Background:SMARCA4-deficient non-small cell lung cancer (NSCLC) is highly aggressive and has a limited response to conventional chemotherapy. The precise mechanisms by which SMARCA4 deficiency contributes to platinum-based chemotherapy resistance in NSCLC remain incompletely understood. This study aims to elucidate this resistance mechanism and provide a theoretical basis for precision treatment in clinical practice. Methods:The role of SMARCA4 deficiency in NSCLC was analyzed using the cBioPortal database. SMARCA4-knockdown NSCLC cell models were established. Cell proliferation was assessed using Cell Counting Kit-8 (CCK-8) and colony formation assays. Apoptosis was tested using flow cytometry. Carboplatin (CBP) sensitivity was evaluated by measuring the half maximal inhibitory concentration (IC50) values. Transcriptomic sequencing was performed to screen underlying platinum resistance mechanisms, which were further validated by quantitative polymerase chain reaction (qPCR), Western blot and immunohistochemistry (IHC). Finally, a xenograft model was established to observe the combined antitumor effects of CBP and potential agents reversing drug resistance. Results:SMARCA4 deficiency correlated with a poor prognosis for NSCLC patients, and SMARCA4 knockdown promoted malignant phenotypes in NSCLC cell lines. The sensitivity to CBP treatment was attenuated by SMARCA4 downregulation, with concomitant activation of the NF-κB signaling pathway and upregulation of BIRC2 and BIRC3 expression. Bioinformatics analysis confirmed a significant negative correlation between SMARCA4 and BIRC2/BIRC3 messenger RNA (mRNA) expression. Targeted inhibition of NF-κB signaling effectively restored platinum sensitivity in SMARCA4-deficient lung cancer cells and significantly suppressed tumor growth in xenograft models. Conclusions:SMARCA4 deficiency contributes to platinum resistance in NSCLC by activating the 
NF-κB-BIRC2/BIRC3 signaling axis. Combination therapy with CBP and either an NF-κB inhibitor or an inhibitor of apoptosis proteins (IAP) inhibitor effectively reverses this resistance, providing a novel strategy for the precise treatment of SMARCA4-deficient NSCLC.

Background and Objectives Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) has been confirmed to predict postoperative recurrence of early-stage non-small-cell lung cancer (NSCLC), outperforming conventional imaging modalities by improving diagnostic efficiency and eliminating radiation-related risks. Integrating ctDNA with other liquid biopsy omics methods might further increase monitoring accuracy. In addition, patients with longitudinal undetectable MRD exhibit a favorable outcome and may be overtreated after radical surgery, while those traditionally not recommended for adjuvant treatment but with positive MRD may have not received appropriate disease management. This prospective real-world trial involving ten clinical centers across China aims to develop a multiomics noninvasive platform for recurrence prediction and to determine whether postoperative management guided by ctDNA is noninferior to standard care.Methods We will recruit pathologically confirmed TNM stage IA-IIIA (8th edition) NSCLC patients who are undergoing radical resection. Eligible participants will be divided into a standard treatment group and a ctDNA-guided group depending on their preference. Patients treated with or without neoadjuvant therapy will be studied in parallel. In the ctDNA-guided group, adjuvant therapy can be avoided for patients whose MRD is undetected at 1 month after surgery, and an additional requirement is to achieve a major pathological response for patients receiving neoadjuvant therapy. Imaging and MRD monitoring will be performed every 3-6 months for 3 years of follow-up, and postoperative management will be determined by the MRD results at each time point. Adjuvant therapy will be stopped if the patient's MRD status is continuously negative; otherwise, a treatment plan will be initiated after discussion among a multidisciplinary team (MDT). The recruitment phase began in April 2025, and 916 patients will be enrolled.Discussion This prospective, multicenter, real-world study provides innovative techniques and is the first to confirm the instructive value of MRD for postoperative management of resectable NSCLC.

