BACKGROUND:There is an unmet need for additional and more efficacious therapies for patients with unresectable metastatic oesophageal cancer. We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma. METHODS:The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60-80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles. The primary outcomes were independent review facility-assessed progression-free survival and overall survival in the intention-to-treat population (defined as all randomly assigned patients, regardless of whether they received any study treatment). This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing. FINDINGS:Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian. Median survival follow-up was 12·6 months (IQR 6·8-18·0). Median independent review facility-assessed progression-free survival (cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7-7·2) versus 5·4 months (95% CI 4·4-5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45-0·70; p<0·0001). Median overall survival (cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3-20·4) and 11·1 months (95% CI 9·6-13·6; HR 0·70, 95% CI 0·55-0·88; p=0·0024). The most common grade 3-4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]). Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse event was pneumonia (17 [7%] of 228 and 13 [6%] of 227). Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause). No new safety signals were identified. INTERPRETATION:Independent review facility-assessed progression-free survival and overall survival were significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma. These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need. FUNDING:F Hoffmann-La Roche-Genentech.

Photodynamic therapy (PDT) is a localized treatment for esophageal stenosis and dysphagia in advanced cancer. This study evaluated the efficacy and safety of Cosiporfin sodium (DVDMS)-mediated PDT for dysphagia in advanced esophageal cancer. In this Phase II trial, patients with advanced esophageal cancer and Grade ≥ 2 dysphagia, who were unsuitable for or declined curative therapies, received 0.2 mg/kg DVDMS followed by PDT (wavelength: 630 nm) at varying regimens: 102 J/cm (24 h post-injection), 200 J/cm (24 h), and 150 J/cm (18 h). Safety was the primary endpoint. The study enrolled 20 patients in the 102 J/cm 24 h group, 6 in the 200 J/cm 24 h group, and 4 in the 150 J/cm 18 h group. Two patients experienced dose-limiting toxicities: One upper abdominal pain (16.7%) in the 200 J/cm 24 h group and one non-cardiac chest pain (25.0%) in the 150 J/cm 18 h group. Common adverse events included non-cardiac chest pain (10.0%) related to DVDMS and non-cardiac chest pain (20.0%) and anemia (20.0%) related to PDT. The photosensitivity test showed that by day 4, 66.7% of patients tested negative, improving to 86.7% by day 7, and all patients were negative by day 28. The esophageal overall response rate was 40.0% on day 28. The median duration of esophageal response and median OS for all patients were 4.86 months (95% CI: 1.51-5.32) and 9.51 months (95% CI: 5.45-NE), respectively. DVDMS-mediated PDT demonstrates acceptable safety and sustained efficacy in improving esophageal stenosis and dysphagia in advanced esophageal cancer. Trial Registration: chictr.org.cn ChiCTR2000032829.

Background:Early detection of esophageal squamous cell carcinoma (ESCC) is critical for optimizing patient outcomes. Magnifying endoscopy and endoscopic ultrasonography (EUS) serve as established diagnostic modalities. The multimodal ultrasound and magnifying endoscopic algorithm for early ESCC diagnostics (MUMA-EDx) integrates deep learning-based magnifying endoscopy and EUS imaging to improve early-stage ESCC identification and invasion depth assessment. Methods:Model development and internal validation used a retrospective dataset; external validation used a prospective cohort. MUMA-EDx developed two TResNet_m-based classifiers (magnifying endoscopy/EUS) followed by feature-level fusion. Model performance was evaluated using area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. Results:MUMA-EDx was developed and validated using a retrospective dataset comprising 358 patients (18 420 images) and subsequently tested prospectively on an independent cohort of 122 patients (8711 images). The feature-level multimodal approach significantly outperformed single-modality models. For tumor discrimination, the model achieved an AUC of 0.94 (95%CI 0.92-0.96) in retrospective validation and a perfect patient-level AUC of 1.00 (95%CI 1.00-1.00) in prospective testing. For the more complex task of multiclass invasion depth classification, it achieved a retrospective AUC of 0.95 (95%CI 0.88-0.99), which remained strong at 0.80 (95%CI 0.67-0.87) in the prospective cohort. In a comparative study on invasion depth classification, MUMA-EDx's performance exceeded that of novice endoscopists and was comparable to expert-level diagnostics. Conclusion:MUMA-EDx demonstrably delivers exceptional early ESCC detection and robust invasion depth classification, achieving performance comparable to expert endoscopists and is poised to significantly enhance diagnostic precision and patient outcomes.

