Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases. Owing to their therapeutic properties and ability to cross the blood-brain barrier, extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions, including ischemic stroke, traumatic brain injury, neurodegenerative diseases, glioma, and psychosis. However, the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body. To address these limitations, multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles, thereby enabling the delivery of therapeutic contents to specific tissues or cells. Therefore, this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles, exploring their applications in treating traumatic brain injury, ischemic stroke, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, glioma, and psychosis. Additionally, we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases. This review offers new insights for developing highly targeted therapies in this field.

N6-methyladenosine (m6A) RNA methylation is crucially involved in the genesis and advancement of gastric cancer (GC) by controlling various pathobiological aspects including gene expression, signal transduction, metabolism, cell death, epithelial-mesenchymal transition, angiogenesis, and exosome function. Despite its importance, the exact mechanisms by which m6A modification influences GC biology remain inadequately explored. This review consolidates the latest advances in uncovering the mechanisms and diverse roles of m6A in GC and proposes new research and translational directions. Key regulators (writers, readers, and erasers) of m6A, such as METTL3/14/16 and WTAP, significantly affect cancer progression, anticancer immune response, and treatment outcomes. m6A modification also impacts immune cell infiltration and the tumor microenvironment, highlighting its potential as a diagnostic and prognostic marker. Interactions between m6A methylation and non-coding RNAs offer further novel insights into GC development and therapeutic targets. Targeting m6A regulators could enhance immunotherapy response, overcome treatment resistance, and improve oncological and clinical outcomes. Models based on m6A can precisely predict treatment response and prognosis in GC. Additional investigation is needed to fully understand the mechanisms of m6A methylation and its potential clinical applications and relevance (e.g., as precise markers for early detection, prediction of outcome, and response to therapy and as therapeutic targets) in GC. Future research should focus on in vivo studies, potential clinical trials, and the examination of m6A modification in other types of cancers.

Metabolic heterogeneity resulting from the intra-tumoral heterogeneity mediates massive adverse outcomes of tumor therapy, including chemotherapeutic resistance, but the mechanisms inside remain largely unknown. Here, we find that the de novo pyrimidine synthesis pathway determines the chemosensitivity. Chemotherapeutic drugs promote the degradation of cytosolic Carbamoyl-phosphate synthetase II, Aspartate transcarbamylase, and Dihydroorotase (CAD), an enzyme that is rate-limiting for pyrimidine synthesis, leading to apoptosis. We also find that CAD needs to be cleaved by caspase-3 on its Asp1371 residue, before its degradation. Overexpressing CAD or mutating Asp1371 to block caspase-3 cleavage confers chemoresistance in xenograft and Cldn18-ATK gastric cancer models. Importantly, mutations related to Asp1371 of CAD are found in tumor samples that failed neoadjuvant chemotherapy and pharmacological targeting of CAD-Asp1371 mutations using RMY-186 ameliorates chemotherapy efficacy. Our work reveals the vulnerability of de novo pyrimidine synthesis during chemotherapy, highlighting CAD as a promising therapeutic target and biomarker.

Gastric cancer (GC), a malignant neoplasm that arises from the epithelium of the gastric mucosa, endangers patients' lives and health severely. Regulator of G-protein signaling 16 (RGS16) has been found to be correlated with the malignant progression of various cancers, and BHLHE40 is highly expressed in GC. However, it remains unclear whether there is a regulatory mechanism between the them.

The bioinformatics tools were applied to assess the differentially expressed genes in GC. Next, the expression levels of mRNA and protein were evaluated by qRT-PCR and Western blot. Cellular behaviors were assessed using CCK-8, EdU, Transwell, and flow cytometry assays. Meanwhile, the ferroptosis-related indicators were measured. Subsequently, the xenograft models were set up to estimate the role of RGS16 in vivo. Besides, the interaction between BHLHE40 and RGS16 was determined using ChIP assay and dual-luciferase reporter assay.

RGS16 exhibited an upregulated pattern in GC. In addition, silencing RGS16 impeded the proliferation, migration and invasion of GC cells while reinforcing apoptosis and ferroptosis. Moreover, RGS16 boosted the growth of tumors in vivo. Furthermore, BHLHE40 could bind to RGS16 and positively regulate its expression. Overexpression of RGS16 reversed the effects of silencing BHLHE40 on GC cells.

BHLHE40 curbed ferroptosis and oxidative stress of GC cells by modulating the expression of RGS16, thereby facilitating the malignant progression of GC.

Gastric cancer (GC) remains a major global health burden. Despite the advancements in immunotherapy for patients with GC, the heterogeneity of GC limits response rates, especially in immune "cold" subtypes, including genomically stable and epithelial-mesenchymal transition GC. Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1), a newly recognized immune checkpoint molecule predominantly expressed on tumor-associated macrophages (TAMs), remains poorly understood in GC. This study aims to explore the clinical significance of CLEVER-1+TAM infiltration, elucidate its role in modulating the tumor immune landscape, and investigate the therapeutic potential of CLEVER-1 blockade in enhancing immunotherapy.

This study analyzed two independent GC cohorts and single-cell RNA sequencing data (GSE183904). CLEVER-1 expression in TAMs was assessed via multiplex immunofluorescence, flow cytometry, and RNA sequencing. The clinical relevance of CLEVER-1+TAM infiltration was evaluated in relation to tumor, node, metastases staging, molecular subtypes, prognosis, and immunochemotherapy response. Transcriptomic and pathway analyses characterized the immunophenotype of CLEVER-1+TAMs. Functional assays examined their suppression on CD8+T cells, while interventional experiments assessed the impact of CLEVER-1 blockade alone or with programmed cell death protein-1 (PD-1) inhibition.

CLEVER-1 was predominantly expressed on TAMs in GC and was associated with worse clinical outcomes. Transcriptomic and phenotypic analyses revealed that CLEVER-1+TAMs display a dynamic immunophenotype and critically suppress T-cell function, fostering an immunosuppressive microenvironment. High CLEVER-1+TAM infiltration was linked to poor response or adaptive resistance to PD-1 blockade therapy. CLEVER-1 blockade reprogrammed TAMs toward a pro-inflammatory phenotype, resulting in enhanced CD8+T cell cytotoxicity and proliferation. Co-targeting CLEVER-1 and PD-1 synergistically enhanced antitumor responses.

High infiltration of CLEVER-1+TAMs indicates immune suppression and poor prognosis in GC. The combination of CLEVER-1 and PD-1 blockade emerges as a dual-pronged strategy to boost immune-mediated tumor control and prevent treatment relapse in GC.

