Participation of preovulatory follicles in the activation of primordial follicles in mouse ovaries.

The mechanisms behind the selection and initial recruitment of primordial follicles (PmFs) from the non-growing PmF pool during each estrous cycle in females remain largely unknown. This study demonstrates that PmFs closest to the ovulatory follicle are preferentially activated in mouse ovaries under physiological conditions. PmFs located within 40 µm of the ovulatory follicles were more likely to be activated compared to those situated further away during the peri-ovulation period. Repeated superovulation treatments accelerated the depletion of the PmF reserve, whereas continuous suppression of ovulation delayed PmF reserve consumption. Spatial transcriptome sequencing of peri-ovulatory follicles revealed that ovulation primarily induces the degradation and remodeling of the extracellular matrix (ECM). This ECM degradation reduces mechanical stress around PmFs, thereby triggering their activation. Specifically, Cathepsin L (CTSL), a cysteine proteinase and lysosomal enzyme involved in ECM degradation, initiates the activation of PmFs adjacent to ovulatory follicles in a distance-dependent manner. These findings highlight the link between ovulation and selective PmF activation, and underscore the role of CTSL in this process under physiological conditions.

Suppression of SENP3 enhances macrophage alternative activation by mediating IRF4 de-SUMOylation in ESCC progression.

Esophageal cancer is common worldwide, with ESCC being the most frequent tumor in East Asia. Tumor-associated macrophages are an important component of the ESCC microenvironment. SUMOylation is a post-translational modification of proteins, and SUMO-specific proteases (SENPs) play an important role in de-SUMOylation. In human patients, we discovered that the levels of SENP3 were upregulated in the tumor-associated macrophages. Furthermore, the loss of SENP3 enhanced the alternative activation of macrophages in the 4-NQO-induced ESCC mice model. This is the first study to identify SENP3-mediated macrophage polarization via the de-SUMOylation of interferon regulatory factor 4 (IRF4) at the K349 site. Alternative activation of macrophages increases the migration and invasion potential of ESCC cells and promotes their progression in vivo. Moreover, patients with relatively low SENP3 expression in macrophages exhibit higher primary PET SUVmax value and lymph node metastasis rates. In summary, this study revealed that SENP3-mediated IRF4 de-SUMOylation is crucial for the alternative activation of macrophages and influences the progression of ESCC.

Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses.

T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein α (GABPα) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPARγ and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases.

In situ imaging of intracellular miRNAs in tumour cells by branched hybridisation chain reaction.

The ability to visualise microRNA in situ is crucial for studying microRNAs, their microRNA-associated biological functions and disease diagnosis. Traditional fluorescence in situ hybridisation methods based on paraformaldehyde fixation of microRNAs suffer from release of microRNAs from cells, which limits the sensitivity of in situ hybridisation, making them unsuitable for the detection of small, low-abundance microRNAs. To reduce the loss, microRNAs were covalently cross-linked to proteins within cells by combining EDC and paraformaldehyde, and the target microRNA was used as the initiator chain for a branched hybridisation chain reaction to detect microRNA expression levels in situ. A simplified branched hybridisation chain reaction can be realised by coupling two hybridisation chain reaction circuits with a hairpin linker. Upon forming the primary hybridisation chain reaction product with extended sequence, this sequence reacts with the linker hairpin H3 to release the initiator sequence, resulting in the formation of numerous dendritic branched hybridisation chain reaction products. Imaging results show that this technique can detect microRNAs with high sensitivity and selectivity at both the single-cell and single-molecule levels. Compared with the traditional fluorescence in situ hybridisation technique, this method greatly improves the sensitivity and image resolution of in situ imaging detection. Therefore, we believe that the target-initiated branched hybridisation chain reaction based in situ detection method provides a reliable assay platform for analysing disease-related microRNA expression.

A new pragmatic classification system for thymoma associated myasthenia gravis: a retrospective cohort study.

The management and outcomes of patients with thymoma associated with myasthenia gravis (TAMG) are heterogeneous. Here, we propose a novel classification system based on Masaoka stage and Myasthenia Gravis Foundation of America (MGFA) classification, aiming to guide surgical decisions and perioperative management for these patients. Considering both oncological and neurological factors, this novel TAMG classification provides valuable information on outcome stratification and clinical decision-making for TAMG.

Efficacy and safety of Xileisan combined with mesalazine for ulcerative colitis: A meta-analysis and trial sequential analysis.