4047 Background: SYS6010 is an EGFR- ADC composed of an EGFR-specific antibody, a cleavable linker, and the topoisomerase I inhibitor (TOPOi) JS-1. Preliminary clinical data from the phase I study of SYS6010 monotherapy in patients with solid tumors showed an acceptable safety and encouraging preliminary efficacy (ChiCTR2300072141). Here, we report the efficacy and safety results of SYS6010 in patients with ESCC in the phase II trial. Methods: Patients with advanced ESCC that was refractory or intolerant to standard therapy were enrolled. In the dose-expansion part, SYS6010 was administered intravenously at a dose of 3.6 mg/kg every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) assessed by the investigator. Results: As of Jan 14, 2026, 48 patients with ESCC (median age, 64.5 years; male, 89.6%; ECOG PS 1, 87.5%; metastatic disease, 93.8%) were enrolled and received SYS6010. Ten patients (20.8%) had received ≥3 prior lines of systemic therapy. The median follow-up was 3.9 months (mo; Q1-Q3: 3.1-5.6). Among 40 efficacy-evaluable patients, the confirmed ORR (cORR) was 35% (95%CI 20.6-51.7), and the disease control rate (DCR) was 67.5% (95%CI 50.9-81.4). Median progression-free survival (mPFS) was 4.6 mo (95% CI, 2.7–NR; 48% maturity). The 3-mo and 6-mo PFS rates were 56.3% and 41.4%, respectively. 15 patients remain on treatment with SYS6010. For TOPOi-naïve patients (n = 34), cORR and DCR were 41.2% (95%CI 24.7-59.3) and 70.6% (95%CI 52.5-84.9), respectively. mPFS was 4.6 mo (95%CI 2.8-NR; 45% maturity), with 3-mo and 6-mo PFS rates of 62.5% and 43.2%, respectively. 14 patients remain on treatment with SYS6010. Overall, 97.9% (47/48) of patients experienced treatment-related adverse events (TRAEs). Grade ≥3 TRAEs occurred in 31 (64.6%) patients. Common grade ≥3 TRAEs (≥5%) included neutropenia (29.2%), anemia (18.8%), leukopenia (18.8%), thrombocytopenia (12.5%), lymphocytopenia (8.3%), vomiting (8.3%), and nausea (6.3%). TRAEs led to treatment discontinuation in 4 (8.3%) patients. One death of unknown reason was reported and assessed by the investigator as related to the study drug. Conclusions: SYS6010 demonstrated a manageable safety profile and promising antitumor activity, supporting further development in patients with advanced ESCC, especially TOPOi-naïve patients. A phase 3 study is planned to compare SYS6010 with standard of care (SOC) in patients with TOPOi-naïve ESCC. Clinical trial information: ChiCTR2500099933.

OBJECTIVES:To develop a hollow Cu9S8-based nanoparticles loaded with the photosensitizer IR780, investigate its photothermal and photodynamic (PTT-PDT) effects against esophageal cancer cells and analyze the underlying mechanisms. METHODS:Hollow Cu9S8 nanoparticles were synthesized using a sacrificial-template strategy, and IR780 was encapsulated within a lauric acid matrix to serve as a phase-change material for preparing IR780@Cu9S8 composite nanoparticles. The composite nanoparticles were characterized for morphology and structural attributes using transmission electron microscopy, X-ray diffraction, and UV-visible spectroscopy. The effects of IR780@Cu9S8 on proliferation, invasion, and migration of esophageal cancer cells under near-infrared (NIR) irradiation (808 nm, 1.5 W/cm², 5 min) were assessed using CCK-8 assay, live/dead staining, reactive oxygen species, mitochondrial membrane potential assay, wound-healing assay, and Transwell assay. The in vivo PTT-PDT therapeutic efficacy and biosafety of IR780@Cu9S8 was evaluated in a mouse model bearing subcutaneous esophageal cancer xenografts. RESULTS:The synthesized IR780@Cu9S8 nanoparticles exhibited a uniform quasi-spherical morphology with a photothermal conversion efficiency of 44.0%. Under NIR irradiation, IR780@Cu9S8 produced pronounced synergistic PTT-PDT effects against KYSE150 cells, causing a significant reduction of cell viability and marked suppression of cell proliferation, migration, and invasion. In the tumor-bearing mice, IR780@Cu9S8 and 808 nm laser irradiation exhibited strong synergistic PTT-PDT effects and significantly inhibited tumor growth with a good biocompatibility. CONCLUSIONS:The IR780@Cu9S8 composite nanoparticles achieve synergistic PTT-PDT antitumor activity in esophageal cancer cells which can be a promising strategy for combined therapy and targeted drug delivery for esophageal cancer.

