Background and Aims Hepatocellular carcinoma (HCC) is a highly immunosuppressive cancer with limited treatment options and poor prognosis. Neutrophils, as prominent immune cells in the tumour microenvironment, critically shape disease progression and treatment response. Here, we aimed to identify pivotal neutrophil subsets driving HCC progression.Methods Neutrophil-specific marker genes were identified through single-cell RNA sequencing (scRNA-seq) analyses. The clinical significance of neutrophils with triggering receptor expressed on myeloid cells-1 (TREM1) positive was assessed in HCC patient cohort by immunofluorescence staining. The immune landscape of HCC and the functional phenotype of TREM1+ neutrophils were further characterised using cytometry by time-of-flight (CyTOF).Results scRNA-seq analyses revealed that TREM1 was mainly expressed in intratumoural neutrophils within the HCC microenvironment. A high abundance of intratumoural TREM1+ neutrophils was significantly associated with poor prognosis in HCC patients. CyTOF profiling demonstrated that HCC tumours enriched with TREM1+ neutrophils exhibited CD8+ T-cell exclusion and increased infiltration of immunosuppressive macrophages. Moreover, TREM1+ neutrophils exhibited an immunosuppressive functional state. Pharmacological inhibition of TREM1 by VJDT enhanced the therapeutic efficacy of anti-PD-1 antibody in HCC preclinical models.Conclusions TREM1 is mainly expressed in neutrophils in HCC and drives the immunosuppressive reprogramming of neutrophils and tumour microenvironment. Infiltration of TREM1+ neutrophils correlates with unfavourable clinical outcomes in HCC. Targeting TREM1 may augment the efficacy of anti-PD-1 therapy in HCC.

BACKGROUND:Diffuse Gastric Cancer (DGC) is a highly aggressive form of gastric cancer with a poor prognosis. Oxaliplatin (OX) is one of the first-line chemotherapeutic agents for the treatment of gastric cancer. However, some patients with DGC do not benefit from OX therapy. Resibufogenin (RBF), one of the main active components of the Chinese medicine Huachansu, has demonstrated significant anti-cancer effects. Nevertheless, the potential of RBF to enhance the sensitivity of OX treatment in DGC and its underlying mechanisms have not been reported. OBJECTIVE:The aim of this study is to investigate the sensitizing effect of RBF on OX therapy for DGC, as well as to elucidate the potential targets and mechanisms of action. This exploration is of significant importance for the development of sensitizers that can improve the therapeutic efficacy of OX and for the advancement of patentable innovations in this field. METHODS:MTT assay, flow cytometry, Western blotting, and immunofluorescence assays were employed to assess the inhibitory effects of Resibufogenin (RBF) in combination with OX on DGC in vitro. Human DGC cell xenografts were established in a mouse model to evaluate the efficacy and safety of RBF and OX for treating DGC in vivo. RESULTS AND DISCUSSION:It was found that RBF inhibited the proliferation of DGC cells in a timeand dose-dependent manner. When RBF was used in combination with OX, the sensitivity of DGC cells to OX was improved. Significantly, the combination of OX and RBF acts synergistically to induce apoptosis and autophagy while inhibiting migration and invasion of DGC cells in vitro. In vivo, the combination of OX and RBF dramatically inhibited the progression of DGC in the subcutaneous xenograft model without observable toxicity. Mechanistically, RBF significantly inhibited the expression and activation of FAK. OX and RBF synergistically inhibited the phosphorylation of FAK, AKT, and GSK3β to abrogate the entry of β-catenin into the cell nucleus. RBF sensitizes DGC to oxaliplatin via FAK suppression. CONCLUSION:RBF exhibits a pronounced suppressive effect on FAK, and its combination with OX synergistically blocks the FAK/AKT/GSK3β/β-catenin signaling cascade, thereby inhibiting the growth and metastasis of DGC. This study provides a novel avenue for future research and patent development of FAK inhibitors, with the potential to enhance the therapeutic efficacy of DGC treatment and overcome drug resistance.