Backgroud:Ureteritis and cystitis is a rare immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs), challenging to distinguish from urinary tract infection (UTI), easily leading to missed diagnosis. We aim to describe clinical features, radiological characteristics and treatment of patients who suffer from ICI-related ureteritis and cystitis (ICI-UC). Methods:This was a single centre case series of patients diagnosed with solid tumor who received ICIs treatment and subsequently suffered from ICI-UC. All clinical demographic data, laboratory parameters, imaging characteristics, and treatment information were collected. Results:Between Mar 1st, 2020 and Mar 31th 2025, 12 of 1239 patients treated at Peking Union Medical College Hospital with ICIs were confirmed to have ICI-related ureteritis and cystitis (0.96%), 10 males and 2 females. Only 1 patient received anti-programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) dual immunotherapy, the other 11 patients received PD-1/PD-ligand 1 plus chemotherapy or/and target therapy. The median time to onset was 83 days (range 28-442 days). All patients (100%) exhibited significant urinary tract irritation symptoms. 12 patients demonstrated characteristic imaging abnormalities, including hydroureteronephrosis, irregular ureteral wall thickening, bladder wall thickening with irregular margins, or/and conspicuous renal fascia. Spontaneous remission was observed in 2 patients, while 10 patients received steroids and all showed rapid improvement of symptom after treatment.The median time from symptom onset to the initiation of steroids was 24 days, and the median prednisone dose was 0.60 mg/kg/day. Six patients (6/10, 60%) experienced disease recurrence during the corticosteroid tapering phase, and two patients who failed steroid tapering were successfully treated with a combination of corticosteroid and JAK inhibitor therapy. Conclusion:This pioneering cohort study provides the first systematic investigation of ICI-UC, establishing its incidence and comprehensively characterizing clinical and imaging features. Through cohort analysis, we propose a novel severity grading system with corresponding treatment algorithms, while additionally exploring the therapeutic potential of JAK inhibitors for steroid-dependent cases.

Background Chicoric acid (CA), a bioactive natural compound found in Chicory and Echinacea purpurea, exhibits antiinflammatory, antioxidant, and apoptosis-inducing properties. However, its therapeutic potential and underlying mechanisms in non-small cell lung cancer (NSCLC) remain unclear.Methods We utilized bioinformatics analysis to identify potential hub genes targeted by CA. The clinical relevance of glycogen phosphorylase liver form (PYGL) was assessed via immunohistochemistry in NSCLC tissues. Functional assays, including Cell Counting Kit-8, flow cytometry, and xenograft models, were employed to evaluate the impact of PYGL on tumor growth. Glycogen metabolism and glycolytic flux were monitored using PAS staining and Seahorse assays. Direct binding between CA and PYGL was confirmed through virtual screening, molecular docking, cellular thermal shift assay, and surface plasmon resonance. Binding specificity was further validated using site-directed mutagenesis.Results Here, we demonstrate that CA restores glucose metabolic homeostasis and inhibits the proliferation of NSCLC cells. We identified PYGL as a key driver of NSCLC, where its upregulation enhances glycogenolysis to fuel glycolytic flux and promote tumor growth. Mechanistically, CA allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273) and inducing conformational changes, thereby suppressing glycogenolysis and reducing glycolysis. Furthermore, CA disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating the proteasomal degradation of LDHA and further reshaping glucose metabolic homeostasis.Conclusions Our findings highlight PYGL as a metabolic vulnerability in NSCLC and establish CA as a promising lead compound that targets the PYGL-LDHA axis to reprogram glucose metabolism and inhibit tumor growth.

BACKGROUND:Colorectal cancer (CRC) is the most common malignant tumor of the digestive system. Exploring effective diagnostic markers and therapeutic targets has great significance for the diagnosis and treatment of CRC. ARID1A is frequently mutated in CRC, but its prognostic value for this disease remains controversial. Therefore, our aim was to explore the biological role of ARID1A in CRC and the underlying molecular mechanisms. METHODS:The clinical relevance of ARID1A in CRC was evaluated using integrating multiple biological databases and a clinical cohort. In vitro and in vivo functional assays (CCK-8, colony formation, transwell, and xenograft models) assessed its tumor-modulating effects. Autophagy was examined via transmission electron microscopy and immunofluorescence, while western blotting quantified epithelial-mesenchymal transition, autophagy-related, and signaling pathway proteins. RESULTS:Based on CRC mutation data from TCGA-COAD and cBioPortal, the ARID1A mutation frequency was 14% and 16%, respectively. Survival analysis showed that the low-ARID1A-expression group had a poorer prognosis than the high-expression group. In vitro and in vivo studies showed that downregulation of ARID1A promotes various malignant biological behaviors of CRC cells, including proliferation, invasion, and metastasis. These phenotypic changes were accompanied by alterations in autophagy-related markers (such as decreased Beclin1 and LC3B, and increased p62) and activation of the AKT/mTOR/p70S6K signaling pathway. In addition, analyses of clinical samples indicated that low ARID1A expression is an independent risk factor for CRC recurrence and metastasis. CONCLUSION:In summary, ARID1A has a tumor-suppressive role in CRC. These data suggest that ARID1A expression is a potential biomarker for CRC, which could lead to novel clinical diagnostic and treatment approaches.