Introduction RBF neural networks are widely used in gastric carcinoma prognostic models, but they face challenges including difficulty in determining the Gaussian radial basis function parameters of the hidden layer and the diversity/ambiguity of factors affecting gastric carcinoma prognosis. The cloud model, a key tool in uncertainty theory, is adept at handling fuzziness and randomness of complex medical data by quantifying uncertainty. This study integrates the cloud model with RBF neural networks to address the aforementioned limitations.Methods The study included 11,474 gastric carcinoma patients from the SEER database and 769 from the Linzhou Centre for Disease Control and Prevention database. A new model combining a cloud model with RBF neural networks was used, where high-dimensional cloud transformations identified RBF hidden layer neurons to optimize the network structure.Results Comparison with conventional methods showed that the new model predicted overall survival (OS) with a C-index of 0.715. This value is not only significantly higher than that of clinical standard TNM staging (0.591) but also outperforms machine learning methods including random forest (0.614) and traditional RBF neural networks (0.632). It achieves excellent prognostic accuracy meeting the clinical criterion of good discriminative ability, even relying solely on simple clinical factors, which enhances its clinical applicability.Conclusion The model is a new and effective prognostic model that provides better and more accurate prognostic assessment for gastric carcinoma patients.

Cancer therapy-related cognitive impairment (CTRCI) is a debilitating neurotoxic condition adversely impacting cancer patients during and post-cancer treatments. The cancer treatments linked to CTRCI include chemotherapy, hormone therapy, targeted therapy, and immunotherapy. Despite CTRCI severely affecting the psychological and social, cognitive functions, and the overall quality of life of cancer survivors, no effective medications are available currently. Our prior studies have indicated hippocampal tyrosine phosphatase protein tyrosine phosphatase receptor type O (PTPRO) as a putative target for CTRCI. However, phosphatase is historically considered undruggable, and delivering drugs across the blood-brain barrier (BBB) is challenging. Here, we developed a novel delivery system using neuron-targeted extracellular vesicles (EVs) engineered with a neuron-specific peptide rabies virus glycoprotein (RVG) to transport a small activating RNA (saRNA) targeting Ptpro (RVG-EVs-saPtpro). We evaluated the stability, dynamic distribution, cytotoxicity, and brain specificity of RVG-EVs-saPtpro in cellular and animal models. A single intravenous injection of RVG-EVs-saPtpro resulted in sustained elevation of PTPRO in the brain for at least 28 days in CTRCI mice. More importantly, RVG-EVs-saPtpro significantly alleviated CTRCI symptoms by enhancing neuronal survival, neurogenesis, and synaptic plasticity. These findings highlight the potential of RVG-EVs-saPtpro system for targeted treatment of CTRCI.

Protein tyrosine phosphatase receptor-type O (PTPRO), a member of the PTP family, has garnered attention for its diagnostic and prognostic potential through the methylation of circulating tumor DNA (ctDNA). However, the utility of ctDNA has shown limited sensitivity and specificity, particularly in early-stage lung adenocarcinoma (LUAD). Given the enhanced stability of tumor-derived DNA in small extracellular vesicles (sEVs) from cancer cells, this research investigates the feasibility of using PTPRO methylation in saliva-derived sEVs as a non-invasive and easily accessible biomarker for the early detection of LUAD. To explore the relationship between PTPRO methylation and prognosis in early-stage LUAD, we conducted Kaplan-Meier survival analyses and assessed the methylation status of the PTPRO promoter using methylation-specific PCR (MSP) and q-MSP. Saliva samples were collected from 60 early-stage LUAD patients, 30 pneumonia patients, and 21 healthy controls, with isolation and characterization of salivary sEVs through transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and immunoblotting. Kaplan-Meier analysis revealed hypermethylation of PTPRO was linked to poorer overall survival in early-stage LUAD patients. PTPRO methylation was detected in salivary sEVs of 73.3% of early-stage LUAD patients, compared to only 35% in plasma sEVs. Receiver operating characteristic (ROC) analysis confirmed that PTPRO methylation in salivary sEVs effectively distinguished early-stage LUAD patients from both pneumonia patients and healthy individuals. This suggests that PTPRO hypermethylation is associated with adverse prognosis in early-stage LUAD. The detection of PTPRO methylation in salivary sEVs demonstrates high sensitivity and specificity, indicating its potential as an epigenetic biomarker for the non-invasive diagnosis of early-stage LUAD.

