Background: Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer, with poor outcomes following neoadjuvant chemoradiotherapy (NCRT). Neoadjuvant chemoimmunotherapy (NCIT) has emerged as a promising strategy, but reliable predictive biomarkers remain lacking. This study aimed to develop an AI-driven pathomic model for NCIT response prediction and explore its biological mechanisms. Methods: We analyzed 269 H&E-stained whole-slide images (WSIs) from 198 ESCC patients (104 from Tongji Hospital, 94 from TCGA). Using ResNet152, we segmented WSIs into four tissue categories (tumor cells, stroma, lymphocytes, and necrosis), extracted spatially weighted pathomic features, and constructed the ECiT score via logistic regression. An integrated model combining the ECiT score with clinical variables (T stage, P53 status) was developed. Mechanistic analyses were performed using TCGA-ESCA and GSE160269 datasets. Results: The integrated model achieved AUCs of 0.897 (training) and 0.809 (temporal validation), outperforming clinical (AUC = 0.624) and pathomic-only (AUC = 0.751) models. Mechanistically, a high ECiT score correlated with enhanced immune activation (elevated CD4+ memory T cell infiltration), while low scores were linked to endoplasmic reticulum (ER) stress-unfolded protein response (UPR) activation. EIF2S3 was identified as a key molecular mediator, correlating with three pathomic features, UPR activation, and poor prognosis. Conclusions: This study may offer a preliminary indicator that could assist in personalized clinical decision-making. Correlative evidence suggests that the EIF2S3-mediated ER stress-UPR axis represents a potential candidate therapeutic target to overcome NCIT resistance, generating testable hypotheses to advance precision oncology for resectable locally advanced ESCC.

Small cell lung cancer (SCLC) is an aggressive and immunologically "cold" malignancy characterized by profound immunosuppression and limited responsiveness to immunotherapy. Its tumor immune microenvironment (TIME) exhibits defective antigen presentation, suppressive cytokine signaling, and abnormal stromal-metabolic interactions that collectively restrict immune activation and promote tumor progression. Overcoming this immune-cold state is an urgent prerequisite for improving therapeutic efficacy and achieving durable responses in SCLC.Converting SCLC from an immune-cold to an immune-active state requires integrated therapeutic strategies that relieve immunosuppression, restore antigen presentation, enhance effector lymphocyte infiltration and function, and overcome metabolic and stromal barriers that shape the suppressive TIME. This review integrates mechanistic insights with emerging therapeutic strategies for remodeling the SCLC TIME, focusing on radiotherapy, immunomodulatory therapies, stromal-targeted therapies, epigenetic therapy, and engineered immunotherapy platforms such as delta-like ligand 3 (DLL3)-directed bispecific T-cell engagers, CAR-T and cytokine-armored cells, biological vector-based immunotherapies, and nano-immunotherapy platforms. These advances outline a translational framework for converting immune-cold SCLC into an immune-responsive disease and achieving durable immunotherapeutic efficacy.

Abstract Anticancer therapy, encompassing systemic therapies such as chemotherapy, targeted therapy, and immunotherapy, as well as radiotherapy, can induce neutropenia. This condition is a frequent hematological adverse event and a dose-limiting toxicity. Neutropenia can cause interruptions or delays in anticancer therapy, febrile neutropenia, and serious infections, which in turn raises treatment costs, reduces therapeutic efficacy, and may even lead to life-threatening complications. Consequently, accurately assessing the risk of neutropenia, promptly identifying febrile neutropenia and infections, and implementing appropriate preventive and therapeutic measures are crucial for mitigating anticancer therapy-related complications, enhancing the safety and effectiveness of anticancer therapy. Grounded in evidence-based medicine and expert consensus, the Committee of Neoplastic Supportive-Care (CONS) of the China Anti-Cancer Association has developed these guidelines to assist clinical oncologists in managing neutropenia resulting from anticancer therapy.