Plastic stabilizers (PSs) are chemical additives that are widely used to inhibit the degradation of plastics. However, their safety concerns and potential carcinogenic risks remain unclear. This study employed network toxicology strategies to elucidate the potential toxic effects and underlying molecular mechanisms of representative PSs, including 2,6-di-tert-butylphenol (2,6-DTB), tert-butylhydroquinone (TBHQ), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328) in breast cancer (BC). Herein, we identified 69 potential genes related to PSs exposure and BC, and optimized five core targets: GSK3B, MAPK14, PARP1, PIM1, and TRDMT1, through subsequent LASSO and SVM algorithms. Based on these core genes, we constructed risk score and nomogram models, both of which revealed that high expression of these five core genes predicts poor prognosis in BC patients. Additionally, molecular docking and dynamic simulations indicated high-affinity interactions between PSs and these core targets (binding energies < -5 kcal/mol). Further correlation analysis with prediction analysis of microarray 50 (PAM50) revealed increased expression of all core genes in the basal-like subtype, especially PIM1 and TRDMT1, which also exhibited the highest risk scores. In vitro, PSs transcriptionally upregulated MAPK14, PIM1, and TRDMT1, with STAT3 mediating their transcription. Importantly, cell counting kit-8 and wound healing assays demonstrated that PSs promote BC cell proliferation and migration. Our research re-evaluates the carcinogenic risks of plastic stabilizers and suggests that PSs may enhance breast cancer progression via targets such as MAPK14, PIM1, and TRDMT1. This study introduces a new approach for evaluating the safety of plastic additives and offers novel insights into the toxicological effects of PSs.

The choice of treatment options for recurrent advanced ovarian cancer is very important. However, the most effective treatment options remain unclear. We searched the PubMed, Web of Science, and Cochrane Library databases and the proceedings of the last 5 years of several meetings on ovarian cancer according to the inclusion and exclusion criteria. Randomized controlled trials (RCTs) of recurrent treatment for advanced ovarian cancer with progression-free survival (PFS) were reticulated network meta-analyzed. RCTs were also analyzed for Grades 3 or higher drug-associated adverse events. We included 24 RCTs involving 6,250 patients with advanced recurrent ovarian cancer and a total of 10 treatment regimens. Our network meta-analysis revealed that the PARP plus anti-angiogenic regimen (Surface Under the Cumulative Ranking Curve, SUCRA 95.26 https://www.crd.york.ac.uk/PROSPERO/view/CRD420251007476 .

Germline pathogenic mutation of the BAP1 gene is a common molecular event in malignant mesothelioma (MM). A patient with a positive family history of tenacious peritoneal effusions presented with hydropneumothorax and suffered from recurrent pleural and peritoneal effusions since. Tuberculosis (TB) was assumed by preceding clinicians who prescribed futile anti-TB regimens. Finally, a diagnostic laparoscopy and omental biopsy revealed the histology of MM. Next-generation sequencing uncovered a novel BAP1 germline frameshift mutation (c. 1077_1083delinsTG, pPhe360fs), which was rated as pathogenic due to its potential to introduce a termination codon, resulting in nonsense-mediated mRNA decay and due to the fact of BAP1 protein nuclear loss in tumor tissue. Dual immunotherapy with nivolumab and ipilimumab was given for 3 cycles and only achieved stable disease. Steven-Johnson syndrome occurred afterward and was relieved after steroid treatment. The present study reported a case of MM with a new BAP1 frameshift mutation, treated by dual immune checkpoint inhibitors, achieving a modest drug effect and serious skin-related adverse events.