Recently, enzyme dynamic therapy (EDT) has attracted great attention in cancer therapy. Nevertheless, the limited H2O2 concentration in the tumor microenvironment (TME) and the induction of autophagy significantly impair the anticancer efficacy of EDT. Herein, a bacterial outer membrane vesicles (OMVs)-based nitric oxide (NO)-releasing nanogenerator was synthesized to enhance the anticancer efficacy of EDT. Specifically, hollow polydopamine nanospheres (HPDA) were first prepared and used as a carrier to load lactate oxidase (LOX), the NO-releasing donor BNN6 and chloroperoxidase (CPO), followed by surface coating with OMVs to obtain the biomimetic nanogenerator HPDA@LBC@OMV. Due to the excellent tumor-targeting ability of OMVs, HPDA@LBC@OMV displayed highly efficient accumulation in 4T1 tumor tissues. In the TME, HPDA@LBC@OMV firstly catalyzed lactic acid to produce a substantial amount of H2O2, which subsequently triggered the simultaneous generation of NO and singlet oxygen (1O2) through cascade catalytic reactions, ultimately resulting in significant inhibition of 4T1 tumors. Mechanistic studies revealed that the synergistic NO/1O2 anticancer effect inhibited 4T1 tumors by inducing excessive autophagy. More importantly, it was demonstrated that the synergistic effect-induced excessive autophagy effectively triggered immunogenic cell death (ICD) in dying tumor cells, thereby further activating the body’s immune response by converting “cold” tumors into “hot” tumors to enhance anticancer immunotherapy.

3026 Background: Treatment options in China are limited for patients with late-line, HER2-expressing advanced solid tumors. In Part 1 of DESTINY-PanTumor02, T-DXd showed clinically meaningful antitumor activity in HER2-expressing advanced solid tumors, with the greatest benefit observed in HER2 IHC 3+ tumors. Based in part on these findings, T-DXd has been approved in multiple countries worldwide, including the US, as treatment for patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior treatment and/or have no satisfactory alternative therapies. Following the results from DESTINY-PanTumor02, DESTINY-PanTumor03 is evaluating T-DXd in patients in China with HER2-expressing advanced solid tumors. The primary analysis of Part 1 of DESTINY-PanTumor03 is presented here. Methods: DESTINY-PanTumor03 is an open-label, Phase 2 study (NCT06271837). Part 1 is evaluating T-DXd (5.4 mg/kg IV Q3W) in patients in China with HER2 IHC 3+ (by central testing), locally advanced, unresectable, or metastatic solid tumors (excluding breast and gastric cancers) after ≥1 prior systemic treatment for advanced disease or without treatment options. The primary endpoint is confirmed objective response rate (ORR) by independent central review (ICR) per RECIST 1.1. Secondary endpoints include ORR by investigator assessment (INV) per RECIST 1.1; duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) by INV and ICR per RECIST 1.1; overall survival (OS); and safety. Results: At primary analysis data cutoff (November 28, 2025), 50 patients with biliary tract (n = 11), colorectal (n = 6), cervical (n = 10), endometrial (n = 7), ovarian (n = 5), non-small cell lung (n = 7), or other cancers (n = 4) had received T-DXd. Median follow-up duration was 9.9 (range 1.1–18.3) months. Median number of prior treatment regimens was 2 (range 1–10). By ICR, ORR (95% CI) was 58.0% (43.2, 71.8), median DOR (95% CI) was 15.4 (12.5, not evaluable [NE]) months, DCR (95% CI) at Week 6 was 88.0% (75.7, 95.5), and median PFS (95% CI) was 15.7 (7.2, NE) months. By INV, ORR (95% CI) was 56.0% (41.3, 70.0). Median OS was not reached. Grade ≥3 drug-related adverse events occurred in 31 (62.0%) patients, and adjudicated drug-related interstitial lung disease / pneumonitis occurred in 4 (8.0%) patients (Grade 2 n = 3 [6.0%], Grade 3 n = 1 [2.0%]). Conclusions: T-DXd demonstrated durable and clinically meaningful antitumor activity in pretreated patients in China with HER2 IHC 3+ advanced solid tumors. Safety was generally consistent with the established T-DXd profile. Results from DESTINY-PanTumor03 Part 1 support T-DXd as a tumor-agnostic treatment for patients in China with HER2 IHC 3+ solid tumors. Clinical trial information: NCT06271837 .