BACKGROUND: The benefits and risks of Xileisan (XLS) in the treatment of ulcerative colitis (UC) remain unclear. AIM: The present study aimed to evaluate the efficacy and safety of the combination of XLS and mesalazine when treating UC. METHODS: We searched eight databases for clinical trials evaluating the combination of XLS and mesalazine in the treatment of UC, up to January 2024. Meta-analysis and trial sequential analysis (TSA) were performed using Revman 5.3 and TSA 0.9.5.10 beta, respectively. RESULTS: The present study included 13 clinical studies involving 990 patients, of which 501 patients received XLS combined with mesalazine while 489 patients received mesalazine alone. The meta-analysis showed that, in terms of efficacy, the combination of XLS and mesalazine significantly improved the clinical efficacy rate by 22% [risk ratio (RR) = 1.22; 95%CI: 1.15-1.28; P < 0.00001] and mucosal improvement rate by 25% (RR = 1.25; 95%CI: 1.12-1.39; P = 0.0001), while significantly reducing the duration of abdominal pain by 2.25 days [mean difference (MD) = -2.25; 95%CI: -3.35 to -1.14; P < 0.0001], diarrhea by 2.06 days (MD = -2.06; 95%CI: -3.92 to -0.20; P = 0.03), hematochezia by 2.32 days (MD = -2.32; 95%CI: -4.02 to -0.62; P = 0.008), tumor necrosis factor alpha by 16.25 ng/mL (MD = -16.25; 95%CI: -20.48 to -12.01; P < 0.00001), and interleukin-6 by 14.14 ng/mL (MD = -14.14; 95%CI: -24.89 to -3.39; P = 0.01). The TSA indicated conclusiveness in the meta-analysis of the efficacy endpoints. In terms of safety, the meta-analysis revealed that the combination of XLS and mesalazine did not increase the occurrence of total and gastrointestinal adverse events, abdominal distension, and erythema (P > 0.05). The TSA showed non conclusive findings in the meta-analysis of the safety endpoints. Harbord's test showed no publication bias (P = 0.734). CONCLUSION: Treatment with XLS alleviated the clinical symptoms, intestinal mucosal injury, and inflammatory response in patients with UC, while demonstrating good safety.

EGR1 Promotes Erastin-induced Ferroptosis Through Activating Nrf2-HMOX1 Signaling Pathway in Breast Cancer Cells.

Purpose: Early growth response 1 (EGR1) is a crucial transcription factor composed of zinc finger structures, inhibitory and activating regulatory regions. We identified the biological effect and molecular mechanisms of EGR1 in breast cancer (BC). Methods: We used qRT-PCR, western blot and immunohistochemistry to examine the expression of EGR1 in BC samples. CCK-8 and colony assay were performed to reveal the effect of EGR1 on the proliferation of BC cells. LDH release assay, MCB assay, MDA assay, C-AM assay and TMRE assay were performed to measure the levels of LDH release, GSH, MDA, LIP and mitochondrial membrane potential. The regulation of EGR1 on the expression of Nrf2 and HMOX1 was investigated through Western blot. Xenograft models were conducted to determine the impact of EGR1 overexpression on BC in vivo. Results: The expression of EGR1 was downregulated in BC tissues compared with the normal tissues, and lower expression of EGR1 associated with poorer clinical outcome in BC patients. Through in vitro experiments, we found that EGR1 downregulation facilitated the proliferation of BC cells, and overexpression of EGR1 inhibited the proliferation of BC cells. In addition, EGR1 knockdown alleviated erastin-induced ferroptosis and overexpression of EGR1 facilitated erastin-induced ferroptosis in BC cells. Moreover, overexpression of EGR1 facilitated the anti-tumor effect caused by erastin in vivo. Mechanistically, the phosphorylation levels of Nrf2 and the expression of HMOX1 were reduced due to the downregulation of EGR1, and increased due to the upregulation of EGR1. Additionally, the finding that EGR1 facilitated erastin-induced ferroptosis was alleviated by the inhibition of Nrf2-HMOX1. Conclusion: The expression of EGR1 is downregulated in BC, which is correlated with poor prognosis of BC patients. EGR1 suppresses the proliferation of BC cells and facilitates erastin-induced ferroptosis by activating Nrf2-HMOX1 signaling pathway in BC cells.

The diagnostic value of CT-based radiomics nomogram for solitary indeterminate smoothly marginated solid pulmonary nodules.