The tumor microenvironment (TME) plays a crucial role in the occurrence and progression of gastric cancer. Yet, we still don't understand how immune and stromal components of TMEs are modulated. In this study, we applied the ESTIMATE algorithm to calculate the number of immune and stromal components in 410 STAD cases in the Cancer Genome Atlas (TCGA) database. COX regression analysis and protein-protein interaction (PPI) network construction were used to analyze differentially expressed genes (DEGs). Then, P-selectin (SELP) was identified as a predictor by cross-analysis of univariate COX and PPI. After verifying the clinical significance of SELP for study, we performed an immune infiltration analysis and identified 54 immunomodulators associated with SELP through public data. Immunomodulation associated with gastric cancer prognosis was then confirmed by LASSO regression, and the previous results were further validated with single-cell data. Finally, we verified that SELP can promote EMT on gastric cancer cells. In conclusion, we validated that SELP may affect the biological phenotype of gastric cancer with the immune microenvironment alteration of gastric cancer.

Immunotherapy, specifically PD-1 blockade, is a promising treatment for advanced gastric cancer (AGC). However, predicting patient response is challenging. Cytokines, key immune response regulators, could be important biomarkers for forecasting patient outcomes and susceptibility to PD-1 blockade immunochemotherapy in AGC. This meta-analysis aims to evaluate the potential of cytokine profiles as predictive biomarkers for treatment outcomes in patients with AGC undergoing immunochemotherapy. Meta-analysis. Original studies on the evaluation of various serum samples of cytokines in AGC patients after immunochemotherapy were searched in PubMed, Google Scholar, Embase, Cochrane Library, and Web of Science, with a focus on literature published up to October 31, 2023. Data from multiple studies were pooled to analyze the impact of IL-2, IL-4, IL-6, IL-8, IL-10, and IFN-γ expression on treatment outcomes using RevMan 5.4.1. Prospero ID: CRD42024557837. Five studies were included. In AGC patients receiving immunochemotherapy, high levels of IL-4 were correlated with enhanced PFS following therapy. In contrast, there were no significant differences observed in the expression of IL-2, IL-6, IL-10, and IFN-γ for PFS in AGC after treatment. Notably, elevated IL-6 expression was significantly associated with poorer OS in AGC patients undergoing immunochemotherapy. The findings suggest that expression levels of cytokines, particularly IL-4 and IL-6, play a significant role in predicting treatment outcomes in AGC patients undergoing immunochemotherapy. Further research is warranted to validate these results and elucidate the underlying mechanisms driving these associations.

Helicobacter pylori (H. pylori) is a known risk factor for gastric cancer, possibly via the PD-1/L1 pathway, and this infection may reduce the efficacy of immune checkpoint inhibitors (ICIs). This study explored the effects of H. pylori infection status on survival outcomes in patients with gastric cancer.

This single-center, retrospective study included patients with gastric adenocarcinoma between June 1985 and August 2022. Patients with different histological subtypes were excluded. Primary variables of interest included H. pylori infection status and treatment with ICIs. Other clinical information included demographics, cancer histology, the presence of other cancers, and vital status.

A total of 2930 patients were included, of whom 206 (7.0%) received ICIs, 196 (6.7%) had prior H. pylori infection, and 1037 (35.4%) had a diffuse subtype. Diffuse cancer subtypes were associated with better survival (P<0.05) at 3 and 5 years compared to intestinal-type adenocarcinomas. Diffuse cancers demonstrated better survival outcomes than intestinal cancers at 10 years, but only among H. pylori-positive patients (P=0.013). H. pylori positivity was associated with worse survival at 3 years (P=0.041) among patients taking ICIs, but not in those not receiving ICIs (P=0.325).

These findings suggest H. pylori infection may be an obstacle to successful immunotherapy, and may interact with cancer subtypes to differentially impact survival. Future studies are needed to validate the potential prognostic value of H. pylori positivity in gastric cancer.

Recently, the regulatory effects of microRNAs (miRNAs) on gene expression have been exploited for applications in the diagnosis and treatment of cancer, neurological diseases, and cardiovascular diseases. However, the susceptibility of miRNAs to degradation during somatic circulation and the challenges associated with their delivery to target tissues and cells have limited the clinical application of miRNAs. For application in tumor therapy, it is essential for miRNAs to specifically target cancer cells. Therefore, various novel miRNA delivery systems that protect miRNA against the activity of serum nuclease and deliver miRNA to target cells have been developed and optimized. This review introduces the passive and active targeting strategies of nanoparticles, summarizes the recent progress of miRNA nanocarriers with tumor-targeting ability, and discusses various nanoparticle delivery systems and their antitumor applications. Additionally, this review focuses on the translational challenges and potential strategies for advancing miRNA-based therapies into the clinic.

Programmed cell death (PCD) genes play crucial roles in cancer progression and response to therapies, yet their impact on gastric cancer remains inadequately elucidated. This study aimed to create a prognostic cell death signature (PCDs) for gastric cancer, providing insights into potential therapeutic targets and survival predictors.

We utilized TCGA-STAD and five GEO datasets, representing thousands of gastric cancer samples, for a comprehensive analysis of PCD genes. Differential gene expression, functional enrichment, survival, and machine learning analyses were conducted to construct a PCD-based prognostic model.

A total of 249 differentially expressed PCD genes were identified between cancerous and noncancerous gastric tissues. Subsequently, a PCD signature based on seven genes was developed and cross-validated across multiple cohorts. The high-PCD subtype correlated with poorer survival outcomes, lower tumor mutational burden, higher infiltration of M2 macrophages, lower levels of immune checkpoint expression, and decreased response to immunotherapy. A nomogram incorporating the PCDs provided accurate survival rate predictions. Additionally, nine machine learning algorithms were implemented for recurrence prediction, with the random forest model displaying high effectiveness. In this model, thrombospondin 1 (THBS1) showed the highest weight, and its knockdown significantly reduced gastric cancer cell proliferation and invasion.

This study underscores the significance of PCD genes, particularly THBS1, in gastric cancer progression and highlights their value as potential therapeutic targets. The predictive models developed here can aid in assessing patient prognosis and tailoring personalized treatment strategies.