e15096 Background: Glucose metabolism reprogramming often drives the malignant progression of tumors, and targeted therapies against aberrant tumor metabolism have emerged as promising strategies to combat tumor growth. Liver glycogen phosphorylase (PYGL) is a key protein in the regulation of glucose metabolic homeostasis for the breakdown of glycogen to glucose. Chicoric acid (CA) is a pharmacologically active natural compound extracted from chicory and Echinacea purpurea with anti-inflammatory, antioxidant and apoptosis-inducing properties. However, the role of CA in cancer therapy remains unclear. Methods: Bioinformatics screening and analyses were performed to identify hub gene. The relationship between PYGL expression and clinicopathological features in non-small cell lung cancer (NSCLC) was assessed by immunohistochemistry. The effects of PYGL on cell proliferation and apoptosis were evaluated in vitro and in vivo by CCK-8, flow cytometry and xenograft model. PAS glycogen staining, 2-NDBG molecular probe and seahorse were utilized to measure the regulation of PYGL to glucose and glycogen metabolism. Virtual screening, molecular docking, cellular thermal shift assay (CETAS) and surface plasmon resonance (SPR) were performed to find and verify the target drugs of PYGL. Moreover, bind sites of CA and PYGL were demonstrated by point mutation, the Native-PAGE was conducted to detect protein activity. The transcriptomic and other biological methods were used to explore related pathways. Results: In this study, we founded that PYGL can be used as a potential marker for the diagnosis and prognosis in NSCLC. Our results suggested that PYGL dependents on enzymatic activity to accelerate NSCLC cell growth by facilitating glycolysis. Mechanistically, we revealed that E2F1 enhances PYGL transcription, and then PYGL upregulated LDHA through the AMPK/mTOR signaling axis, leading to glycolytic reprogramming and malignance in NSCLC. Therapeutically, we identified that CA as a small molecule drug of PYGL strongly binds to PYGL ( K d : 10 μmol/L) through specific amino acid residues (R248A, E274A, and S277A), which crippled phosphorylation level PYGL and increased glycogen storage and thereby inhibiting glycolysis and progression of tumor cell. Conclusions: Our results suggest that PYGL plays a carcinogenic role by reshaping glucose metabolism. CA interferes phosphorylation of PYGL to attenuate progression in NSCLC, it may be a promising therapy for patients with high PYGL expression warrants further clinical studies.

BackgroundConcurrent genetic alterations (e.g., TP53 comutations) significantly impair EGFR-TKI responsiveness and survival outcomes in EGFR-mutant lung adenocarcinoma (LUAD). AT-rich interactive domain 1A (ARID1A), which is a key subunit of SWI/SNF complexes, demonstrates critical regulatory functions as a tumour suppressor gene in cancer. The aim of this study is to determine the role of ARID1A deficiency in the therapeutic efficacy of EGFR-TKIs in LUAD.MethodsWe identified the ARID1A mutation as a potential prognostic marker in EGFR-mutant LUAD by analysing data from cBioPortal. The expression of ARID1A was detected via immunohistochemical staining. A lentivirus was employed to construct the ARID1A knockdown model in PC9 cell. We further analyzed the biological roles of ARID1A knockdown through CCK8, flow cytometry analysis and transwell assay.ResultsThe ARID1A mutation was associated with poor OS in EGFR-mutant LUAD patients, and the prognostic influence was greater than that of concurrent EGFR mutations with TP53, KRAS, CDKN2A, PIK3CA, RB1 or PTEN. By analysing the clinical data of our centre, we revealed that patients with loss of ARID1A expression demonstrated poorer median progression-free survival (mPFS, 10.3 versus 30 months, P = 0.005) when they received EGFR-TKIs as the first-line treatment after postoperative progression (cohort A). A shorter median disease-free survival (mDFS, 29 versus NA months, P = 0.003) was also observed in the ARID1A low-expression cohort than in the ARID1A high-expression group in patients receiving postoperative adjuvant EGFR-TKI treatments (cohort B). We also found that ARID1A deficiency attenuated the efficacy of osimertinib by activating the EGFR/AKT/mTOR signalling axis in PC9 cell.ConclusionARID1A deficiency may be an independent prognostic factor and attenuates the response to EGFR-TKIs in patients with EGFR-mutant LUAD. In addition, loss of ARID1A expression confers resistance to EGFR-TKI by activating the EGFR/AKT/mTOR signalling axis.