PURPOSE:Despite significant advances in immunotherapy, lung adenocarcinoma (LUAD) remains challenging to treat due to its low immunogenicity. Platinum-based chemotherapy is a well-established DNA-damaging agent. PARP inhibitor is effective for tumors with DNA repair defects while showing limited efficacy in BRCA-proficient non-small cell lung cancer (NSCLC). This study investigated whether combining a PARP inhibitor with platinum chemotherapy enhances the response to PD-L1 blockade in LUAD and elucidated the underlying mechanism. METHOD:Immunoblotting, colony formation assays, real-time PCR, immunofluorescence, flow cytometry, and immunohistochemistry were employed to investigate the underlying mechanisms in cell lines and the tumor microenvironment. The LLC tumor model was used to assess the efficacy of the combination of PARP inhibitors, platinum, and PD-L1 blockade. Clinical relevance was explored using public databases. RESULTS:PARP inhibitor synergized with platinum to activate the cGAS-STING pathway, leading to an upregulation of PD-L1 expression and stimulation of type I interferon responses in LUAD cells. In LLC mouse models, the triple combination most effectively suppressed tumors, increased dendritic cell and CD8+ T-cell infiltration, thereby augmenting anti-tumor immunity. Clinical data linked high PARP1 expression to MDSC infiltration and poor prognosis, and emerging trial evidence supports this combinatorial strategy. CONCLUSION:The combination of PARP inhibitors and platinum activates the cGAS-STING pathway, leading to increased infiltration of mature DCs and CD8+ T cells, thereby sensitizing NSCLC to anti-PD-L1 therapy. This study presents a promising strategy for treating patients with LUAD with low immunogenicity and poor prognosis.

The infiltration of immune cells within the tumor microenvironment is a crucial determinant of the therapeutic efficacy of cancer immunotherapy. In non-small cell lung cancer (NSCLC), elucidating the regulatory mechanisms that govern the immune microenvironment is of substantial clinical importance. This study identifies Annexin A1 (ANXA1) as a key mediator in promoting the establishment of an immunosuppressive microenvironment driven by tumor cells. Clinical findings demonstrate that increased ANXA1 expression in NSCLC is highly correlated with worse prognosis and reduced effectiveness of immunotherapy. Complementary in vivo experiments further demonstrate that ANXA1 facilitates subcutaneous tumor progression and enhances the recruitment of myeloid-derived suppressor cells (MDSCs), thus fostering an immunosuppressive tumor microenvironment. Mechanistically, ANXA1 modulates the methylation status of UHRF1 (Ubiquitin-like plant homeodomain and RING finger domain-containing protein 1), disrupting DNA damage repair processes and leading to the accumulation of cytosolic double-stranded DNA (dsDNA), which triggers the activation of the STING/NF-κB/CXCL5 signaling axis. CXCL5 binds to its receptor CXCR2 on MDSCs, thereby promoting their recruitment. Importantly, inhibition of CXCR2 effectively reverses ANXA1-mediated MDSCs infiltration. These results elucidate the essential function of ANXA1 in modulating the recruitment of MDSCs within the immune environment of NSCLC, establishing ANXA1 as a significant therapeutic target for the advancement of innovative immunotherapeutic approaches.

Converting autologous tumors into therapeutic cancer vaccines represents an attractive strategy for achieving personalized antitumor immunity. However, the antitumor immune response is significantly compromised by the tumor microenvironment (TME). Herein, we developed a polymersomal nanoagonist (cDVPMA) to potentiate photodynamic therapy (PDT)-driven in situ cancer vaccination (ISCV) by inhibiting intratumoral thrombosis. cDVPMA was constructed by encapsulating the stimulator of interferon genes (STING) agonist 2'3'-cGAMP in the aqueous core of a tertiary ammonium group-containing polymersome, while embedding both the photosensitizer verteporfin-phospholipid (VL) and thrombin inhibitor dabigatran etexilate within the hydrophobic layer. Upon tumor accumulation, cDVPMA swells in response to the acidic TME, promoting controlled drug release. VL-mediated PDT not only kills cancer cells but also triggers immunogenic cancer cell death and enhances tumor antigen exposure, thus achieving ISCV by synergizing with 2'3'-cGAMP-mediated STING activation. Dabigatran etexilate effectively inhibits tumor thrombosis, thereby restoring tumor microcirculation, alleviating hypoxia, and reducing the secretion of immunosuppressive cytokines. In a 4T1 mouse breast cancer model, cDVPMA combined with near-infrared (NIR) laser irradiation elicited robust antitumor immunity, significantly suppressing primary tumor growth and metastasis, while establishing durable immune memory that prevented tumor recurrence. This study provides valuable insights into the development of nanomedicines for immunotherapy targeting tumors in a hypercoagulable state.