e15569 Background: For patients with metastatic colorectal cancer (mCRC) who progress after first-line oxaliplatin-based therapy, irinotecan-based regimens represent a standard second-line option. Liposomal irinotecan, designed to exploit the enhanced permeability and retention (EPR) effect, may improve tumor targeting while reducing systemic toxicity. This study evaluated the efficacy and safety of liposomal irinotecan combined with 5-FU/LV and bevacizumab as second-line treatment for mCRC. Methods: This was a multicenter, single-arm phase II study conducted across multiple institutions in China. Eligible patients were aged 18-75 years with histologically confirmed unresectable mCRC, progressive disease after first-line oxaliplatin-based therapy. Patients received liposomal irinotecan (70 mg/m²) + 5-FU (2400 mg/m²) + LV (400 mg/m²) + bevacizumab (5 mg/kg) on Day 1, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 2023 and September 2025, 172 patients were enrolled and included in the full analysis set. At data cutoff, 60 patients remained on treatment and 112 had completed treatment. Median age was 60 years (range: 18-75), 57.6% were male, and 39.0% had rectal primary tumors. Among 111 efficacy-evaluable patients, the ORR was 18.0% (95% CI: 11.4–26.4%) and the DCR was 82.9% (95% CI: 74.6–89.4%). After a median follow-up of 4.7 months (range: 0.03-19.0), the median PFS was 7.8 months (95% CI: 5.54-9.96), and median OS was not reached. Subgroup analyses revealed longer PFS in patients with baseline CEA < 5 ng/L (9.3 vs. 6.5 months, p = 0.037) and in those who had not received bevacizumab in the first-line setting (9.6 vs. 6.1 months, p = 0.015). Treatment-related adverse events (TRAEs) occurred in 90.1% of patients, with grade ≥3 TRAEs in 43.6%. The most common grade ≥3 TRAEs were neutropenia (21.5%), leukopenia (13.4%), and diarrhea (8.7%). Serious adverse events (SAEs) occurred in 6.4% of patients, with no new safety signals identified. Conclusions: Liposomal irinotecan combined with 5-FU/LV and bevacizumab showed promising antitumor activity and a manageable safety profile as second-line therapy for mCRC. These results support this regimen as a valuable therapeutic option for patients progressing after oxaliplatin-based first-line treatment. Clinical trial information: NCT06184698 .