Gastric cancer (GC) remains a leading cause of cancer-related deaths and exhibits considerable heterogeneity among patients. Thus, accurate classifications are essential for predicting prognosis and developing personalized therapeutic strategies. To address this, we retrospectively analyzed multi-omics data from 359 GC samples, incorporating transcriptomic RNA (mRNA), DNA methylation, mutation data, and clinical parameters. Using ten clustering algorithms, we integrated these datasets to classify GC into molecular subtypes. The robustness of our clustering approach was externally validated using an independent cohort generated from different sequencing technologies, and we characterized the heterogeneity of each subtype. Our analysis identified three distinct molecular subtypes of GC, designated CS1, CS2, and CS3. These subtypes exhibited significant differences in survival outcomes, activation of cancer-related pathways, immune microenvironment composition, genomic alterations, and responses to immunotherapy and chemotherapy. Notably, Cathepsin V (CTSV) was significantly downregulated in the immunologically active and highly responsive CS3 subtype, while it was upregulated in the immunologically exhausted CS2 subtype. These findings suggest that CTSV could serve as both a prognostic marker and a molecular classifier. Furthermore, this study provides the first evidence of CTSV's high expression in GC and its potential role in tumor progression. The novel clustering approach, based on ten clustering algorithms and comprehensive analysis of multi-omics data in gastric cancer, can guide prognosis, characterize different clinical and biological features, and elucidate the tumor immune microenvironment, providing insights into the intratumor heterogeneity of GC and potential novel therapeutic strategies. Additionally, CTSV emerges as a prognostic marker linked to tumor immunity and disease progression, which lays the foundation for improved stratification strategies and the development of targeted therapeutic approaches in GC.

With the annual increase in the incidence and mortality rates of gastric cancer, it has gradually become one of the significant threats to human health. Approximately 90% of gastric cancer patients are diagnosed with adenocarcinoma. Although the 5-year survival rate for early-stage gastric cancer can exceed 90%, due to its concealed symptoms, less than half of the patients are eligible for radical surgical treatment upon diagnosis. For gastric cancer patients receiving palliative treatment, the current expected survival time is only about one year. In China, the majority of gastric cancer patients, accounting for about 80% of the total, are in the locally advanced stage. For these patients, radical surgery remains the primary treatment option; however, surgery alone is often inadequate in controlling tumor progression. In the pivotal MAGIC study, the recurrence rate was as high as 75%, and similar results were obtained in the French ACCORD07-FFCD9703 study. Numerous clinical trials are currently exploring preoperative neoadjuvant therapy for patients with locally advanced gastric cancer. Data indicates that preoperative neoadjuvant therapy can not only reduce the size of the local tumor but also shrink surrounding lymph nodes, thereby downstaging the tumor and improving the R0 resection rate. Additionally, it can decrease tumor cell activity and eliminate potential micrometastases. The emergence of various immunotherapies has ushered in a new era for neoadjuvant treatment options for gastric cancer.

C-type lectin domain family 12 member A (CLEC12A) is a type II transmembrane glycoprotein widely expressed in innate immune cells, where it plays a crucial role in immune modulation and has been implicated in cancer progression. However, its precise function in oncogenesis and immune infiltration remains incompletely understood. To investigate this, we utilized multiple databases to assess the mRNA and protein expression levels of CLEC12A across normal tissues and a broad spectrum of cancers. We also evaluated its prognostic and diagnostic significance in pan-cancer contexts. Furthermore, the relationship between CLEC12A expression and immune cell infiltration, immune checkpoints, and immune predictors was explored. In addition, Weighted Gene Co-Expression Network Analysis (WGCNA) and differential expression analysis were performed to examine the biological relevance of CLEC12A in lung adenocarcinoma (LUAD). We also leveraged various databases to predict CLEC12A's response to immunotherapy and drug sensitivity. Finally, in vitro experiments validated the functional role of CLEC12A in LUAD. Our comprehensive pan-cancer analysis revealed that CLEC12A exhibited distinct expression patterns across different cancer types, suggesting its potential as both a diagnostic and prognostic biomarker. Notably, CLEC12A expression was strongly correlated with immune cell infiltration, immune checkpoints, and immune predictors. Functional enrichment analysis highlighted that increased CLEC12A expression in LUAD was associated with a variety of immune-related biological processes and pathways. Moreover, CLEC12A showed significant predictive value for immunotherapy outcomes, and several drugs targeting CLEC12A were identified. In vitro experiments further demonstrated that CLEC12A overexpression inhibited the proliferation, migration, and invasion of LUAD cells. Taken together, our findings position CLEC12A as a promising candidate for cancer detection, prognosis, and as a therapeutic target, particularly in LUAD, where it may serve as a potential target for both immunotherapy and targeted therapy.

Immunotherapy in clinical application faces numerous challenges pertaining to both effectiveness and safety. Poly(ADP-ribose) polymerases (PARPs) exhibit multifunctional characteristics by transferring ADP-ribose units to target proteins or nucleic acids. In recent years, more and more attention has been paid to the biological function of PARPs in immune response. This article reviews the relationship between PARP family members and immune response. PARP1 and PARP2 inhibit anti-tumor immune activity by regulating immune checkpoint expression and the cGAS/STING signaling pathway. PARP7 and PARP11 play an important role in promoting immunosuppressive tumor microenvironment. PARP9 promotes the production of Type I interferon and the infiltration of macrophages. PARP13 is a key tumor suppressor that promotes anti-tumor immune response. PARP14 plays a crucial role in promoting the differentiation of macrophages towards the M2 pro-tumor phenotype. Summarizing the molecular mechanisms of PARP7, PARP9, PARP11, PARP13 and PARP14 in regulating immune response is helpful to deepen our comprehension of the role of PARPs in immune function regulation. This provides a reference and basis for targeted PARP-based cancer treatment strategies and drug development. PARP1, PARP7 inhibitors or other PARP inhibitors in combination with immune checkpoint inhibitors or other immunotherapy strategies may be a more effective cancer therapy.