BackgroundImmune checkpoint inhibitors (ICIs) have demonstrated promising antitumor activity. However, it may induce immune-related adverse events (irAEs). Multi-organ irAEs remain heterogeneous and incompletely characterized. We report a unique irAE pattern with synchronous hepatic, renal and pancreatic involvement which is first reported.Case presentation5 males developed a rare multi-organ irAE pattern with concurrent cholestatic hepatitis, renal injury and pancreatic enzyme elevation, representing 0.40% of the ICI-treated cohort. The syndrome showed early, rapidly onset and often began with nonspecific complaints requiring close monitoring.ManagementResponses of high dose glucocorticoid were varied by organs. Compared with renal and pancreatic injury, cholestatic hepatitis was less responsive to steroids. Out of 3 cases who were refractory to steroids, 2 cases were given artificial liver treatment and 1 case was given bilirubin adsorption after steroid failure.OutcomesImmunosuppression by standard glucocorticoid showed limited efficacy in cholestatic hepatitis. The 2 patients received artificial liver support improved biochemically, while bilirubin adsorption alone provided only transient reduction of bilirubin in one case. As for final clinical outcome, one patient died from severe infection during therapy agianst irAE; one patient died from cancer progression despite irAE recovery; and the others achieved full recovery from this irAE combination.

Objective AT-rich interaction domain 1A (ARID1A), is frequently mutated in cancer, leading to loss-of-function and posing challenges to therapeutic targeting. This study aimed to systematically explore epigenetic regulation of ARID1A, specifically promoter hypermethylation, in gastric cancer (GC) and its functional/immunological consequences. Methods We employed multi-omics bioinformatics analyses (UALCAN, cBioPortal, MEXPRESS and UCSC Xena) combined with in vitro functional validation in GC cell lines, including pharmacological demethylation using 5-Aza-2’-deoxycytidine (5-aza-CdR) and mechanistic interrogation via AKT agonism (SC79). Results Promoter hypermethylation was identified as a key mechanism silencing ARID1A transcriptional, showing a significant negative correlation between methylation β-values and mRNA expression (Spearman’s ρ = − 0.29, p = 2.06 × 10−8). 5-aza-CdR treatment restored ARID1A expression (p < 0.001), suppressed malignant phenotypes (proliferation, invasion, and apoptosis resistance), and revealed that ARID1A lose activates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (elevated p-AKT, p-mTOR) and upregulates PD-L1. Rescue experiments with SC79 reversed 5-aza-CdR’s effects, confirming the ARID1A-PI3K/AKT/mTOR-PD-L1 axis. Integrative analysis linked ARID1A hypermethylation to elevated immune/ESTIMATE scores (p < 0.05). Conclusion ARID1A promoter hypermethylation drives an epigenetic-immune checkpoint cascade in GC. Combined with its association with immune signatures and PD-L1 upregulation, ARID1A hypermethylation emerges as a candidate biomarker for predicting immune checkpoint blockade (ICB) responsiveness and patient stratification in GC. Future studies should evaluate 5-aza-CdR-ICB-AKT inhibitor regimens in advanced models to guide clinical translation.

BackgroundHigh-grade serous ovarian cancer (HGSOC) poses significant treatment challenges due to frequent recurrence and resistance to conventional therapies. Combination of anlotinib with immunotherapy have showed promise in various cancers, but its impact on HGSOC remains to be fully elucidated.MethodsA retrospective analysis was performed on 36 HGSOC patients treated with anlotinib-based therapies, including both monotherapy and combination treatment with anti-PD-L1/anti-PD-1 antibody (aPD-L1/aPD-1). Peripheral blood mononuclear cell-derived patient-derived xenograft (PBMC-PDX) model was established from drug-resistant recurrent HGSOC patient-derived tumor cells, and single-cell RNA sequencing (scRNA-seq) was conducted to dissect the TME following treatment with anlotinib, anlotinib + aPD-L1 and anlotinib + aPD-1.ResultsClinical analysis revealed a disease control rate (DCR) of 71.43% for anlotinib monotherapy, which improved to 100% when combined with aPD-L1/aPD-1. In PBMC-PDX models, treatment evaluation showed that anlotinib decreased tumor volume, an effect further enhanced by its combination with aPD-L1. scRNA-seq analysis demonstrated that anlotinib reduced the proportions of myofibroblastic cancer-associated fibroblasts and ESM1+ endothelial cells, resulting in decreased angiogenesis. The combination of anlotinib and aPD-L1 further amplified these effects, promoting CD8+ T cell infiltration and reversing T cell exhaustion, whereas anlotinib + aPD-1 showed limited efficacy in this regard. Additionally, anlotinib + immunotherapy induced a shift toward M1 polarization of myeloid cells, enhanced anti-tumor activity, and inhibited immune escape. Cell-cell communication analysis revealed reduced APP-CD74 signaling and increased CD99-CD99 signaling, which might contribute to immune activation.ConclusionThe combination of anlotinib and aPD-L1 effectively modulates the HGSOC tumor microenvironment by inhibiting angiogenesis, enhancing immune infiltration, and reversing T cell exhaustion.