OBJECTIVE:To compare camrelizumab plus capecitabine and oxaliplatin followed by camrelizumab plus apatinib (camre+CAPOX followed by camre+apa), CAPOX alone, and camrelizumab plus CAPOX followed by camrelizumab (camre+CAPOX followed by camre) as initial treatment for gastric or gastro-oesophageal junction adenocarcinoma. DESIGN:Randomised, open label, phase 3 study. SETTING:75 hospitals in China, 13 March 2019 to 16 August 2021. PARTICIPANTS:885 adults (≥18 years) with previously untreated, human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. INTERVENTIONS:Patients were randomised (2:2:1) to receive camre+CAPOX followed by camre+apa, CAPOX only, or camre+CAPOX followed by camre, stratified by Eastern Cooperative Oncology Group performance status, peritoneal metastasis, and programmed death ligand 1 (PD-L1) combined positive score. Assignment to camre+CAPOX followed by camre was introduced midway through enrolment. MAIN OUTCOME MEASURES:The primary endpoint was overall survival for camre+CAPOX followed by camre+apa versus CAPOX alone in the PD-L1 positive population (combined positive score >1) and the overall population who received at least one dose of study drug. Comparisons of camre+CAPOX followed by camre versus CAPOX alone and of camre+CAPOX followed by camre+apa versus camre+CAPOX-camre were descriptive. Safety was assessed in all patients who received at least one dose of study drug. RESULTS:352 patients received camre+CAPOX followed by camre+apa, 349 received CAPOX alone, and 177 received camre+CAPOX followed by camre. At the time of data cut off, 454 of 592 (76.7%) deaths had occurred in the PD-L1 positive population and 709 of 878 (80.8%) in the overall population. Overall survival was longer with camre+CAPOX followed by camre+apa than with CAPOX alone in the PD-L1 positive population (median 15.0 v 12.5 months; hazard ratio 0.80 (95% CI 0.65 to 0.98); one sided P=0.02) and in the overall population (median 13.5 v 12.1 months; hazard ratio 0.80 (0.68 to 0.94); one sided P=0.004). Use of camre+CAPOX followed by camre also showed longer overall survival versus CAPOX in the PD-L1 positive population (median 15.3 v 12.5 months; hazard ratio 0.76 (0.58 to 0.97); one sided nominal P=0.01) and overall population (median 14.2 v 12.1 months; hazard ratio 0.80 (0.65 to 0.98); one sided nominal P=0.02). No overall survival benefit was observed with camre+CAPOX followed by camre+apa versus camre+CAPOX followed by camre. Treatment related adverse events of grade ≥3 occurred in 239 of 352 (67.9%) patients in the camre+CAPOX followed by camre+apa group, 158 of 349 (45.3%) in the CAPOX alone group, and 83 of 177 (46.9%) in the camre+CAPOX followed by camre group. CONCLUSIONS:Initial treatment with camrelizumab plus CAPOX followed by camrelizumab based maintenance was associated with longer overall survival than CAPOX alone in human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Exploratory comparisons between the two camrelizumab based regimens showed no additional survival benefit, with higher rates of treatment related adverse events of grade ≥3 and treatment discontinuations when apatinib was added during maintenance. TRIAL REGISTRATION:ClinicalTrials.gov NCT03813784.

The combination of trastuzumab and chemotherapy, with or without pembrolizumab, is the current first-line standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer and gastroesophageal junction cancer. However, upon disease progression, subsequent therapies often yield limited clinical benefit. The mechanisms of drug resistance to trastuzumab remain unresolved. Current studies on its resistance mechanisms have largely focused on alterations in the HER2 pathway, including HER2 heterogeneity, reduced or absent HER2 expression, variations in HER2 dimerization, and mutations in downstream components, among others. Crucially, as a monoclonal antibody, the antitumor activity of trastuzumab is partially mediated by the immune system, yet the immunology-related mechanisms of resistance are frequently overlooked. In this review, we systematically analyse the outcomes of both successful and failed clinical trials of anti-HER2 agents to propose that immune escape within the tumor microenvironment is a key driver of trastuzumab resistance in HER2-positive gastric cancer.

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, an evolutionarily conserved cascade governing multiple pivotal cellular processes, represents a double-edged sword in cancer biology. Although JAK/STAT inhibitors have demonstrated clinical efficacy in autoimmune diseases and myeloproliferative neoplasms, their application in solid tumors remains mired in therapeutic paradoxes. This review systematically deconstructs the mechanistic dichotomy of JAK/STAT signaling pathway, revealing upstream effectors and downstream targets dependent oncogenic versus tumor suppressive roles that underpin the limited efficacy, paradoxical immune exhaustion, and rapid adaptive resistance observed with direct JAK inhibition. To date, no STAT inhibitors have been approved for clinical use. We propose a paradigm-shifting therapeutic strategy that inhibits the upstream effectors and downstream targets of the JAK/STAT axis, based on clinical and preclinical evidence, to overcome the therapeutic dilemma. This review provides a framework for overcoming the JAK/STAT targeting impasse through system-level pathway interrogation rather than conventional node inhibition.