Most patients with gastric cancer (GC) exhibit microsatellite stability, yet comprehensive subtyping for prognostic prediction and clinical treatment decisions for microsatellite-stable GC is lacking. In this work, RNA-sequencing gene expression data and clinical information of patients with microsatellite-stable GC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We employed several machine learning methods to develop and validate a signature based on immune-related genes (IRGs) for subtyping patients with microsatellite-stable GC. Moreover, 2 deep learning models based on the Vision Transformer (ViT) architecture were developed to predict GC tumor tiles and identify microsatellite-stable GC subtypes from digital pathology slides. Microsatellite status was evaluated by immunohistochemistry, and prognostic data as well as hematoxylin and eosin whole-slide images were collected from 105 patients with microsatellite-stable GC to serve as an independent validation cohort. A signature comprising 5 IRGs was established and validated, stratifying patients with microsatellite-stable GC into high-risk (microsatellite-stable-HR) and low-risk (microsatellite-stable-LR) groups. This signature demonstrated consistent performance, with areas under the receiver operating characteristic curve (AUC) of 0.65, 0.70, and 0.70 at 1, 3, and 5 years in the TCGA cohort, and 0.70, 0.60, and 0.62 in the GEO cohort, respectively. The microsatellite-stable-HR subtype exhibited higher levels of tumor immune dysfunction and exclusion, suggesting a greater potential for immune escape compared with the microsatellite-stable-LR subtype. Moreover, the microsatellite-stable-HR/LR subtypes showed differential sensitivities to various therapeutic drugs. Leveraging morphologic differences, the tumor recognition segmentation model achieved an impressive AUC of 0.97, whereas the microsatellite-stable-HR/LR identification model effectively classified microsatellite-stable-HR/LR subtypes with an AUC of 0.94. Both models demonstrated promising results in classifying patients with microsatellite-stable GC in the external validation cohort, highlighting the strong ability to accurately differentiate between microsatellite-stable GC subtypes. The IRG-related microsatellite-stable-HR/LR subtypes had the potential to enhance outcome prediction accuracy and guide treatment strategies. This research may optimize precision treatment and improve the prognosis for patients with microsatellite-stable GC.

Immunotherapy for gastrointestinal cancers has elicited considerable amount of attention as a viable therapeutic option for several cancer types. Gut microbiome as a whole plays a critical role in shaping immune responses and influencing cancer progression. Recent evidence suggests that Helicobacter pylori (H. pylori), may influence immunotherapy efficacy by modulating the tumor microenvironment. Infection with H. pylori is common as it affects approximately 50% of the global population and remains the leading risk factor for gastric cancer. Interestingly, recent clinical and preclinical data has associated H. pylori with colorectal cancer carcinogenesis. Gut microbiome appears to be a modulator of the relationship between the immune system, gastrointestinal cancer development and existing therapies. Infection with H. pylori may affect immunotherapy results in both gastroesophageal and colorectal cancer; favorable results were noticed in H. pylori positive patients with gastric cancer, while in colorectal cancer patients the pathogen seemed to impede immunotherapy's action. This article aims to review current data on the role of H. pylori in triggering gastric inflammation and cancer, as well as its potential involvement in colorectal cancer development. Additionally, it seeks to highlight the impact of H. pylori infection on the response to immunotherapy in gastrointestinal cancers.

Advanced gastric cancer remains a significant global health challenge, with limited therapeutic options available. In contrast, immunotherapy have emerged as promising alternatives, offering greater potency in treating advanced gastric cancer. However, the development of novel and efficient immunotherapeutic strategy is crucial to enhance the body's immune response against gastric cancer.

This study developed a single-injection peptide hydrogel-based nanovaccine therapy for gastric cancer treatment. The therapy utilizes a RADA32 peptide hydrogel, which is sensitive to metal ion concentration, to encapsulate manganese ions and HPPS nanovaccines. The HPPS nanovaccines contain antigen peptide and CpG-ODN, designed to activate both the toll-like receptor 9 (TLR9) and cGAS-STING signaling pathways in antigen-presenting cells. This design aims to facilitate a stable and sustained release of the nanovaccine, thereby enhancing the body's effective recognition and response to antigens.

The efficacy of the system was confirmed using the model antigen OVA and the gastric cancer-specific antigen MG7-related peptide. The results demonstrated that the nanovaccine effectively activated the immune response, leading to enhanced recognition and response to the antigens. This activation of both TLR9 and cGAS-STING pathways in antigen-presenting cells was crucial for the observed immune response, highlighting the potential of this approach to stimulate a robust and sustained immune response against gastric cancer.

This study presents a novel strategy for clinical anti-tumor vaccine administration, offering a promising approach for the prevention and treatment of gastric cancer. The single-injection peptide hydrogel-based nanovaccine system provides a convenient and effective method to enhance the body's immune response against gastric cancer. This approach could potentially be expanded to other types of cancer, providing a versatile platform for cancer immunotherapy.

Nowadays, gastric cancer has become a significant issue in the global cancer burden, and its impact cannot be ignored. The rapid development of artificial intelligence technology is attempting to address this situation, aiming to change the clinical management landscape of gastric cancer fundamentally. In this transformative change, machine learning and deep learning, as two core technologies, play a pivotal role, bringing unprecedented innovations and breakthroughs in the diagnosis, treatment, and prognosis evaluation of gastric cancer. This article comprehensively reviews the latest research status and application of artificial intelligence algorithms in gastric cancer, covering multiple dimensions such as image recognition, pathological analysis, personalized treatment, and prognosis risk assessment. These applications not only significantly improve the sensitivity of gastric cancer risk monitoring, the accuracy of diagnosis, and the precision of survival prognosis but also provide robust data support and a scientific basis for clinical decision-making. The integration of artificial intelligence, from optimizing the diagnosis process and enhancing diagnostic efficiency to promoting the practice of precision medicine, demonstrates its promising prospects for reshaping the treatment model of gastric cancer. Although most of the current AI-based models have not been widely used in clinical practice, with the continuous deepening and expansion of precision medicine, we have reason to believe that a new era of AI-driven gastric cancer care is approaching.

In the progression of gastric cancer (GC), various cell types in the tumor microenvironment (TME) exhibit upregulated expression of programmed death ligand 1 (PD-L1), leading to impaired T-cell function and evasion of immune surveillance. Infection with H. pylori and EBV leads to increased PD-L1 expression in various cell types within TME, resulting in immune suppression and facilitating immune escape of GC cells. In the TME, mesenchymal stem cells (MSCs), M1-like tumor-associated macrophages (MI-like TAM), and myeloid-derived suppressor cells (MDSCs) contribute to the upregulation of PD-L1 expression in GC cells. Conversely, mast cells, M2-like tumor-associated macrophages (M2-like TAM), and tumor-associated neutrophils (TANs) exhibit elevated levels of PD-L1 expression in response to the influence of GC cells. Together, these factors collectively contribute to the upregulation of PD-L1 expression in GC. This review aims to provide a comprehensive summary of the cellular expression patterns of PD-L1 in GC and the underlying molecular mechanisms. Understanding the complex regulatory pathways governing PD-L1 expression may offer novel insights for the development of effective immunotherapeutic interventions.

Immunotherapy has surfaced as a promising therapeutic modality for gastric cancer (GC). A comprehensive review of advancements, current status, and research trends in GC immunotherapy is essential to inform future investigative efforts.