Background:Dysregulation of fatty acid (FA) metabolism represents a critical contribution to the tumorigenesis and progression of lung adenocarcinoma (LUAD). This study aimed to identify the roles of FA metabolism and search for potential therapeutic targets. Methods:The genomic and clinical data from The Cancer Genome Atlas (TCGA)-LUAD cohort underwent univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses to establish a FA metabolism-related gene (FAMG) signature. Immunotherapy efficacy was evaluated via the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. Pharmacological sensitivity to conventional chemotherapeutic agents and molecular targeted therapies was evaluated using the "pRRophetic" R package. Through integrative multi-omics analysis, ANLN was identified as a key gene with significant prognostic value. Gene silencing via small interfering RNA (siRNA) transfection was employed for functional validation. We further analyzed the biological role and mechanism of ANLN through bioinformatics and experimental analyses in LUAD cell lines. Results:The FAMG prognostic signature indicated clinical utility in predicting patient outcomes and stratifying survival probabilities. The signature showed predictive capacity for therapeutic responses across immunotherapy, chemotherapy, and targeted drugs, supporting precision oncology applications. Experimental validation confirmed that ANLN knockdown significantly attenuated malignant phenotypes through impairing cellular proliferation and migration, enhancing apoptotic induction in LUAD. Mechanistically, we discovered for the first time that ANLN knockdown inhibited FA synthesis, glycolysis, and epithelial-mesenchymal transition (EMT) by downregulating the AKT/mTOR/HIF-1α signaling axis, representing a novel regulatory mechanism in LUAD metabolism. Conclusions:This work delineates FA metabolic heterogeneity and its predictive function of personalized treatment in LUAD. ANLN is established as both a prognostic biomarker and metabolic regulator through modulation of the AKT/mTOR/HIF-1α signaling axis. Our findings provide a framework for developing metabolism-targeted treatment strategies.

There has been an increasing incidence of breast cancer around the world in recent years. As a burgeoning model of diagnosis and treatment, precision medicine has become a new trend in breast cancer management. Dysregulated glycometabolism is well established as a tumor feature. SDC1 is a glycometabolism-related gene and participates in the progression, metastasis, resistance and recurrence of malignant tumors. SDC1 promotes the development of breast cancer by disturbing tumor stem cell phenotypes, the cell cycle and apoptosis, and then modulates macrophage migration, epithelial-mesenchymal transformation, angiogenesis and the tumor-bone microenvironment. We summarized the recent advances regarding the role of SDC1 in the mechanism driving the occurrence of breast cancer, and evaluated its potential therapeutic contributions.

Limited treatment options exist for refractory ovarian cancer (OC) due to its poor response to immune therapies. Therefore, there is an urgent need to develop new effective treatment strategies. Chicoric acid (CA) is reported to have immune-enhancing properties, but its efficacy in cancer treatment is not well understood. We hypothesize that CA might improve the efficacy of PD-1/PD-L1 blockade immunotherapy in refractory OC patients. Patient-derived xenograft (PDX) models were constructed from chemoresistant advanced high-grade serous ovarian cancer patients. These models were treated with CA, aPD-1/aPD-L1 antibodies, or a combination of both. Single-cell RNA sequencing was performed to analyze the cellular composition of the tumor microenvironment (TME), evaluate treatment efficacy, and explore therapeutic mechanisms. Variations in peripheral blood lymphocytes were analyzed via fluorescence-activated cell sorting. Immunohistochemistry confirmed the variations in tumor-infiltrating lymphocytes and tumor cells. Immunocompetent peripheral blood mononuclear cell (PBMC)-PDX models were successfully constructed using malignant ascites fluid and PBMCs. After treatment, 158,734 cells from 15 samples were categorized into epithelial cells, T lymphocytes, myeloid cells, fibroblasts, and endothelial cells. CA enhanced the antitumor ability of immune cells against OC cells. Notably, CA stimulated the proliferation of CD45 + and CD3 + cells and promoted the migration of CD8 + and CD4 + T cells from peripheral blood to infiltrate the TME. Additionally, CA enhanced the response of OCs to aPD-L1/aPD-1 treatment, strengthened the interaction between tumor and nontumor cells, and identified APP/CD74 as a critical ligand‒receptor pair. CHI3L1 was also found to be a potential marker for predicting immunotherapy efficacy in OC. This study demonstrated that combination therapy with CA and aPD-1/aPD-L1 might be a promising strategy for treating OC effectively.