e16033 Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has become the standard first-line (1L) treatment for advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC), but the efficacy still needs to be improved. Fruquintinib, an oral and highly selective VEGFR 1/2/3 inhibitor, has shown a synergistic antitumour effect when paired with ICIs/chemotherapy. This study was aimed to evaluate the efficacy and safety of fruquintinib combined with CAPEOX and sintilimab as a 1L therapy in GC/GEJC. Methods: In this phase Ib/II trial, patients (pts) aged 18-75 years without prior exposure to anti-cancer treatment were enrolled. The Ib phase employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d, po, d1-14 (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) in combination with fixed dose of sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and capecitabine (800 mg/m 2 , bid, po, d1-14) every 3 weeks. After up to 6–8 cycles, fruquintinib in combination with sintilimab would be administered as maintenance therapy. The primary objective of phase Ib was to determine the DLT in first treatment cycle defining the MTD and PR2D. Additional 61 pts were enrolled in the phase II dose expansion stage using RP2D. Primary endpoint of phase II was ORR per RECIST 1.1. Secondary endpoints included DCR, PFS, OS, DOR, surgical conversion rate, safety and identification of molecular biomarkers for efficacy. Results: At data cut-off (December 25, 2025), 24 pts (8 in phase Ib; 16 in phase II) had been enrolled. The pts were characterized with a median age of 59 years (range, 51-67), 45.8% GEJC, 75% lymph node metastasis, and 41.7% liver metastases. 20 pts had PD-L1 CPS available and 70% (14/20) were CPS ≥1, 30% (6/20) were CPS≥5. Two consecutive DLTs were observed at DL3, so DL2 was identified as MTD. Fruquintinib 4mg/d was defined as the RP2D. Of the 22 pts evaluable for tumor response, 18 pts achieved PR, 4 pts achieved SD. The confirmed ORR was 81.8%, the DCR was 100%. After a median follow-up of 17.74 months, the median PFS was 9.0 months (95% CI: 4.40–NA) and OS was not mature yet. Conversion surgery had been conducted in 4 pts after multidisciplinary team evaluation, with one case of pathological CR. The R0 resection rate was 100% (4/4) and R0 surgical conversion rate was 18.2% (4/22). Most TRAEs were grade 1-2 and grade 3/4 TRAEs occurred in 41.7% of pts, with platelet count decreased (12.5%) ranking the most frequent. There were no treatment related deaths in the trial. Conclusions: Fruquintinib plus sintilimab and CAPEOX showed encouraging clinical outcomes and manageable safety for untreated advanced GC/GEJC. The trial is still recruiting, more data including the subgroup analysis and potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT06329973 .

2519 Background: CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors. Methods: Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 µg/kg to 600 µg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10µg/kg to 600 µg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4). Conclusions: IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458 .

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.

4055 Background: Chemotherapy for advanced esophageal squamous cell carcinoma (ESCC) is limited due to the lack of effective drugs. Such as traditional two drugs chemotherapy (5-Fluorouracil and Cisplatin) as first-line treatment for metastatic and recurrent ESCC has an efficacy of 25-35%. Nimotuzumab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody. Previous studies have shown that its combination with paclitaxel and cisplatin (TP regimen) has a good efficacy, with an objective response rate (ORR) of up to 55%, median overall survival (mOS) 13.9 months in some small-sample trials. Methods: Eligible patients from 36 centers in China, who were randomly assigned to receive nimotuzumab (400 mg once per week, up to 2 years) or placebo followed by TP regimen (paclitaxel 175 mg/m², cisplatin 60 mg/m², Day 1, with a 21-day cycle, up to 6 cycles) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, quality of life (QoL) and safety. Results: A total of 640 patients were screened. 503 patients were enrolled and 161 patients with EGFR gene amplification tumors were eligible. In the full analysis set of 497 patients who had took at least one dose of medication, there were no differences in baseline characteristics. The mOS were 12 vs 11.5 months, and the median PFS were 5.6 vs 5.4 months respectively, suggesting survival benefit trend in the trial. ORR were 55.5% and 50.4% for both arms. In the EGFR gene amplification subgroup, the mOS was 13.3 vs 9.5 months (log-rank test, hazard ratio [HR] = 0.66 (95%CI, [0.47-0.93]), P = 0.016) for two groups. Patients who were with ESCC at stage IV, as well as who had not undergone surgery, radical radiotherapy, or neoadjuvant and adjuvant therapy showed significant survival benefits after the addition of nimotuzumab. Median PFS were 6.0 vs 5.5 months for two arms (log-rank test, HR = 0.63 [0.43-0.91], P = 0.014). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The ORR of the two groups were 61.3% and 44.0%, respectively (P = 0.029). There were no statistically significant differences in the QoL scores of the FAS population at each time point before and after treatment. The incidence of adverse events were comparable in the experimental group and the control group. Such as the incidence of serious adverse event (SAE) was 30.7% and 34.5%, serious adverse drug reaction (SADR) was 2.7% and 8.3%, the incidence of above grade 3 treatment emergent adverse event (TEAE) was 85.3% and 83.3%, respectively, etc. Conclusions: In patients with metastatic EGFR gene amplification ESCC, nimotuzumab plus TP as first-line treatment significantly improved OS and PFS with a good safety profile.