To delineate the trends, advancements, and focal points in immunotherapy for GC.

We performed a bibliometric analysis of 2906 articles in English concerning GC immunotherapy published from 2000 to December 20, 2023, indexed in the Web of Science Core Collection. Data analysis and visualization were facilitated by CiteSpace (6.1.6R), VOSviewer v.1.6.17, and GraphPad Prism v8.0.2.

There has been an increase in the annual publication rate of GC immunotherapy research. China leads in publication volume, while the United States demonstrates the highest citation impact. Fudan University is notable for its citation frequency and publication output. Co-citation analysis and keyword frequency revealed and highlighted a focus on GC prognosis, the tumor microenvironment (TME), and integrative immunotherapy with targeted therapy. Emerging research areas include gastroesophageal junction cancer, adoptive immunotherapy, and the role of Treg cell in immunotherapy.

GC immunotherapy research is an expanding field attracting considerable scientific interest. With the clinical adoption of immunotherapy in GC, the primary goals are to enhance treatment efficacy and patient outcomes. Unlike hematological malignancies, GC's solid TME presents distinct immunological challenges that may attenuate the cytotoxic effects of immune cells on cancer cells. For instance, although CAR-T therapy is effective in hematological malignancies, it has underperformed in GC settings. Current research is centered on overcoming immunosuppression within the TME, with a focus on combinations of targeted therapy, adoptive immunotherapy, Treg cell dynamics, and precise prognosis prediction in immunotherapy. Additionally, immunotherapy's role in treating gastroesophageal junction cancer has become a novel research focus.

Claudin18.2 has emerged as a promising therapeutic target due to its high expression in gastric (GC) and pancreatic cancers (PC). However, patients with advanced, unresectable, or metastatic GC or PC face poor prognoses, highlighting the urgent need for more effective Claudin18.2-targeted therapies.

We developed 4A7, a fully human monoclonal antibody with superior affinity and specificity for Claudin18.2, using a rigorous positive and negative screening strategy to eliminate cross-reactivity with Claudin18.1. In vitro, 4A7 demonstrated significantly enhanced binding activity, as well as robust antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), outperforming IMAB362, a clinical investigational antibody. In vivo, 4A7 exhibited remarkable tumor growth inhibition both as a monotherapy and in combination with anti-mPD-1, achieving superior efficacy compared to IMAB362. Additionally, 4A7 demonstrated a higher degree of humanization and comparable stability, supporting its translational potential.

4A7 shows great promise as a next-generation therapeutic for Claudin18.2-positive cancers, offering improved efficacy and reduced immunogenicity. This study not only highlights 4A7's potential to address unmet clinical needs but also provides a foundation for future innovations in monoclonal antibody-based cancer therapy.

Growing evidence suggests that dysregulated microRNAs were critical in the development of tumors and the progression number of malignancies. This research aimed to check the effect of microRNA 320a-3p transfection on gastric cancer (GC) cell lines. Following transfection, the efficacy was determined by the RT-PCR method. After that, MTT, scratch assay, DAPI staining, RT-PCR, and flow cytometry were used respectively. The results demonstrated that the viability of GC cells considerably decreased following transfection. Moreover, microRNA 320a-3p transfection significantly suppressed cell migration and induced apoptosis in these cells. We found that transfection of microRNA 320a-3p remarkably decreased PD-L1 gene expression and influenced epithelial-mesenchymal transition (EMT)-related and apoptotic gene expressions. The findings propose that microRNA 320a-3p could decrease cell proliferation and migration and induce apoptosis by increasing TP53 and CASP3 expression levels in GC cells. Notably, microRNA 320a-3p might be a potential target in GC immunotherapy by suppressing the PD-L1 gene expression.

Cancer-associated fibroblasts (CAF) play a crucial role in tumor progression and immune regulation. However, the functional heterogeneity of CAFs remains unclear. Here, we identify antigen-presenting CAFs (apCAF), characterized by high MHC II expression, in gastric cancer (GC) tumors and find that apCAFs are preferentially located near tertiary lymphoid structures. Both in vivo and in vitro experiments demonstrate that apCAFs promote T cell activation and enhances its cytotoxic and proliferative capacities, thereby strengthening T cell-mediated anti-tumor immunity. Additionally, apCAFs facilitate the polarization of macrophages toward a pro-inflammatory phenotype. These polarized macrophages, in turn, promote the formation of apCAFs, creating a positive feedback loop that amplifies anti-tumor immune responses. Notably, baseline tumors in immunotherapy responders across various cancer types exhibit higher levels of apCAFs infiltration. This study advances the understanding of CAFs heterogeneity in GC and highlights apCAFs as a potential biomarker for predicting immunotherapy response in pan-cancer.

Gastric cancer is one of the most frequent malignancies and a serious concern in the global public health realm. Neutrophils, the most numerous myeloid cells in human blood, are emerging as significant regulatory variables in cancer. This study examines the molecular processes behind the link between gastric cancer's malignant character and neutrophils in the disease. This study aims to reveal the role of P2RX1 in neutrophils in gastric cancer and investigate its effects on the migration, invasion, and apoptosis of gastric cancer cells, with the hope of providing new targets and strategies for the treatment of gastric cancer. P2RX1 expression levels in gastric cancer samples were examined using The Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD). The signal pathways enriched by P2RX1-related differential gene expression were examined using GSEA. P2RX1 mRNA levels were examined using qPCR. Jak/Stat signaling pathway-related proteins and P2RX1 expression levels were subjected to western blot analysis. The apoptotic rate, migration, invasion, and cell viability were evaluated using flow cytometry, Transwell, and CCK-8 tests. Immunohistochemistry was used to detect the expression of P2RX1 in tumor tissues. Neutrophils and P2RX1 were both underexpressed in gastric cancer. In gastric cancer neutrophils, overexpression of P2RX1 increased cancer cell apoptosis while suppressing migration, invasion, and viability of the cells. Jak/Stat signaling pathway was connected to production of neutrophil P2RX1, and P2RX1 overexpression could trigger the pathway in vivo and in vitro. By activating its own Jak/Stat signaling pathway, overexpression of P2RX1 in gastric cancer neutrophils improved neutrophil survival, which in turn suppressed the migration, invasion, and viability of gastric cancer cells and raised their apoptosis rate. This suggests that P2RX1 may play a significant anti-tumor role in the tumor microenvironment of gastric cancer, indicating its value as a potential therapeutic target.