364 Background: Chemotherapy is the predominant treatment option for patients with advanced ESCC following disease progression on first-line chemoimmunotherapy, which has limited efficacy. HLX43 is a novel antibody-drug conjugate targeting the programmed cell death-ligand 1 (PD-L1). Its promising efficacy alongside good tolerability was demonstrated in patients with advanced solid tumors refractory to immune checkpoint inhibitors in a phase 1 trial. This phase 2 study evaluated the efficacy and safety of HLX43 in previously treated recurrent/metastatic ESCC. Methods: Patients with histologically or cytologically confirmed recurrent/metastatic ESCC who progressed on or are intolerant to first-line chemoimmunotherapy were enrolled and randomized 1:1:1 to receive intravenous HLX43 at 2 mg/kg, 2.5 mg/kg, or 3 mg/kg once every 3 weeks. The primary endpoints were investigator-assessed objective response rate (ORR) and progression-free survival per RECIST v1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, immunogenicity, and biomarker explorations. Results: As of data cutoff date Aug 26, 2025, 35 patients were randomized to and received HLX43 at 2 mg/kg (n = 11), 2.5 mg/kg (n = 12) and 3 mg/kg (n = 12) groups. Most enrolled patients had an Eastern Cooperative Oncology Group performance status score of 1 (85.7%). Patients received a median line of prior antitumor therapy of 2 (range, 1–4). Among the 7 response-evaluable patients in the 3 mg/kg group, ORR was 57.1% with 4 patients having achieved partial response and DCR was 100.0%; ORR was 60.0% for those with a PD-L1 combined positive score ≥ 1 (n = 5) in this dose group. Overall, treatment-emergent adverse events (TEAEs) occurred in 27 patients (77.1%; grade ≥3, 20.0%). Most common grade ≥3 TEAEs (≥5% in incidence) included anemia (8.6%), and lymphocyte count decreased (5.7%). Conclusions: HLX43 conferred promising efficacy, particularly at 3 mg/kg dose, along with a manageable safety profile in patients with previously treated recurrent/metastatic ESCC. Further investigation is warranted. Clinical trial information: NCT06769113 .

The pathogenic role of Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been well documented to extend far beyond the oral cavity. P. gingivalis can be specifically detected in digestive system tumor tissues, and its infection abundance is closely associated with tumor invasion, metastasis, and poor prognosis in patients. This study systematically reviews basic and clinical research on the association between P. gingivalis and digestive system tumors including oral cancer, esophageal cancer, pancreatic cancer, liver cancer, and colorectal cancer. The potential molecular mechanisms underlying P. gingivalis-induced tumor initiation and progression were further elucidated thoroughly, aiming to provide new theoretical basis and research directions for risk warning, early diagnosis, and targeted therapy of digestive system tumors.

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive epithelial malignancies, with most patients deriving only modest benefit from surgery, chemoradiotherapy, or immune checkpoint inhibition. Recent studies suggest that tumor metabolic reprogramming and immune dysfunction evolve together and reinforce one another, yet the causal links between these processes remain only partially understood. Mast cells (MCs) represent a stromal population that has received more attention. Although associated with allergic reactions, tissue repair, and inflammatory responses under normal physiology, MCs in ESCC frequently occupy stromal, vascular and hypoxic zones where metabolic stress is most pronounced. This spatial distribution suggests that MCs actively shape tumor metabolic states through the release of lipid mediators, including prostaglandins, leukotrienes, and platelet activating factor (PAF). These mediators amplify lipid metabolic programs in tumor cells and contribute to an immunosuppressive environment in which dendritic cell priming is attenuated, and cytotoxic T cell (CTL) function is progressively impaired. MC-derived cytokines and proteases further remodel the extracellular matrix and reorganize stromal architecture, collectively facilitating the invasion of malignant cells into adjacent tissue. Single cell and spatial transcriptomic analyses have revealed substantial heterogeneity among tumor-infiltrating MCs, indicating that distinct phenotypic subsets engage divergent metabolic and immune circuits and that only a subset may be functionally tumor permissive. These findings have generated increasing interest in therapeutic strategies targeting MC-linked mediators, inhibiting lipid metabolic enzymes, or integrating metabolic modulation with immune checkpoint therapy. A rigorous mechanistic understanding of how MCs coordinate metabolic and immune remodeling in ESCC may ultimately support biomarker-guided patient stratification and inform novel therapeutic combinations capable of overcoming resistance to current treatment modalities.