Objectives: This study aimed to explore the value of radiomics nomogram based on computed tomography (CT) on the diagnosis of benign and malignant solitary indeterminate smoothly marginated solid pulmonary nodules (SMSPNs). Methods: This study retrospectively reviewed 205 cases with solitary indeterminate SMSPNs on CT, including 112 cases of benign nodules and 93 cases of malignant nodules. They were divided into training (n=143) and validation (n=62) cohorts based on different CT scanners. Radiomics features of the nodules were extracted from the lung window CT images. The variance threshold method, SelectKBest, and least absolute shrinkage and selection operator were used to select the key radiomics features to construct the rad-score. Through multivariate logistic regression analysis, a nomogram was built by combining rad-score, clinical factors, and CT features. The nomogram performance was evaluated by the area under the receiver operating characteristic curve (AUC). Results: A total of 19 radiomics features were selected to construct the rad-score, and the nomogram was constructed by the rad-score, one clinical factor (history of malignant tumor), and three CT features (including calcification, pleural retraction, and lobulation). The nomogram performed better than the radiomics model, clinical model, and experienced radiologists who specialized in thoracic radiology for nodule diagnosis. The AUC values of the nomogram were 0.942 in the training cohort and 0.933 in the validation cohort. The calibration curve and decision curve showed that the nomogram demonstrated good consistency and clinical applicability. Conclusion: The CT-based radiomics nomogram achieved high efficiency in the preoperative diagnosis of solitary indeterminate SMSPNs, and it is of great significance in guiding clinical decision-making.

Multifunctional Nanoparticle-Loaded Injectable Alginate Hydrogels with Deep Tumor Penetration for Enhanced Chemo-Immunotherapy of Cancer.

Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca2+, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.

Resection of the tumor in the trigone of the lateral ventricle via the contralateral posterior interhemispheric transfalcine transprecuneus approach with multi-modern neurosurgery technology: a case report.

Choroid plexus papilloma (CPP) is a rare benign intracranial tumor origin that predominantly manifests in the lateral ventricle in children, accounting for 0.3%-0.6% of all primary intracranial tumors. It is extremely rare to have the CPP in the trigone of the lateral ventricle through the contralateral posterior interhemispheric transfalcine transprecuneus approach (PITTA). Herein, we report this rare case. A 7-year-old girl presented with headache. Magnetic resonance imaging of the brain showed periatrial lesions, and histopathological examination confirmed CPP (WHO grade I). The contralateral PITTA is a safe, effective, reasonable, and appropriate for some lesions in the trigone of the lateral ventricle. It provides a wider surgical angle (especially for the lateral extension) and reduces the risk of disturbance of the optic radiation compared with the conventional approaches. The use of multiple modern neurosurgical techniques, including interventional embolization, intraoperative navigation, microscope, and electrophysiological monitoring, make the procedure much easier and more accurate, and the neuroendoscope adds to the visualization of the microscope and can reduce surgical complications.

Dissecting the antitumor effects of Scutellaria barbata: Initial insights into the metabolism of scutellarin and luteolin by gut microbiota.

The high prevalence of cancer and detrimental side effects associated with many cancer treatments necessitate the search for effective alternative therapies. Natural products are increasingly being recognized and investigated for their potential therapeutic benefits. Scutellaria barbata D. Don (SBD), a plant with potent antitumor properties, has attracted significant interest from oncology researchers. Its primary flavonoid components-scutellarin and luteolin-which have limited oral bioavailability due to poor absorption. This hinders its application for cancer treatment. The gut microbiota, which is considered a metabolic organ, can modulate the biotransformation of compounds, thereby altering their bioavailability and efficacy. In this study, we employed liquid chromatography tandem mass spectrometry (LC-MS/MS 8060) and ion trap-time of flight (LC-MSn-IT-TOF) analysis to investigate the ex vivo metabolism of scutellarin and luteolin by the gut microbiota. Five metabolites and one potential metabolite were identified. We summarized previous studies on their antitumor effects and performed in vitro tumor cell line studies to prove their antitumor activities. The possible key pathway of gut microbiota metabolism in vitro was validated using molecular docking and pure enzyme metabolic experiments. In addition, we explored the antitumor mechanisms of the two components of SBD through network pharmacology, providing a basis for subsequent target identification. These findings expand our understanding of the antitumor mechanisms of SBD. Notably, this study contributes to the existing body of knowledge regarding flavonoid biotransformation by the gut microbiota, highlighting the therapeutic potential of SBD in cancer treatment. Moreover, our results provide a theoretical basis for future in vivo pharmacokinetic studies, aiming to optimize the clinical efficacy of SBD in oncological applications.

Perioperative outcomes and survival after neoadjuvant immunochemotherapy for locally advanced esophageal squamous cell carcinoma.