DNA methyltransferase 3A (DNMT3A) has been associated with the occurrence or progression of various tumors, including gastric cancer. However, the role of DNMT3A in the efficacy of immune-cell infiltration in the tumor microenvironment and immunotherapy in gastric cancer remains less explored. DNMT3A expression level was analyzed using TIMER 2.0, Sangerbox 3.0, and The Cancer Genome Atlas database and further verified by immunohistochemical staining and RT-qPCR. The UALCAN, chi-square test, and Kaplan-Meier plotter databases were performed to assess the correlation of DNMT3A with clinicopathological characteristics and prognosis. The GeneMANIA database, STRING database, and R package were used to construct a DNMT3A co-expression gene network. Gene set enrichment analysis was used to identify the signaling pathways related to DNMT3A expression. The correlations between DNMT3A and cancer immune infiltrates were investigated using TIMER 2.0, Sangerbox 3.0, Kaplan-Meier Plotter, R package, and TISIDB databases. The TISIDB database and R package were used to construct the correlation between DNMT3A and immunomodulators and Immune cell Proportion Score. The association of DNMT3A expression with tumor mutational burden (TMB), microsatellite instability, and tumor dryness was evaluated using the TMB function of the R package, TIMER 2.0. Finally, the biological function of DNMT3A in gastric cancer cells was further assessed by CCK-8, cloning formation, and transwell assay. DNMT3A expression was remarkably upregulated in gastric cancer. The high expression of DNMT3A was associated with poor clinical features and poor survival in patients with gastric cancer. Moreover, gene set enrichment analyses showed that DNMT3A and its related genes were involved in various pathways that promoted cancer occurrence and progression by influencing the tumor microenvironment. Finally, DNMT3A was significantly related to tumor-infiltrating immune cells, immunomodulators, TMB, microsatellite instability, and immune checkpoints in gastric cancer. Moreover, knockdown of DNMT3A reduced the proliferation and migration of gastric cancer cells. Our findings highlight the potential of DNMT3A as a prognosis biomarker and an immunotherapeutic target for gastric cancer.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.

Gastric cancer (GC) is a significant worldwide health concern and is a leading cause of cancer-related mortality. Immunotherapy has arisen as a promising strategy to stimulate the patient's immune system in combating cancer cells. Nevertheless, the effectiveness of immunotherapy in individuals with gastric cancer (GC) is not yet optimal. Thus, it is crucial to discover biomarkers capable appof predicting the advantages of immunotherapy for tailored treatment. The tumor microenvironment (TME) and its constituents, including cancer-associated fibroblasts (CAFs), exert a substantial influence on immune responses and treatment outcomes. In this investigation, we utilized single-cell RNA sequencing to profile CAFs in GC and established a scoring method, referred to as the CAF score (CAFS), for the prediction of patient prognosis and response to immunotherapy. Through our analysis, we successfully identified distinct subgroups within CAFs based on CAF score (CAFS), namely CAFS-high and CAFS-low subgroups. Notably, we noted that individuals within the CAFS-high subgroup experienced a lessF favorable prognosis and displayed diminished responsiveness to immunotherapy in contrast to the CAFS low subgroup. Furthermore, we analyzed the mutation and immune characteristics of these subgroups, identifying differentially mutated genes and immune cell compositions. We established that CAFS could forecast treatment advantages in patients with gastric cancer, both for chemotherapy and immunotherapy. Its efficacy was additionally confirmed in contrast to other biomarkers, including Tumor Immune Dysfunction and Exclusion (TIDE) and Immunophenotypic Score (IPS). These findings emphasize the clinical relevance and potential utility of CAFS in guiding personalized treatment strategies for gastric cancer.

Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented.

Microsatellite instability (MSI) is a phenotype characterized by changes in the sequence length of microsatellites in tumor cells and is closely linked to tumorigenesis and prognosis. Immune checkpoint inhibitors have shown good therapeutic effects in gastric cancer (GC) with MSI-high (MSI-H). However, the role of the novel immune checkpoint fibrinogen-like protein 1 (FGL1) in GC treatment has not been fully investigated. FGL1 expression in GC tissues and the difference in FGL1 immune infiltration between MSI/ microsatellite stability (MSS) patients were analyzed by bioinformatics and were verified in clinical samples. Xenograft models of MSS and MSI GC were constructed in human immune reconstitution mice, and FGL1 expression in tumors was detected. Immunofluorescence and immunohistochemistry were used to assay the infiltration of immune cells in the two types of mice. Cytotoxicity and chemotaxis tests were used to detect the toxicity and chemotaxis of CD8+T cells to GC cells, respectively. The cytokine content was detected by enzyme-linked immunosorbent assay. The therapeutic effects of FGL1 antibody on different types of GC were analyzed by xenograft mouse models. FGL1 exhibited significantly higher expression in GC, and its expression and immune cell infiltration levels were significantly higher in MSI GC than in MSS GC. CD8+T cells were significantly more effective in killing and chemotaxis of MSI GC cells than MSS GC cells. The FGL1 antibody was more effective in treating MSI GC.The novel immunosuppressor FGL1 antibody exerts a good therapeutic influence on MSI GC. These findings provide a basis for the development of drugs targeting FGL1 for MSI GC treatment.

Gastric cancer (GC) is one of the deadly malignancies of the gastrointestinal tract. Research has confirmed the linkage of P2RX1 with immune cell activation and tumor progression. This project focused on the impact of P2RX1 level in neutrophils on the efficacy of immune checkpoint inhibitor (ICI) treatment in GC.

Blood samples from 23 GC patients eligible for camrelizumab treatment were collected. Flow cytometry was carried out to analyze the proportion of P2RX1 in neutrophils. IHC was utilized to detect the expression level of PD-L1. We also evaluated the chemotaxis ability of neutrophils using a Transwell system, assessed the viability and apoptosis rate of GC cells using CCK-8 and flow cytometry, measured the proportions of CD8+PD-1+ and CD8+GZMB+ cells, determined the expression levels of IL-6, TNFα, IFN-γ, IL-8, IL-12, IL-1β, and GZMB by utilizing enzyme-linked immunosorbent assay (ELISA), and examined the expression levels of P2RX1 and PD-L1 using western blot (WB). By establishing a xenograft mouse model, we studied the impact of P2RX1-blocked neutrophils on the efficacy of ICI treatment in the GC microenvironment.