Introduction: Neuroendocrine tumors (NETs) are a rare and heterogeneous group of neoplasms with both clinical and genetic diversity. The clinical applicability of molecular profiling using liquid biopsy for identifying actionable drug targets and prognostic indicators in patients with advanced NETs remains unclear. METHODS:In this study, we utilized a custom-made 37 genes panel of circulating tumor DNA (ctDNA) based on next-generation sequencing in 47 patients with advanced NETs. RESULTS:A total of 223 non-synonymous mutations were identified, with the highest frequencies found in TSC2, JAG2, NOTCH3, KMT2C, and SETD2. NETs originating from the stomach exhibited the highest average mutation frequency, while paragangliomas had the lowest. TERT mutations were associated with significantly higher hazard ratios for both progression-free survival (PFS) and overall survival (OS). Higher blood tumor mutational burden (bTMB) was linked to poor prognosis in octreotide LAR-treated patients and correlated with higher Ki-67 levels and alterations in the TM, mTOR, and Notch pathways. Treatment responders had higher bTMB, chromatin remodeling signaling mutation burden, and maximum somatic allele frequency (MSAF). Patients with high MSAF demonstrated better PFS, whereas those with low MSAF had better OS. A strong positive correlation was observed between MSAF levels and mutational burden. Co-occurring mutations in the TM, mTOR, and NOTCH pathways suggested future therapeutic strategies. CONCLUSIONS:We constructed an overview of mutations in 37 genes, linking ctDNA to survival in advanced NETs. TERT mutations, bTMB, and MSAF predict PFS or OS. Co-occurring TM, mTOR, and NOTCH pathway alterations highlight ctDNA's potential in guiding precision medicine. .

323 Background: Patients with advanced esophageal squamous carcinoma (ESCC) who experience progression after first-line immunotherapy face a challenging treatment landscape. The potential of anti-vascular therapy combined with chemotherapy in the treatment of esophageal cancer is well-established. Mechanistically, anti-angiogenic agents can promote the normalization of tumor vasculature and facilitate the access of chemotherapeutic agents to tumor targets. Considering the compromised physical condition of advanced ESCC patients, there is a preference for more convenient oral medications. Therefore, we conducted this phase II study to assess the clinical efficacy and safety of combining fruquintinib with S-1 in treating advanced ESCC patients following first-line immunotherapy failure. Methods: This open-label, single-arm, phase II study consists of dose-finding and dose-expansion phases, enrolling advanced or metastatic ESCC patients after first-line immunotherapy failure. The dose-finding phase followed a 3+3 design. Patients received fruquintinib (3mg, 4mg, 5mg, d1-d14, q3w, respectively), in combination with S-1 (40mg, 50mg, 60mg, bid, d1-d14, q3w, based on body surface area (BSA)), until unacceptable toxicities, progressive disease, or death. The initial fruquintinib dose was 4 mg d1-d14, q3w, in combination with an appropriate S-1 dose. Additional patients were enrolled in the dose-expansion phase and received the maximum tolerated dose determined in the dose-finding phase. Results: As of August 1, 2023, seven patients were enrolled in the dose-finding phase. One patient withdrew consent during the DLT assessment period. Among the patients administered a 4mg dose of fruquintinib, one out of three achieved a confirmed partial response (PR) after 7 cycles of treatment. Additionally, two out of three patients at the 5mg dose level achieved PR after 2 cycles of treatment, resulting in an overall response rate (ORR) of 50% (3/6). The disease control rate (DCR) was 100% (6/6). The median progression-free survival (PFS) was observed to be 4.93 months (95% CI: 1.93 – 10.73), with overall survival (OS) at 10.73 months (95% CI: 2.1 – 10.73). In terms of safety, no dose-limiting toxicities (DLTs) were reported at 4mg dose level. While DLTs were observed in two out of the three patients at the 5mg dose level. The most common treatment-related adverse events (TRAE) across all grades were fatigue (5/7) and extremity pain (4/7). Grade 3 TRAE were identified in 5 patients, with hypertension (2/7), mucositis (2/7), and fatigue (2/7) being reported. No grade 4 or higher TRAEs were observed. Conclusions: Potential benefits were demonstrated when using fruquintinib in combination with S-1 for the treatment of ESCC patients after immunotherapy failure. The efficacy and safety of fruquintinib and S-1 will be further investigated in this trial later. Clinical trial information: NCT05636150 .