The N6-methyladenosine (m6A) modification is a significant research direction in the field of epitranscriptomics, and its multifaceted functions in tumor regulation have garnered increasing attention. Through the actions of three core enzyme groups, writers, erasers, and readers, m6A modification dynamically regulates RNA stability, translation efficiency, and localization, thereby influencing key biological processes in tumor cells, such as proliferation, metastasis, and drug resistance. This review outlines the m6A modification’s regulatory roles in tumor autophagy and apoptosis, metabolic reprogramming, and dynamic alterations within the tumor microenvironment. Specifically, it elaborates on how m6A orchestrates microenvironmental remodeling to promote tumor progression through mechanisms including autophagy signaling transduction, apoptotic gene regulation, metabolic gene modulation, as well as functional reprogramming of immune cells and endothelial cells. Although significant progress has been made in m6A-related tumor research, challenges remain, including its dynamic and reversible regulatory mechanisms, heterogeneity-driven functional differences, and clinical translation applications. Future studies should further explore the specific regulatory mechanisms of m6A modification, develop targeted therapeutic strategies, and integrate multi-omics and artificial intelligence technologies to construct dynamic regulatory network models. These efforts will facilitate the translation of basic research findings into clinical applications, providing novel insights and strategies for tumor diagnosis and treatment.

Sirtuin 6 (SIRT6), a (Nicotinamide adenine dinucleotide) NAD+-dependent deacylase and mono- (adenosine diphosphate) ADP-ribosyltransferase, is increasingly recognized as a pivotal regulator of genomic stability, metabolic reprogramming, and epigenetic remodeling. This review synthesizes current evidence on the dual roles of SIRT6 in cancer, highlighting its context-dependent functions as both a tumor suppressor and promoter across various malignancies. We detail its involvement in DNA damage sensing, repair coordination, glycolytic regulation, and chromatin modification, and discuss how these mechanisms contribute to tumor initiation, progression, and therapy resistance. Emerging therapeutic strategies targeting SIRT6, including small-molecule modulators, genetic interventions, and combination therapies, are critically evaluated. Our analysis underscores the necessity for context-specific therapeutic targeting, and pharmacological modulation of SIRT6 represents a promising avenue for precision oncology.

Immunogenic death (ICD) stimulates adaptive immunity and affects immunotherapeutic efficacy, an important part of which is damage-associated molecular patterns (DAMPs). However, the function of these DAMPs for lung adenocarcinoma (LUAD) remains obscure. We initially found differentially expressed genes (DEGs) with prognostic significance related to DAMPs with the TCGA database and then used the least absolute shrinkage and selection operator (LASSO) regression to create a risk signature strongly correlated with overall survival (OS) with eight DEGs. Validation was performed externally using the external data set GSE68465. Lower-risk LUAD patients were found to be more chemotherapy-resistant and enriched for more immune-related pathways than those with higher risk scores, and patients with different risks showed different levels of immune cell infiltration. PANX1, a crucial gene closely associated with lung adenocarcinoma, was identified using the weighted correlation network analysis (WGCNA), and experiments revealed that PANX1 promotes the proliferation as well as invasion of LUAD cells. Furthermore, PANX1 was found to be positively correlated with CD274, CD276, and M2 macrophage markers. We developed and validated an entirely new gene signature related to DAMPs that may be useful for LUAD patient prognosis, immune microenvironment, and chemotherapeutic drug sensitivity prediction. The results may also guide clinical immunotherapy and chemotherapy approaches for LUAD patients.

Background Chronic Myeloid Leukemia (CML) is a blood cancer that remains challenging to cure due to drug resistance and side effects from current BCR-ABL inhibitors. There is an urgent need for novel and more effective BCR-ABL targeting inhibitors and therapeutic strategies to combat this deadly disease. Method We disclose an “OH-implant” strategy to improve a noncovalent BCR-ABL inhibitor, PPY-A, by adding a hydroxyl group to its scaffold. By taking advantage of this OH “hot spot”, we designed a panel of irreversible covalent kinase inhibitors and hypoxia-responsive pro-/dual-drugs, and their biological activities were studied in vitro, in cellulo and in vivo. Result The resulting compound B1 showed enhanced solubility and biological activity. B4 achieved sustained BCR-ABL inhibition by forming a stable covalent bond with ABL kinase. Hypoxia-responsive prodrug P1 and dual-drugs D1/D2/D3 demonstrated significant anti-tumor effects under hypoxic conditions. The in vivo studies using K562-xenografted mice showed that B1 displayed superior antitumor activity than PPY-A, while P1 and D3 offered better safety profiles alongside significant tumor control. Conclusion We have successfully developed a chemical biology approach to convert a known noncovalent BCR-ABL inhibitor into more potent and safer inhibitors through covalent and pro-/dual-drug targeting strategies. Our “OH-implant” approach and the resulting drug design strategies have general applicability and hold promise for improvement the performance of various other reported drugs/drug candidates, thereby providing advanced medicines for disease treatment.