Esophageal cancer (EC) is an aggressive malignancy with poor survival despite advances in multimodal treatment. Local control of the disease is possible with chemotherapeutic, radiotherapeutic, and chemoradiotherapeutic neoadjuvant therapies, although treatment resistance and recurrence are common, and disease progression continues. Several studies show that the so-called immune exhaustion in the tumor microenvironment (TME) is the most significant cause of failure of the aforementioned treatments. Specifically, dysregulated interferon (IFN) signaling may have paradoxical effects in EC, promoting antitumor immune activation in some contexts while contributing to immune suppression, checkpoint upregulation, and tumor adaptation when chronically activated. This review examines whether IFN pathway dysregulation, particularly involving IER2 and IFNGR1, may contribute to immune exhaustion and influence neoadjuvant therapy response. In particular, we examine the role of the interferon-related genes (IRGs) in the immediate early response 2 (IER2) and interferon gamma receptor 1 (IFNGR1) in the mechanistic clinical role of neoadjuvant therapies. It includes radiotherapy, chemotherapy, and immune remodeling. Evidence of persistent IFN signaling T cell exhaustion, immune checkpoint upregulation, the phenomenon of adaptive resistance and the lack of therapeutically adequate sustained efficacy are analyzed. Finally, we show how the changes in the tumor immune microenvironment (TIME) caused by the neoadjuvant therapy (NAT) induced IFN activation. In particular, we examine the changes in the cross-presentation of immunogenic cells, cytokines, cytokine receptors, and exhaustion. This paper outlines a structure connecting IFN-induced immune exhaustion with responses to neoadjuvant therapy in EC, integrating epidemiology, molecular crossroads, and innovative translational research. To conclude, we examine prospective treatment efforts to address immune exhaustion through IFN pathway adjustment, strategic combination therapies, and biomarkers to refine patient stratification. A clearer understanding of context-dependent IFN signaling may support biomarker-guided neoadjuvant strategies and rational combination therapies in EC.

Neoadjuvant immunotherapy (NIT) is transforming the treatment landscape for esophageal squamous cell carcinoma (ESCC), substantially improving the pathological complete response (pCR) rates achieved with traditional chemoradiotherapy. Clinical trials demonstrate that combining PD-1 inhibitors such as pembrolizumab or camrelizumab with chemotherapy markedly increases pCR rates to over 40% and 28%, respectively. The efficacy of NIT is attributed to immune checkpoint inhibitors (ICIs) remodeling the tumor microenvironment, including expanding pre-exhausted SPRY1+CD8+ T cells and promoting M1 macrophage polarization. While conventional biomarkers like PD-L1 have limited predictive value, novel tools such as SPRY1+CD8+ T cell infiltration, the EN-ImiRPS model, and dynamic ctDNA monitoring offer superior predictive accuracy for treatment response. These advances enable more personalized strategies: patients with high PD-L1 expression may benefit from ICI monotherapy, and those achieving a clinical complete response (cCR) with ctDNA negativity can explore non-surgical organ preservation, with encouraging survival outcomes. For patients without pCR after surgery, adjuvant nivolumab extends disease-free survival. However, primary resistance remains a challenge, driven by mechanisms such as M2 macrophage suppression and cancer stem cell escape. Future efforts should focus on multi-omics biomarker integration, optimizing de-escalation strategies for responders, and targeting resistant pathways within the tumor microenvironment to establish a new paradigm of chronic disease management for ESCC.

The oral cavity and esophagus are contiguous mucosal sites whose microbiomes may jointly influence esophageal squamous cell carcinoma (ESCC). To address whether microbial alterations are shared across oral and esophageal niches and possess diagnostic potential in ESCC, we performed five-region 16S rRNA sequencing on paired oral swabs and esophageal tissues from 45 patients with ESCC and matched controls. We identified consistent enrichment of Porphyromonas, Fusobacterium, and Treponema, with the depletion of Neisseria, Rothia, and Actinomyces across both sites. These cross-site signatures showed strong diagnostic performance, supporting proof-of-concept non-invasive ESCC prediction using oral swabs. Functional prediction suggested altered microbiome-associated functional profiles, including enrichment of glycan- and amino acid-related pathways and reduced fatty acid metabolism. In a 4-NQO mouse model, P. gingivalis accelerated ESCC development and promoted inflammatory and immune-suppressive responses. Together, these findings identify shared oral-esophageal microbial signatures with potential diagnostic value in ESCC and support further validation of oral microbiome-based detection strategies.