In GC, clinical analysis revealed increased infiltration of P2RX1-lowly expressed neutrophil subsets and increased expression of PD-L1. In vitro experiments demonstrated that abnormal expression of P2RX1 affected neutrophil function. Furthermore, the blockage or knockdown of P2RX1 in neutrophils modulated CD8+ T cell function, promoting GC progression. In in vivo experiments, the blockage of P2RX1 in neutrophils inhibited the effectiveness of ICI treatment in the GC microenvironment.

This project validated that the loss of P2RX1 in neutrophils induces CD8+ T cell dysfunction and affects the GC development, indicating that P2RX1 may be an accurate biomarker for predicting ICI response, thus providing a theoretical basis for the clinical application of ICI.

Alpha-fetoprotein-producing gastric cancer (AFPGC) is a highly malignant subtype of gastric cancer, but solely alpha-fetoprotein may fail to accurately predict the prognosis. Although the utilization of multi tumor markers could improve stratified patient management, such research in AFPGC is still blank. This study seeks to evaluate whether combining multiple tumor markers can enhance risk stratification and identify AFPGC subtypes with poor prognosis.

We first screened for patients with elevated serum CEA levels within the AFPGC cohort and evaluated their prognosis. Tumor characteristics and overall health conditions were analyzed to identify factors contributing to CEA elevation. Finally, the treatment responses of this group to different treatment modalities were also reviewed.

Approximately 45% of gastric cancer patients with elevated serum AFP also show increased CEA levels, classifying them as the dual-positive gastric cancer (DPGC) subgroup. These patients exhibit significantly shorter overall survival, heightened metastasis risk, and are more susceptible to systemic inflammation, immune response dysregulation, malnutrition, and cancer-related thrombosis. The elevation in serum CEA levels may indicate gastric cancer liver metastasis and increased neutrophils. While surgery is optimal for AFPGC, DPGC patients benefit significantly from immunotherapy combined with chemotherapy.

In AFPGC, combining serum AFP and CEA offers a more accurate prognosis. The poor prognosis in DPGC may be associated with aggressive local properties and systemic complications. Liver metastases and increased neutrophils are associated with increased serum CEA in AFPGC. Immunochemotherapy is a viable option for DPGC patients who cannot undergo surgery.

Gastric cancer liver metastases (GCLM) is a highly heterogeneous disease with a poor prognosis. The multidisciplinary diagnosis and treatment model is applied throughout the entire treatment process. In addition to the previous RECORD study, which was based on the C-GCLM classification system developed by our team, there is a lack of recent data on patient baseline characteristics, clinical treatment and efficacy evaluation. A large-scale prospective observational study is necessary to determine the current situation of GCLM treatment in China. The findings of this study may inform the development of relevant healthcare policies, clinical pathways and treatment guidelines.

This is a prospective, non-interventional, observational, multicentre, real-world study designed to monitor the general condition, treatment pattern and prognosis of patients with GCLM. Patients with GCLM were classified into three distinct categories: type I (resectable type), type II (potentially resectable type) and type III (unresectable type). The patients' general information, medical history, imaging results, laboratory tests, surgical and systemic therapy details will be recorded and subjected to analysis. The 2-year overall survival (OS) will be recorded as the primary endpoint. The different therapeutic modalities employed in the treatment of GCLM, including surgery, chemotherapy and immunotherapy, will be recorded as secondary endpoints. Additionally, the effects of these therapies on prognosis, including OS of type I, II and III; R0 resection and disease-free survival of type I; and successful conversion rate and R0 resection rate and event-free survival of type II will be documented.

This study involving human participants was reviewed and approved by the Ethics Committee of Chinese PLA General Hospital (no. S2023-724-02) and will be conducted in accordance with the guidelines of the Declaration of Helsinki. Study findings will be disseminated through international peer-reviewed journal articles as well as public, academic presentations at national and international conferences.

NCT06493448; ChiCTR2400083955.

With a fourth-place death rate among all malignancies, gastric cancer (GC) is one of the most prevalent tumors globally. As a primary malignant characteristic of GC, metastasis contributes substantially to a high death rate and unfavorable prognosis. miRNA-214-3p can influence cell apoptosis since it is an autophagy-regulating molecule. Its significance in GC malignant development has not, however, been investigated in terms of mechanism. qRT-PCR was utilized to confirm expression of miRNA-214-3p in GC tissues and cells. Bioinformatics analysis was then implemented to examine BNIP3 expression in GC as well as binding interaction between BNIP3 and miRNA-214-3p. The targeting capability of miRNA-214-3p on BNIP3 was confirmed using the dual-luciferase assay. Capacities of cells to proliferate, migrate, and invade were assayed using Transwell assays and colony formation. In order to determine if GC cells were capable of autophagy, immunofluorescence and western blot were employed. In GC, miRNA-214-3p was substantially expressed in GC tissues and cells, but BNIP3 was downregulated, as shown by bioinformatics analysis and verified by cell tests. MiRNA-214-3p targeted BNIP3, as shown by further bioinformatics analysis, and dual-luciferase experiment verified this binding connection. MicroRNA-214-3p facilitated cell invasion, migration, and proliferation, as shown by Transwell tests and colony formation. MiRNA-214-3p accelerated malignant development of GC by targeting BNIP3 to impact autophagy, as demonstrated by immunofluorescence and western blot analyses. By targeting BNIP3 to affect autophagy, miRNA-214-3p aided in the malignant growth of GC. This suggested that miRNA-214-3p may function as a likely therapeutic target or biomarker for the disease, with significant implications for early diagnosis and treatment of patients.

Driver gene-negative advanced-stage lung adenocarcinoma is associated with a poor prognosis and insufficient treatment options. The present study aimed to evaluate the efficacy and safety profile of a programmed cell death protein 1/programmed death-ligand 1 inhibitor plus bevacizumab and chemotherapy (PBC) regimen for the treatment of patients with driver gene-negative advanced-stage lung adenocarcinoma under real-world clinical conditions. Data from 65 patients with advanced-stage lung adenocarcinoma without sensitizing epidermal growth factor receptor, ALK receptor tyrosine kinase or ROS proto-oncogene 1 receptor tyrosine kinase mutations who received a PBC regimen or only a BC regimen were reviewed in the present retrospective cohort study. The results revealed that the objective response rate was higher (70.4 vs. 47.4%; P=0.065) in the PBC group compared with that in the BC group, while not reaching statistical significance. Progression-free survival (PFS) time was longer in the PBC group than in the BC group [median PFS: 10.8 months (95% confidence interval (CI), 7.2-14.4) vs. 7.6 months (95% CI, 5.0-10.2); P=0.016], while overall survival (OS) exhibited a non-significant trend to be longer in the PBC group compared with that in the BC group [median OS: 20.6 months (95% CI, 16.8-24.4) vs. 15.9 months (95% CI, 11.8-20.0); P=0.115]. Following adjustment by multivariate Cox analysis, the PBC (vs. BC) regimen was found to be independently associated with an improved PFS time (P=0.045). The common adverse events in the PBC group were neutropenia, alopecia, leukopenia, nausea and vomiting, fatigue, anemia and peripheral neuropathy. Moreover, the incidence of each adverse event did not differ significantly between the PBC and BC groups. In conclusion, the present study demonstrated that the PBC regimen serves as a superior treatment option for patients with driver gene-negative advanced-stage lung adenocarcinoma; however, further verification of its efficacy is still required.