Several trials of perioperative immunotherapy for resectable non-small cell lung cancer (NSCLC) reported positive results. They were designed to adjuvant, neoadjuvant and sandwich (neoadjuvant plus adjuvant) immunotherapy with immune checkpoint inhibitors and chemotherapy (CT). The differences between neoadjuvant and sandwich modalities were unclear. We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, WHO ICTRP and major international conferences. We analyzed 8 studies involving 3429 patients, including 6 neoadjuvant plus adjuvant (Neo-Adj) and 2 neoadjuvant (Neo) trials. Neo-Adj had better event-free survival (EFS) (hazard ratio [HR] = 0.57, 95

Objective: To compare and analyze the performance of AI against clinicians in classifying benign and malignant pulmonary nodules from computerized tomography (CT) images.Methods: To compare and analyze the performance between 3D convolutional neural network (CNN) and clinicians, 506 CT images were collected as dataset, and a state-of-the-art 3D CNN model were employed as baseline, the diagnostic results produced by CNN and 7 groups of professional clinicians as clinical diagnosis results. For comparing the results, we analyzed the nodules in CT images in a case-by-case manner and the statistical methods of receiver operating characteristic (ROC) were used.Results: AI achieved a better diagnostic accuracy than clinicians, with Area under the ROC Curve (AUC) of 0. 88 and sensitivity of 0.80. Case-by-case analysis provided the professional insights for improving deep learning models.Conclusion: AI demonstrated the great potential in benign-malignant classification of pulmonary nodules.

Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal-epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy.

Fibroblast growth factor receptor 2 (FGFR2) is frequently activated by overexpression or mutation, and an abnormal fibroblast growth factor (FGF)/FGFR signaling pathway is associated with the occurrence, development, and poor prognosis of colorectal cancer (CRC). Our preliminary analysis found that plasminogen activator inhibitor-1 (PAI-1) expression may be related to FGF/FGFR signaling, however, their role in the tumor immune microenvironment remains unclear. In this study, we observed markedly higher PAI-1 expression in CRC patients with poor survival rates. PAI-1 is regulated by FGF/FGFR2 in colon cancer cells and is involved in M2 macrophage polarization. Mechanistically, inhibiting the JAK2/STAT3 signaling pathway could cause PAI-1 downregulation. Furthermore, the activation of phosphorylated STAT3 upregulated PAI-1. In vivo, FGFR2 overexpression in tumor-bearing mouse models suggested that a PAI-1 inhibitor could rescue FGFR2/PAI-1 axis-induced M2 macrophage polarization, which leads to effective immune activity and tumor suppression. Moreover, the combination of a PAI-1 inhibitor and anti-PD-1 therapy exhibited superior antitumor activity in mice. These findings offer novel insights into the molecular mechanisms underlying tumor deterioration and provide potential therapeutic targets for CRC treatment.