Because of the unique tumor microenvironment (TME), immunotherapy and targeted therapies have shown limited efficacy in treating pancreatic adenocarcinoma (PAAD). CD8 + T cells play crucial roles in regulating the TME in PAAD; therefore, exploring the function of CD8 + T-cell-related genes (CD8RGs) in PAAD has high potential clinical value and could provide a comprehensive understanding of the microenvironment of PAAD. We employed the weighted gene coexpression network analysis and CIBERSORT algorithms to assess PAAD transcriptome data from The Cancer Genome Atlas (TCGA) dataset and identify modules strongly associated with CD8 + T cell infiltration. Using least absolute shrinkage and selection operator regression analysis and Kaplan–Meier curves, we developed a prognostic risk score model for patients with PAAD. We validated this model using single-cell and transcriptome datasets obtained from the Gene Expression Omnibus (GEO). We also examined the correlations between the risk score and factors such as the TME, clinical characteristics, and tumor mutation burden (TMB). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed on differentially expressed genes between the high- and low-risk groups. In addition, the Tumor Immune Dysfunction and Exclusion website and “pRRophetic” R package were used to predict response to immunotherapy and chemotherapy in the high- and low-risk groups, respectively. Finally, we analyzed the expressions of hub genes at the cellular level with quantitative real-time PCR. A risk model based on five CD8RGs was established and validated using TCGA and GEO datasets. The low-risk group exhibited significantly longer overall and progression-free survival. A positive correlation between the TMB and the risk score was observed. The TME analysis revealed a significant correlation between the risk score and immune function, as well as immune checkpoints. The expression of hub genes was significantly correlated with the infiltration level of CD8 + T cells. The high-risk group responded better to immunotherapy, paclitaxel, cisplatin, mitomycin C, afatinib (BIBW2992), and gefitinib. In contrast, the low-risk group showed higher sensitivity to sunitinib, MK.2206, palbociclib (PD.0332991), and axitinib. Compared with that in normal pancreatic epithelial cells, the expression levels of BCL11A, PHOSPHO1, and GNG7 were significantly decreased, while those of KLK11 and VCAM1 were significantly increased in pancreatic tumor cells. CD8RGs play an important role in regulating the TME of PAAD. Five hub genes—BCL11A, KLK11, GNG7, PHOSPHO1, and VCAM1—are closely associated with the prognosis of PAAD patients, providing new references for the exploration of biomarkers. Furthermore, our findings offer novel insights for clinical decision-making.

BackgroundIn recent years,the lack of specific markers for the diagnosis of colorectal cancer has led to an upward trend in both morbidity and mortality from this condition. There is an urgent need to identify molecular biomarkers that contribute to early cancer detection. This study aimed to identify specific exosomal microRNAs that hold potential as diagnostic biomarkers for CRC. MethodsWe screened for differentially expressed miRNAs using the CRC exosome dataset GSE39833. To validate the results in the public database, we collected serum from 168 CRC patients and 168 healthy volunteers. The expression levels of exosomal miR-1470 in healthy volunteers and CRC patients were analyzed using qRT-PCR. To evaluate the diagnostic potential of the selected miR-1470 in distinguishing CRC patients from healthy controls, we analyzed its receiver operating characteristic curve. To explore the biological functions of miR-1470 in CRC cell lines, we detected the miR-1470's ability to regulate the growth and metastasis of CRC cells by CCK8, transwell and other assays after transfection of miR-1470 in SW480, HCT-116 cells. ResultsExosomal miR-1470 exhibited significant up-regulation in CRC patients compared to healthy volunteers. The ROC curve analysis revealed an area under the curve (AUC) of 0.74 (95% confidence interval: 0.6876-0.7920) for exosomal miR-1470, indicating its potential as a diagnostic biomarker. Furthermore, the expression level of miR-1470 in CRC patients showed correlations with age, metastasis, and HDL content. We overexpressed miR-1470 in CRC cell lines. CCK8 proliferation assay showed that miR-1470 promoted the proliferation ability of SW480 and HCT-116 cells. Transwell assay showed that miR-1470 promoted the migration and invasion ability of SW480 and HCT-116 cells. ConclusionThis suggested that non-invasive diagnosis of CRC is possible by detecting the level of miR-1470 in exosomes, which has important implications for early detection and treatment of this disease.