OBJECTIVE: This study aimed to compare the difference in perioperative outcomes and prognosis between neoadjuvant immunochemotherapy and neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. METHODS: The patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant immunochemotherapy or neoadjuvant chemoradiotherapy were identified from a prospectively maintained database at Zhongshan Hospital of Fudan University between January 2018 and March 2022. Propensity score matching was performed to balance the 2 groups. RESULTS: A total of 124 patient pairs were enrolled in the final analysis. The complete pathological response rate (20.2% vs 29.0%, P = .140) was similar in the 2 groups, whereas the lower major pathological response rate (44.4% vs 61.3%, P = .011) was observed in the neoadjuvant immunochemotherapy group. Neoadjuvant immunochemotherapy was associated with a lower rate of adverse events (42.7% vs 55.6%, P = .047) without additional postoperative complications (38.7% vs 35.5%, P = .693). The neoadjuvant immunochemotherapy group had lower distant metastasis (6.5% vs 16.1%, P = .027) and overall recurrence (11.3% vs 23.4%, P = .019) in the postoperative 1 year. Also, neoadjuvant immunochemotherapy was associated with better progression-free survival (hazard ratio, 0.50; 95% CI, 0.32-0.77; P = .002). Cox proportional hazard analysis showed that neoadjuvant immunochemotherapy (univariable: hazard ratio, 0.55; 95% CI, 0.37-0.82; P = .003; multivariable: hazard ratio, 0.44; 95% CI, 0.29-0.65; P < .001) was one of the independent prognostic factors for progression-free survival. The 2 groups had similar overall survival (hazard ratio, 0.62; 95% CI, 0.36-1.09; P = .094) at the latest follow-up. CONCLUSIONS: This retrospective study showed that neoadjuvant immunochemotherapy was safe and effective for patients with locally advanced esophageal squamous cell carcinoma. Further verification is needed in randomized controlled trials.

Model for end-stage liver disease-dependent prognostic capacity of platelet-to-lymphocyte ratio following liver transplantation for hepatocellular carcinoma.

BACKGROUND: To improve liver organ allocation, the model for end-stage liver disease (MELD) score was adopted in candidates reflecting the severity of liver disease and the physical condition of patients. Inflammatory markers are prognostic factors for various cancers and play prognostic roles in patients after liver transplantation (LT) for hepatocellular carcinoma (HCC). Researchers focused more on pre-LT inflammatory markers, while the role of dynamic change of these inflammatory markers is still unknown. The purpose of this study was to estimate the prognostic value of pre-LT and post-LT inflammatory markers. MATERIAL AND METHODS: We collected the pre-LT complete blood count and the post-LT result with highest count of white blood cells within 48 h. Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and systemic immune-inflammation index were calculated, and their prognostic roles were analyzed for their MELD scores. RESULTS: This retrospective two-center cohort study enrolled 290 patients after LT for HCC. Multivariate analysis identified pre-LT PLR as independent risk factor for recurrence-free survival (RFS) [HR (95%CI): 1.002 (1.000-1.003), p = 0.023]. A high pre-LT PLR or post-LT PLR were associated with poorer RFS (p < 0.001 and p = 0.004, respectively). Based on the MELD scores, the pre-LT PLR value was able to predict the RFS in high MELD group (p < 0.001) but had no predictive power in low MELD group (p = 0.076). On the contrary, the post-LT PLR value was better to predict the overall RFS value in low MELD group (p = 0.007) but could not predict the overall RFS value in high MELD group (p = 0.136). CONCLUSIONS: Both pre-LT PLR and post-LT PLR demonstrated prognostic value in patients following LT for HCC. Monitoring PLR values based on the MELD score can improve the predictive prognosis and more effectively guide the individual decisions for the postoperative intervention.

Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

The changes of intestinal microbiota and metabolomics during the inhibition of bladder cancer by liquiritigenin.

Liquiritigenin is a natural medicine. However, its inhibitory effect and its potential mechanism on bladder cancer (BCa) remain to be explored. It was found that it could be visualized that the transplanted tumours in the low-dose liquiritigenin -treated group and the high-dose liquiritigenin -treated group were smaller than those in the model group. Liquiritigenin treatment led to alterations in Lachnoclostridium, Escherichia-Shigella, Alistipes and Akkermansia. Non-targeted metabolomics analysis showed that a total of multiple differential metabolites were identified between the model group and the high-dose liquiritigenin-treated group. This provides a new direction and rationale for the antitumour effects of liquiritigenin.

PPIA dictates NRF2 stability to promote lung cancer progression.