Abstract Lung adenocarcinoma (LUAD) is the most common pathological subtype of non-small cell lung cancer. Although the application of immune checkpoint inhibitors has greatly improved the therapy of solid tumors, treatment of lots of patients with lung adenocarcinoma is still not satisfactory. For most diseases with low immunogenicity, it’s urgent to seek for new combination treatment strategies. Platinum is a widely used DNA damage agent. PARP inhibitors are more effective for tumors with defects in DNA damage and repair. In the context of inhibition of PARP1, tumor cells are easier to form more immunogenic tumor antigen libraries and increase immunogenicity. Nonetheless, the efficacy of PARP inhibitors, combined with platinum and immune checkpoint inhibitors is still undefined. In this research, we have demonstrated that inhibiting PARP1 activated cGAS-STING pathway to up-regulate PD-L1 expression in lung adenocarcinoma cells by real-time quantitative PCR and immunoblotting. Then, we constructed a LLC tumor model to verify that PARP inhibitors, combined with platinum and immune checkpoint inhibitors could change the lymphocyte infiltration in tumor microenvironment, increase the proportion of CD8+T cells and activated DC cells, and enhance anti-tumor immunity. To sum up, we confirmed that PARP inhibitors combined with platinum can enhance the immune checkpoint effect by activating cGAS-STING pathway, further increase the infiltration of CD8+ T and DC cells and reshape tumor immune microenvironment. Therefore, this research provides a novel strategy for the treatment of lung adenocarcinoma patients with poor prognosis.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. However, the acquired resistance greatly limits the survival benefit of EGFR-TKIs for EGFR-mutant NSCLC patients. We aimed to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus EGFR-TKIs in these patients.Methods: In this prospective, randomized, controlled, phase 2 study, participants were recruited from 4 different hospitals in Wuhan, China. Eligible patients were histologically confirmed to have NSCLC with an EGFR-sensitive mutation (19DEL or 21L858R) and diagnosed at stage IV. Patients who had received first-line EGFR-TKIs treatment including gefitinib, erlotinib, and icotinib and achieved stable disease or partial response were enrolled after three months. Eligible participants were randomly assigned (1:1) to receive SBRT plus EGFR-TKIs or EGFR-TKIs treatment alone. In the combination-group, different tumor sites were irradiated at doses ranging from 30-50 Gy in five fractions. Considering the short duration of SBRT, the TKIs were continued during the radiotherapy. The primary endpoint was progression-free sur-vival (PFS), and the secondary endpoints were overall survival (OS) and safety. This study was registered at ClinicalTrials.gov, with the registration number of NCT03595644. Results: Between May 4, 2018 and Dec 20, 2019, 74 patients were screened, of whom 62 patients were enrolled and randomized. The study was closed early with 62/72 patients due to slow accrual. The enrolled patients were randomly assigned to receive SBRT plus EGFR-TKI(n = 31) or EGFR-TKI alone (n = 31). One patient who was randomized to the SBRT plus EGFR-TKI group refused to receive SBRT dur-ing the treatment, and, 61 patients were included the modified intention-to-treat (mITT) analysis, with 30 in the SBRT plus EGFR-TKI and 31 in the EGFR-TKI group. As of the clinical cutoff date (Feb 14, 2022), the median follow-up was 29.4 months (IQR 6.9-38.9). The median PFS of the EGFR-TKI group and SBRT combination group was 9.0 vs 17.6 months (hazard ratio [HR] = 0.52, 95% confidence interval [95%CI], 0.31-0.89, P = 0.016). Meanwhile, the median OS was 23.2 vs 33.6 months (HR [95%CI], 0.53 (0.30-0.95); P = 0.026). There was no grade 3 or greater toxicity observed in either group, the grade 2 adverse events were 50% in the EGFR-TKIs + SBRT group while the percentage was 45.2% in the EGFR-TKIs group.Conclusions: The addition of SBRT significantly delayed the onset of acquired resistance to EGFR-TKIs and prolonged the PFS and OS of patients. Radiotherapy of the primary lesion alone might be superior to metastatic sites. Further confirmatory studies are needed to confirm our findings.(c) 2023 Published by Elsevier B.V. Radiotherapy and Oncology 184 (2023) 1-7

Background: Radiation therapy plays an important role in the treatment of patients with non-small cell lung cancer (NSCLC). However, the radiocurability is greatly limited because of radioresistance which leads to treatment failure, tumor recurrence, and metastasis. Cancer stem cell (CSC) has been identified as the main factor that contributes to radiation resistance. SOX2, one of the transcription factors specifically expressed in CSC, is involved in tumorigenesis, progression, and maintenance of cell stemness. But the association between SOX2 and NSCLC radioresistance is not clear now. Methods: We constructed the radiotherapy-resistant cell line of NSCLC by multiple radiotherapy treatments. Colony formation assay, western blot, and immunofluorescence were performed to detect the radiosensitivity of cells. Western blot, qRT-PCR, and sphere formation assay were used to detect CSC characteristics of cells. Wound healing assay and Transwell assay were used to determine cell migration motility. The SOX2-upregulated model and SOX2-downregulated model was constructed by lentivirus transduction. Finally, the expression and clinical relevance of SOX2 in NSCLC were investigated by bioinformatics analysis based on TCGA and GEO datasets. Results: The expression of SOX2 was increased in radioresistant cells and a trend of dedifferentiation were observed. The results of wound healing assay and Transwell assay showed that SOX2 overexpression significantly promote the migration and invasion of NSCLC cells. Mechanistically, overexpression of SOX2 enhanced radioresistance and DNA damage repair capability of parental cells, while down-regulation of SOX2 led to decreased radioresistance and DNA repair ability in radioresistant cells, all of which were related to cells dedifferentiation regulated by SOX2. In addition, bioinformatics analysis show that high expression of SOX2 was strongly associated with the progression and poor prognosis of patients with NSCLC. Conclusions: Our study revealed that SOX2 regulates radiotherapy resistance in NSCLC via promoting cell dedifferentiation. Therefore, SOX2 may be a promising therapeutic target for overcoming radioresistance in NSCLC, providing a new perspective to improve the curative effect.