PURPOSE:Exosomal RNAs are emerging as cancer signatures, and saliva is a noninvasive biospecimen. Given the high mortality of patients with esophageal squamous cell carcinoma (ESCC) and limited early detection tools, we investigated a salivary exosome‑based Tri-signature for its diagnostic and prognostic potential. MATERIALS AND METHODS:The salivary exosome‑based signature (ie, a chimeric RNA seG-NchiRNA, a tRNA fragment GlyGCC-5, and a novel sRESE RNA) was quantified by qRT-PCR in a multicenter observational study across two ESCC-endemic regions. Model development and validation were performed in the training (n = 359) and validation (n = 225) cohorts using logistic regression, survival analyses, and Shapley Additive exPlanations-based feature interpretation. RESULTS:The Tri-signature showed excellent diagnostic accuracy (training cohort: AUC, 0.987; validation cohort: AUC, 0.964) and robust prognostic value (training cohort: overall survival [OS] hazard ratio [HR], 5.52, progression-free survival [PFS] HR, 4.46; validation cohort: OS HR, 4.76, PFS HR, 2.79). In the high Combined Risk Score for Prognosis (CRSP) subgroup, patients with relatively lower CRSP derived significant benefit from adjuvant therapy (training cohort: OS HR, 0.54, PFS HR, 0.47; validation cohort: OS HR, 0.38, PFS HR = 0.32), whereas no such benefit was observed in low Tri-signature patients. The Tri-signature exhibited strong early diagnostic performance, distinguishing early-stage ESCC without lymph node metastasis from healthy controls (training cohort: AUC = 0.975; validation cohort: AUC = 0.950). Patients with early-stage ESCC and high CRSP had significantly worse outcomes (training cohort: OS HR, 5.09, RFS HR, 3.80; validation cohort: OS HR, 8.79, RFS HR, 4.55). CONCLUSION:The salivary exosome-based tri-RNA signature showed robust multicenter reproducibility and strong diagnostic, prognostic, and treatment response-predictive performance, supporting its translational potential as a noninvasive biomarker panel for ESCC management.

Esophageal squamous cell carcinoma (ESCC) represents a major therapeutic challenge due to the rapid development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Recent evidence highlights that this resistance is driven not only by genetic mutations but also by spatial heterogeneity of tumor microenvironments and compensatory signaling mechanisms. In this review, we propose a “spatial-signaling-intervention” framework with a particular focus on the NTRK2/MAPK signaling axis, which plays dual roles in signaling compensation and immune evasion. By integrating spatial multi-omics, proteomics, and AI-assisted topological modeling, three resistant niches are identified: (1) cancer stemness-enriched zones, (2) MAPK hyperactive islands, and (3) immune-cold regions. Based on this atlas, we design precision nanotherapeutic platforms, including responsive, dual-target, and feedback-loop nanocarriers, to selectively modulate resistant spatial niches. Preclinical validation in patient-derived xenografts and organoid models further demonstrates the translational potential of these strategies. This work provides a conceptual and technological roadmap for overcoming EGFR-TKI resistance in ESCC. Atlas-guided nanocarrier systems offer a promising avenue for spatially targeted and feedback-responsive therapy, highlighting the role of pharmaceutics in advancing precision oncology.