LBA3563 Background: The optimal second-line treatment for metastatic colorectal cancer (mCRC) after failure of oxaliplatin-based chemotherapy therapy remains an area of active research, while bevacizumab combined with chemotherapy is a standard option. Fruquintinib (Fru) is a highly selective and potent oral tyrosine kinase inhibitor of VEGFR 1, 2, and 3. This study aimed to compare the efficacy and safety of fruquintinib combined with chemotherapy versus bevacizumab combined with chemotherapy as second-line treatment for mCRC. Methods: This was a non-inferiority trial conducted across 12 hospitals and cancer centers in China. Patients with mCRC who had progressed on fluoropyrimidine and oxaliplatin-based first-line chemotherapy therapy were randomly assigned (1:1) to receive either Fru (4 mg orally, once daily for 3 weeks on/1 week off) plus FOLFIRI, or bevacizumab (Bev) (5 mg/kg intravenous, every 2 weeks) plus FOLFIRI. Randomization was stratified by primary tumor location and RAS/BRAF status. During combination therapy, pts who achieve disease control after 4-6 months of treatment proceeded to maintenance therapy, receiving either fruquintinib combined with capecitabine or bevacizumab combined with capecitabine. The primary endpoint was progression-free survival (PFS). Final analysis occurred after either 97 PFS events or after the last patient had completed 12 months of follow-up, whichever occurred first. The non-inferiority upper margin of HR was 1.33. Results: Between Jul 13, 2023, and Mar 4, 2025, 122 pts were enrolled and randomly assigned to the Fru group (n=60) or the Bev group (n=62). The median age was 59.0 (IQR 54-69) and 60.0 (IQR 51-70) years, 45 (75%) and 48 (77%) had left-sided tumors, 36 (60%) and 36 (58%) were RAS/BRAF mutant, respectively. At data cut-off (Feb 28, 2026), the median PFS of the Fru group was non-inferior to the Bev group, whether in the Intention to Treat Population (ITT) (9.40 vs 7.39 months, hazard ratio [HR]=0.806 [95% CI 0.522–1.244, 80% CI 0.607-1.07]; p=0.33) or the per-protocol set (PPS) (9.49 vs 7.85 months, HR=0.848 [95% CI 0.542–1.326, 80% CI 0.633-1.136]; p=0.469). In the subgroup analysis , the Fru group showed longer PFS in prior never used VEGF inhibitor pts (10.6 vs 8.5 months, HR=0.94, 95% CI 0.54-1.62), and pts without liver metastasis (14.5 vs 9.9 months, HR=0.97, 95% CI 0.43-2.22) compared to the Bev group. The objective response rate was 35.0% with Fru vs 22.6% with Bev group. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% (Grade ≥3, 28.1%) of the Fru group and 93.2% (Grade ≥3, 28.8%) of the Bev group. Conclusions: Fruquintinib combined with FOLFIRI demonstrated non-inferiority in PFS compared with bevacizumab combined with FOLFIRI as a second-line treatment for mCRC, with a manageable safety profile. Clinical trial information: NCT05555901 .