Purpose: Tumor mutation burden (TMB) and tumor-infiltrating lymphocytes (TILs) have been well recognized as molecular determinants of immunotherapy responsiveness. In this study, we aimed to construct a TMB prognostic model and explore biomarkers that have predictive potential for prognosis and therapeutic effect in lung adenocarcinoma (LUAD). Patients and Methods: The TCGA, GEO and Immport databases were used to analyze the mutation profiles and immune infiltration of LUAD. TMB scores were calculated and differential analysis was conducted to identify TMB-related genes. Then, Cox regression model and survival analysis were applied to identify the prognostic genes and construct a TMB prognostic model. The expression and prognostic value of CD1B were further verified by immunohistochemistry (IHC) in 92 patient tissue samples. GSEA was performed to analyze the signaling pathways associated with CD1B expression. Results: High-TMB samples exhibited higher infiltration of CD8+ T cells, CD4+ memory T cells, and M1 macrophages. A total of 397 TMB-related differentially expressed genes were identified, of which 47 were immune-related genes. Cox regression analyses determined 3 hub TMB-related immune genes (CD1B, SCGB3A1, and VEGFD) with prognostic effects, and a TMB prognostic model was constructed. The model demonstrated robust predictive ability in both the training (TCGA) and testing (GEO) datasets. Notably, CD1B was identified as an independent prognostic factor. IHC of clinical samples showed that low expression of CD1B was related to poor overall survival and advanced pathological stages. In addition, there was a strong positive correlation between CD1B and most immune checkpoint molecules, including PD-L1. CD1B expression was associated with immune cell infiltration and immune activation in LUAD. Conclusion: Our study constructed a TMB prognostic model that effectively predicted the prognosis of LUAD patients. CD1B expression is correlated with better prognosis and promotes antitumor immunity in LUAD, which may serve as a potential prognostic biomarker and immune-related therapeutic target for LUAD.

BACKGROUND:Bladder cancer (BLCA) is one of the most common malignancies worldwide. One of the main reasons for the unsatisfactory management of BLCA is the complex molecular biological mechanism. Annexin A1 (ANXA1), a Ca2+-regulated phospholipid-binding protein, has been demonstrated to be implicated in the progression and prognosis of many cancers. However, the expression pattern, biological function and mechanism of ANXA1 in BLCA remain unclear. METHODS:The clinical relevance of ANXA1 in BLCA was investigated by bioinformatics analysis based on TCGA and GEO datasets. Immunohistochemical (IHC) analysis was performed to detect the expression of ANXA1 in BLCA tissues, and the relationships between ANXA1 and clinical parameters were analyzed. In vitro and in vivo experiments were conducted to study the biological functions of ANXA1 in BLCA. Finally, the potential mechanism of ANXA1 in BLCA was explored by bioinformatics analysis and verified by in vitro and in vivo experiments. RESULTS:Bioinformatics and IHC analyses indicated that a high expression level of ANXA1 was strongly associated with the progression and poor prognosis of patients with BLCA. Functional studies demonstrated that ANXA1 silencing inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of BLCA cells in vitro, and suppressed the growth of xenografted bladder tumors in vivo. Mechanistically, loss of ANXA1 decreased the expression and phosphorylation level of EGFR and the activation of downstream signaling pathways. In addition, knockdown of ANXA1 accelerated ubiquitination and degradation of P-EGFR to downregulate the activation of EGFR signaling. CONCLUSIONS:These findings indicate that ANXA1 is a reliable clinical predictor for the prognosis of BLCA and promotes proliferation and migration by activating EGFR signaling in BLCA. Therefore, ANXA1 may be a promising biomarker for the prognosis of patients with BLCA, thus shedding light on precise and personalized therapy for BLCA in the future.