of pro-invasive ligand–receptor interactions in ovarian cancer cell lines

BACKGROUND:TG-43 formalism dose calculation for brachytherapy with the homogeneous water-based assumption is widely used, which can lead to dose inaccuracy in treatment planning. PURPOSE:Extremity malignancies are also treated with high-dose-rate (HDR) 192Ir interstitial brachytherapy, a treatment site that has not been specifically investigated in prior comparative dosimetric studies, and the proximity of source dwell positions to bone and air introduces significant heterogeneity. BrachyPlanCheck, an in-house brachytherapy second dose verification program for Monte Carlo (MC) simulations, incorporates these heterogeneities and is used for a comparative dosimetric study on extremity malignancies. METHODS:BrachyPlanCheck was commissioned and validated in both a homogeneous water phantom and a heterogeneous breast phantom. The clinical evaluation included 8 patient-specific lower limb brachytherapy plans, comparing TG-43 and MC calculation using BrachyPlanCheck. Dosimetric differences were evaluated using dose comparisons, gamma index analysis, and dose-volume histogram (DVH) metrics for clinical target volume (CTV) and organ-at-risk (OAR), including bone and skin. RESULTS:In commissioning Level 1, MC simulations using BrachyPlanCheck demonstrated point dose agreement within ± 0.9%. Gamma passing rates exceeded 99.9% with criteria 1 mm/1% in commissioning Level 2. In clinical evaluation, TG-43 calculation overestimated CTV V150 by up to 10.50% and CTV D90 by up to 7.25%. OAR doses were generally higher with TG-43, with mean differences of 1.09% for bone D1cc (p =  0.109), 1.38% for bone D0.1cc (p =  0.078), 7.30% for skin D2cc (p =  0.008), and 5.68% for skin D0.1cc (p =  0.008). CONCLUSION:Validated by phantom and patient study, BrachyPlanCheck demonstrated robust performance for independent secondary dose verification. TG-43 calculation overestimated dose to CTV and OAR in extremity malignancy cases compared with BrachyPlanCheck.

Abstract Background: Elisrasib is a next-generation KRAS-G12C inhibitor (G12Ci) designed to improve target engagement (TE) efficiency and overcome growth factor-induced nucleotide exchange. This unique MoA distinguishes elisrasib from first-generation G12Ci and has led to robust anti-tumor activity in G12Ci-naïve/-resistant PDX models. Ph1 results demonstrated favorable safety and promising efficacy across NSCLC, CRC and PDAC. Here, we present updated findings in previously treated locally advanced or metastatic NSCLC patients (pts) (naïve and refractory to G12Ci) from the ongoing Ph1/2 trial (NCT05410145). Methods: Pts with locally advanced or metastatic KRAS G12C-mutated NSCLC were eligible. All pts must had received at least one prior line of systemic treatment, including IO and/or platinum doublet chemotherapy. For G12Ci-refractory pts, they were required to have radiologically or clinically documented PD following a KRAS G12Ci. Elisrasib was administered orally QD in 21-day cycles at 6 planned dose levels (50-900mg) in the dose escalation and 600mg was selected as the treatment dose for expansion cohorts. The key objectives included safety, efficacy, and ctDNA kinetics by liquid biopsy (Guardant360® CDx or OncoCompass® Target). Results: As of 06 Jan 2026, total 165 NSCLC pts across 9 countries received elisrasib monotherapy (2 in 50mg, 5 in 100mg, 4 in 200mg, 6 in 400mg, 144 in 600mg and 4 in 900mg). Median study follow up time for 2L+ G12Ci-naive and G12Ci-refractory NSCLC were 11.3m and 10.6m, respectively. TRAEs of any grade occurred in 143/165 (87.9%) pts, ≥G3 TRAEs occurred in 19/165 (11.5%) pts. The safety profile in NSCLC pts is comparable with overall population. In 2L+ G12Ci-naïve NSCLC (50-900mg QD), 84 pts were evaluable for efficacy. ORR was 57.1% (48/84) with 1 CR and DCR of 98.8%. mPFS, mDOR and 12m OS rate (OS was not matured) were 8.8m, 12.5m, and 67%, respectively. At 600mg QD (68 evaluable pts), ORR was 55.9% (38/68) with 1 CR and DCR of 98.5%. mPFS, mDOR and 12m OS rate (OS was not matured) were 11.8m, 14.9m, and 71%, respectively. In 2L+ G12Ci-refractory NSCLC (600mg QD), 31 pts were evaluable for efifcacy. ORR was 32.3% (10/31) and DCR of 83.9%. mPFS, mDOR and 12m OS rate (OS was not matured) were 8.1m, 8.2m, and 69%, respectively. PK at 600mg QD achieved Ctrough exposure (5.6 nM) which was 5x greater than required exposure (1 nM) for complete TE. Baseline ctDNA G12C+ was detected in 68% (54/80, 4 pts were excluded due to incomplete data) of G12Ci-naïve and 68% (21/31) G12Ci-refractory pts, with 93% (50/54) and 76% (16/21) achieved molecular response (≥90% G12C MAF reduction), respectively. Notably, 4/5 G12Ci-refractory pts with G12C amplification, a known resistant MoA, showed tumor shrinkage, including three achieved cPR. Conclusions: Elisrasib monotherapy demonstrates robust and durable efficacy and favorable tolerability in 2L+ NSCLC pts, naïve and refractory to G12Ci. Citation Format: Byoung Chul Cho, Shun Lu, Ziming Li, John Park, Jun Zhao, Herbert Ho Fung Loong, Antoine Hollebecque, Bin Yang, Binchao Wang, Cheng Chen, Jia Wang, Shaonan Wang, Yandong Shen, Zifei Fan, Qian Chen, Hui Wang, Jing Zhang, George Zhi Jian Chen, Melissa Johnson, Tony Shu Kam Mok. Safety and efficacy of Elisrasib (D3S-001), a next generation GDP-bound KRAS G12C inhibitor, as monotherapy in advanced non-small cell lung cancer (NSCLC) previously treated with or without a KRAS G12C inhibitor: Results from a phase 1/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT020.

Spatial distribution of plasma cells in high-grade serous ovarian carcinoma