As an emerging biomarker, tumor mutational burden (TMB) has attracted increasing attention from clinicians in predicting the efficacy of tumor immunotherapy. Currently, TMB is detected primarily by whole-exome sequencing or targeted panel sequencing on high-throughput sequencing platforms. However, the lack of uniformity in detection methods, threshold settings, and reporting formats, as well as the significant differences in TMB values among different cancer types, have hindered the standardized application of this biomarker in clinical practice. This consensus focuses on the definition, standardization of detection, clinical significance, and limitations of TMB, and provides consensus recommendations for the clinical application of TMB in real-world practice in China. This consensus is aimed at helping clinicians and laboratory personnel understand the clinical significance and testing standards of TMB, promoting more accurate interpretation of test results, and improving patient care.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with significant geographical disparities, particularly high in East Asia. The prognosis for advanced patients remains poor, largely due to profound intertumoral and intratumoral molecular heterogeneity, which drives variable treatment responses. This review delineates progress in molecular classification, where multiomics studies have defined distinct subtypes-cell cycle activated (CCA), NRF2-oncogenic activated (NRFA), immune suppressive (IS), and immune modulatory (IM)-each with specific therapeutic implications. This framework guides targeted therapies and predicts immunotherapy outcomes. We further evaluate biomarker-driven strategies (PD-L1, TMB, and NOTCH1 mutations) and emerging therapies targeting driver genes and the metabolic microenvironment. Translating subtyping into clinical practice requires validating strategies through innovative trial designs, establishing dynamic monitoring using liquid biopsy and spatial multiomics, and integrating multidimensional biomarkers. Constructing a molecular subtype-based precision medicine framework is pivotal to overcoming therapeutic limitations and improving survival in ESCC.

Bevacizumab plus chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC). To date, no phase 3 trial has compared first-line oral multitargeted TKI versus bevacizumab plus chemotherapy in RAS/BRAF wild-type mCRC. The open-label, noninferiority, randomized, phase 3 trial (ANCHOR; NCT04854668; CTR20210940) evaluated first-line anlotinib versus bevacizumab plus oxaliplatin and capecitabine (CapeOX) in this setting. Patients were centrally randomized (1:1) to receive 4-8 cycles of CapeOX in combination with either anlotinib (12 mg once daily on days 1-14) or bevacizumab (7.5 mg/kg on day 1) every 3 weeks, followed by maintenance therapy with anlotinib or bevacizumab plus capecitabine until unacceptable toxicity or disease progression. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intention-to-treat population. The hazard ratio (HR) for the noninferiority margin was 1.09. Between May 25, 2021, and August 30, 2023, 373 patients were assigned to the anlotinib group and 375 to the bevacizumab group. As of February 2, 2025, the median follow-up was 25.1 months (95% confidence interval [CI] 23.8-26.3). The median PFS was 11.0 months (95% CI 9.8-11.2) in the anlotinib group versus 11.0 months (9.7-11.2) in the bevacizumab group (stratified HR, 1.00; 95% CI 0.84-1.18; p = 0.87). The incidences of grade ≥3 treatment-related adverse events were 64.9% and 44.8%, respectively. Compared with bevacizumab plus CapeOX, anlotinib plus CapeOX showed similar antitumor activity but failed to reach the prespecified noninferiority margin for PFS and was associated with increased manageable toxicity.

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.