Nuclear factor erythroid 2-related factor 2 (NRF2) hyperactivation has been established as an oncogenic driver in a variety of human cancers, including non-small cell lung cancer (NSCLC). However, despite massive efforts, no specific therapy is currently available to target NRF2 hyperactivation. Here, we identify peptidylprolyl isomerase A (PPIA) is required for NRF2 protein stability. Ablation of PPIA promotes NRF2 protein degradation and blocks NRF2-driven growth in NSCLC cells. Mechanistically, PPIA physically binds to NRF2 and blocks the access of ubiquitin/Kelch Like ECH Associated Protein 1 (KEAP1) to NRF2, thus preventing ubiquitin-mediated degradation. Our X-ray co-crystal structure reveals that PPIA directly interacts with a NRF2 interdomain linker via a trans-proline 174-harboring hydrophobic sequence. We further demonstrate that an FDA-approved drug, cyclosporin A (CsA), impairs the interaction of NRF2 with PPIA, inducing NRF2 ubiquitination and degradation. Interestingly, CsA interrupts glutamine metabolism mediated by the NRF2/KLF5/SLC1A5 pathway, consequently suppressing the growth of NRF2-hyperactivated NSCLC cells. CsA and a glutaminase inhibitor combination therapy significantly retard tumor progression in NSCLC patient-derived xenograft (PDX) models with NRF2 hyperactivation. Our study demonstrates that targeting NRF2 protein stability is an actionable therapeutic approach to treat NRF2-hyperactivated NSCLC.

B7-H4 reduces the infiltration of CD8+T cells and induces their anti-tumor dysfunction in gliomas.

B7-H4 is a promising immune checkpoint molecule in tumor immunotherapy. Our previous study showed that high B7-H4 expression was strongly correlated with deficiency in tumor infiltrated lymphocytes (TILs) in glioma patients. On this basis, we investigated the impact of B7-H4 on CD8+TILs in gliomas and the associated molecular mechanism here. B7-H4-positive tumor samples (n=129) from our glioma cohort were used to assess B7-H4 expression and CD8+TIL quantification by immunohistochemistry. CD8+TILs from five glioma patients cultured with B7-H4 protein were used to evaluate anti-tumor dysfunction by flow cytometry and ELISpot. An orthotopic murine glioma model was used to investigate the role of B7-H4 in glioma CD8+TILs by immunohisto- chemistry and flow cytometry. CD8+TILs from glioma patients cultured with B7-H4 protein were used to explore the potential molecular mechanism by RNA sequencing and western blot. Our results showed that glioma CD8+TIL density was negatively correlated with B7-H4 expression both in glioma patient cohort (P < 0.05) and orthotopic glioma murine model (P < 0.01). B7-H4 also lowered the expression of CD137 and CD103 (P < 0.05 for both) in glioma CD8+TILs and reduced their secretion of the anti-tumor cytokines IFN-γ and TNF-α (P < 0.01 for both) in a dose-dependent manner. Furthermore, B7-H4 was found to induce early dysfunction of glioma CD8+TILs by downregulating the phosphorylation of AKT and eNOS (P < 0.05 for both). In conclusion, B7-H4 reduced the infiltration of glioma CD8+TILs and induced an anti-tumor dysfunction phenotype. B7-H4 may also impair the anti-tumor function of glioma CD8+TILs via the AKT-eNOS pathway. These results indicated that B7-H4 may serve as a potential target in future glioma immunotherapy.

Alarmin S100A8 imparts chemoresistance of esophageal cancer by reprogramming cancer-associated fibroblasts.

Chemotherapy remains the first-line treatment for advanced esophageal cancer. However, durable benefits are achieved by only a limited subset of individuals due to the elusive chemoresistance. Here, we utilize patient-derived xenografts (PDXs) from esophageal squamous-cell carcinoma to investigate chemoresistance mechanisms in preclinical settings. We observe that activated cancer-associated fibroblasts (CAFs) are enriched in the tumor microenvironment of PDXs resistant to chemotherapy. Mechanistically, we reveal that cancer-cell-derived S100A8 triggers the intracellular RhoA-ROCK-MLC2-MRTF-A pathway by binding to the CD147 receptor of CAFs, inducing CAF polarization and leading to chemoresistance. Therapeutically, we demonstrate that blocking the S100A8-CD147 pathway can improve chemotherapy efficiency. Prognostically, we found the S100A8 levels in peripheral blood can serve as an indicator of chemotherapy responsiveness. Collectively, our study offers a comprehensive understanding of the molecular mechanisms underlying chemoresistance in esophageal cancer and highlights the potential value of S100A8 in the clinical management of esophageal cancer.