Esophageal carcinoma (ESCA) is a highly aggressive malignancy with a poor prognosis. The apelin gene (APLN) encodes a secreted peptide involved in various physiological processes, but its role in ESCA progression and chemoresistance remains unclear. We integrated transcriptomic data from the TCGA and GEO databases with CRISPR screening to identify key oncogenes in ESCA. ALPN was identified as a key gene. Functional assays both in vitro and in vivo were conducted to explore the biological role of APLN. Mechanistic studies explored the involvement of APLN in the regulation of autophagy and chemoresistance. Furthermore, we developed an exosome-based siRNA delivery system targeting APLN and constructed a prognostic nomogram incorporating APLN expression. APLN was significantly overexpressed in ESCA tissues and correlated with poor patient prognosis. DNA hypomethylation contributed to APLN upregulation. Functional experiments demonstrated that APLN knockdown suppressed tumor cell proliferation, induced apoptosis, and increased sensitivity to cisplatin. Mechanistically, APLN promoted autophagic flux, which mediated chemoresistance in ESCA cells. Exosome-mediated delivery of APLN siRNA effectively inhibited tumor growth in vivo without causing systemic toxicity. Additionally, a nomogram combining APLN expression with clinical stage accurately predicts patient survival, providing a practical tool for individualized prognosis. Our study identified APLN as a novel driver of ESCA progression and chemoresistance through the regulation of autophagy. Targeting APLN via exosome-based siRNA delivery is a promising therapeutic strategy. Moreover, the APLN-based prognostic nomogram has potential for guiding personalized treatment decisions in ESCA patients.

Sex-based disparities in immune-related adverse events and immune response remain to be fully elucidated. In this study, we aim to explore the efficacy of immunotherapy in esophageal cancer (EC) in response to patient sex. The study followed the guidelines of Preferred Reporting Items for the Systematic review and Meta-Analyses (PRISMA). PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library were searched to compare immunotherapy outcomes in male and female EC patients from clinical trials. The ratio of hazard ratios (HRs) and 95

4008 Background: Chemotherapy plus a PD-1/PD-L1 inhibitor is the standard first-line treatment for PD-L1 expressing advanced ESCC. However, most patients (pts) inevitably develop resistance to first-line therapy, and second-line chemotherapy shows an ORR of less than 10% and a median OS of less than 6 mo, highlighting the urgent need for novel therapeutics. Iza-bren is a potentially first-in-class ADC consisting of an EGFR-HER3 bispecific antibody conjugated to a potent topoisomerase I inhibitor Ed-04 via a cleavable linker. Iza-bren has shown promising clinical activity in previously treated ESCC pts in phase I study. Here, we present results from a phase III, randomized, open-label, multicenter study conducted in China evaluating the efficacy and safety of iza-bren versus chemotherapy as second line treatment for advanced ESCC. Methods: Pts with recurrent or metastatic ESCC who had progressed after first-line treatment with a PD-1/PD-L1 inhibitor plus platinum-based chemotherapy were randomized (1:1) to receive iza-bren (2.5 mg/kg at D1D8 Q3W) or physician’s choice of chemotherapy (irinotecan, paclitaxel, or docetaxel Q3W). Dual primary endpoints were OS and PFS by Blinded Independent Central Review (BICR) per RECIST v1.1. Results: As of Oct 17, 2025, a total of 497 pts were randomized to iza-bren (n = 249) or chemotherapy (n = 248). Baseline characteristics were balanced between the two groups. At interim analysis, median follow-up for OS was 7.8 mo in the iza-bren group and 7.6 mo in the chemotherapy group. Iza-bren has demonstrated statistically significant and clinically meaningful improvement in both OS and PFS by BICR compared with chemotherapy. The median OS was 9.8 mo (95% CI, 7.9 to 11.0) with iza-bren and 7.2 mo (95% CI, 6.2 to 8.2) with chemotherapy (HR, 0.64; 95% CI, 0.49 to 0.83; P = 0.0004). The median PFS by BICR was 4.2 mo (95% CI, 3.6 to 4.5) with iza-bren and 2.0 mo (95% CI, 1.6 to 2.7) with chemotherapy (HR, 0.50; 95% CI, 0.40 to 0.63; P < 0.0001). ORR by BICR was 35.3% for iza-bren and 13.1% for chemotherapy. Grade≥3 TRAEs, which were predominantly hematologic in nature, occurred in 85.1% in the iza-bren group and 60.2% in the chemotherapy group. TRAEs leading to drug discontinuation were 2.0% in the iza-bren group and 3.3% in the chemotherapy group. TRAEs leading to death were 1.2% in the iza-bren group and 1.6% in the chemotherapy group. Conclusions: The study met both dual primary endpoints at prespecified interim analysis. Iza-bren demonstrated statistically significant and clinically meaningful improvements in OS and PFS compared with chemotherapy in pts with recurrent or metastatic ESCC who had progressed after first line PD-1/PD-L1 inhibitor plus platinum-based chemotherapy. The safety profile was manageable. The results support iza-bren as a new second-line standard of care for ESCC. Clinical trial information: NCT06304974 .