Ammonia death is a recently identified form of regulated cell death with unique molecular mechanisms and prominent anticancer activity. Nevertheless, its efficacy is severely restricted by the absence of tumor-targeted ammonia delivery vehicles and poorly defined immunogenic properties. Herein, we develop a lysosome-targeted ammonia nanogenerator (denoted AlN@HA) to induce ammonia death in hepatocellular carcinoma (HCC) cells and boost HCC immunotherapy. Following CD44 receptor-mediated endocytosis, AlN@HA preferentially accumulates within lysosomes and undergoes in situ hydrolysis to produce excessive ammonia and nanoscopic aluminum hydroxide (Al(OH)3). Intralysosomal ammonia overload further drives lysosomal alkalinization and membrane permeabilization, autophagic flux blockade, and mitochondrial dysfunction. This sequential signaling cascade elicits tumor cell ammonia death and triggers robust immunogenic cell death. Meanwhile, the hydrolytic byproduct Al(OH)3 functions as an intrinsic adjuvant to facilitate dendritic cell maturation. Additionally, ammonia-mediated neutralization of intratumor lactic acid reverses the immunosuppressive tumor microenvironment. In vivo results verify that AlN@HA-initiated ammonia death markedly suppresses local tumor proliferation and activates systemic antitumor immune responses, thereby sensitizing HCC to antiprogrammed cell death 1 immunotherapy. This study clarifies the immunological features of tumor ammonia death, establishes a lysosome-targeted ammonia delivery strategy, and highlights ammonia death as a viable synergistic modality for HCC combination immunotherapy.

Abstract: Germ cell tumors of the mediastinum (GCTM) are a type of extragonadal tumor, accounting for <5% of both mediastinal tumors and germ cell tumors. Based on histopathological classification, GCTMs can be divided into three major types: teratomas, seminomatous germ cell tumors, and non-seminomatous germ cell tumors, which can be further subdivided into subtypes such as yolk sac tumors and choriocarcinomas. Due to the scarcity and diversity of GCTMs, there is a lack of clear international standards in diagnosis and treatment, leading to clinical challenges such as high misdiagnosis rates and non-standardized treatment. To promote the standardization of GCTM management, experts from the Pan-Yangtze River Delta Alliance of Research for Thymomas (PRD-ART) conducted panel discussions, integrating the medical evidence in pathology, molecular biology, and new drug development, to create clinical recommendations for diagnosis, treatment, and follow-up. This expert consensus: 1) emphasizes molecular testing in clinical management, 2) encourages multidisciplinary consultation to facilitate personalized therapies, 3) promotes international collaboration to validate novel biomarkers and therapies, and 4) suggests the use of real-world, umbrella trial designs to address the scarcity and heterogeneity problems. These measures aim to standardize and improve the clinical management of GCTMs.

Preclinical and clinical studies highlight the enhanced anticancer efficacy of combining anti-VEGF/VEGFR drugs with immune checkpoint inhibitors (ICIs). PD-L1/VEGF bispecific antibodies outperform monotherapy or combined PD-L1 inhibitors and anti-VEGF antibodies by simultaneously blocking the PD-1/PD-L1 immune pathway and VEGF-driven angiogenesis, providing a dual mechanism for superior antitumor activity. We developed CVL006, a novel bispecific antibody, by fusing an anti-PD-L1 VHH domain with a humanized IgG1 anti-VEGF monoclonal antibody. CVL006 retains antibody-dependent cellular cytotoxicity (ADCC) functionality. Preclinical evaluations included binding affinity and specificity assessments, dual-pathway blockade testing, and in vivo efficacy comparisons to atezolizumab and PD-1/VEGF bispecific antibody AK112 (ivonescimab). CVL006 demonstrated high affinity and specificity for human PD-L1 and VEGF. It effectively inhibited VEGF/VEGFR signaling and the PD-L1/PD-1 axis, suppressing VEGF-induced angiogenesis and reactivating T cells. This reactivation led to increased cytokine secretion critical for immune response. In vivo studies revealed CVL006's superior antitumor efficacy, achieving greater tumor growth inhibition and angiogenesis suppression than atezolizumab. CVL006 also outperformed AK112 in preclinical models, showcasing robust antitumor activity. CVL006 integrates immune checkpoint inhibition and tumor vascularization disruption, offering a comprehensive anticancer strategy. Its superior preclinical performance compared to atezolizumab and AK112 underscores its therapeutic potential, paving the way for further development and clinical translation.