MicroRNAs (miRNAs) are crucial factors in gene regulation, and their dysregulation plays important roles in the immunity of gastric cancer (GC). However, finding specific and effective miRNA markers is still a great challenge for GC immunotherapy. In this study, we computed and analysed miRNA-seq, RNA-seq and clinical data of GC patients from the TCGA database. With the comparison of tumour and normal tissues in GC, we identified 2056 upregulated and 2311 downregulated protein-coding genes. Based on the miRNet database, more than 2600 miRNAs interact with these genes. Several key miRNAs, including hsa-mir-34a, hsa-mir-182 and hsa-mir-23b, were identified to potentially play important regulatory roles in the expression of most upregulated and downregulated genes in GC. Based on bioinformation approaches, the expressions of hsa-mir-34a and hsa-mir-182 were closely linked to the tumour stage, and high expression of hsa-mir-23b was correlated with poor survival in GC. Moreover, these three miRNAs are involved in immune cell infiltration (such as activated memory CD4 T cells and resting mast cells), particularly hsa-mir-182 and hsa-mir-23b. GSEA suggested that the changes in their expression may possibly activate/inhibit immune-related signal pathways, such as chemokine signalling pathway and CXCR4 pathway. These results will provide possible miRNA markers or targets for combined immunotherapy of GC.

Gastric cancer (GC) is characterized by a complex and heterogeneous tumor microenvironment (TME) that significantly influences disease progression and treatment outcomes. The tumor stroma, which is composed of a variety of cell types such as cancer‑associated fibroblasts, immune cells and vascular components, displays significant spatial and temporal diversity. These stromal elements engage in dynamic crosstalk with cancer cells, shaping their proliferative, invasive and metastatic potential. Furthermore, the TME is instrumental in facilitating resistance to traditional chemotherapy, specific treatments and immunotherapy strategies. Understanding the underlying mechanisms by which the GC microenvironment evolves and supports tumor growth and therapeutic resistance is critical for developing effective treatment strategies. The present review explores the latest progress in understanding the intricate interactions between cancer cells and their immediate environment in GC, highlighting the implications for disease pathogenesis and therapeutic interventions.

Gastric cancer is one of the major cancers with high cancer mortality and shows significant heterogeneity. The development of precise prognostic models is crucial for advancing treatment strategies. Recognizing the pivotal role of DNA damage in tumor progression, we conducted a consensus clustering analysis of DNA damage-related genes to categorize gastric cancer patients from the TCGA clinical cohort into distinct subtypes. Prognostic models were then constructed utilizing machine learning algorithms following Cox regression with differentially expressed genes. Validation was performed using the GSE gastric cancer cohort. Additionally, we investigated other characteristic responses of patients through gene mapping and drug sensitivity analysis. This study 12 differentially prognostic signature genes between the 2 DNA damage subtypes identified were used to calculate risk scores for the patients. This score predicts the prognosis of patients with gastric cancer and their overall survival time. Higher risk scores mean less drug sensitivity, lower survival, and possibly a poorer response to immunotherapy. Our findings provide the basis for future studies targeting DNA damage and its immune microenvironment to improve prognosis and response to immunotherapy.

Despite the wide range of treatment options available for cancer therapy, including chemotherapy, radiation therapy, and surgical procedures, each of these treatments has a different side-effect profile and leaves the patient with no option but to choose. Due to their insensitivity and nonspecificity, conventional treatments damage normal cells together with cancer cells. In recent years, a significant amount of attention has been focused on photodynamic therapy (PDT) as a treatment for cancer and drug-resistant microbes. An activated photosensitizer is used as a part of the procedure along with oxygen molecules and a specific wavelength of light belonging to the visible or NIR spectral zone. A light-sensitive laser dye, rhodamine 6G (R6G), was used in the present study as a photosensitizer, taking a challenge to improve the aqueous solubility and ROS quantum yield using optimum concentration (160 mg/ml) of chitosan-alginate (Cs-Alg) blended polymeric nanoformulations. As evidenced by steady-state spectrophotometric and fluorometric measurements, ROS quantum yield increases three-fold over aqueous solution along with solubility gaining that was validated by PDT experiment using human epithelial carcinoma (KB) cell line. Phantom optical imaging was taken using the IVIS imaging system to establish the formulations as a fluorescence-based optical contrast agent, and zebrafish embryos were used to establish their safe in vivo use. The release profile of R6G was fitted using kinetic models, which followed the Non-Fickian kinetic profile. In conclusion, we recommend the formulations as a potential theranostic agent that will aid in PDT-based therapy in conjunction with optical imaging-based diagnosis.

Anti-CTLA-4 and anti-PD-1/PD-L1 antibodies have significantly revolutionized cancer immunotherapy. However, the persistent challenge of low patient response rates necessitates novel approaches to overcome immune tolerance. Targeting immunostimulatory signaling may have a better chance of success for its ability to enhance effector T cell (Teff) function and expansion for antitumor immunity. Among various immunostimulatory pathways, the evidence underscores the potential of activating OX40-OX40L signaling to enhance CD8+ T cell generation and maintenance while suppressing regulatory T cells (Tregs) within the tumor microenvironment (TME). In this study, we introduce a potent agonistic anti-OX40 antibody, SHR-1806, designed to target OX40 receptors on activated T cells and amplify antitumor immune responses. SHR-1806 demonstrates a high affinity and specificity for human OX40 protein, eliciting FcγR-mediated agonistic effects, T cell activation, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities in vitro. In human OX40 knock-in mice bearing MC38 tumor, SHR-1806 shows a trend toward a higher potency than the reference anti-OX40 antibody produced in-house, GPX4, an analog of pogalizumab, the most advanced drug candidate developed by Roche. Furthermore, SHR-1806 displays promising anti-tumor activity alone or in combination with toll-like receptor 7 (TLR7) agonist or PD-L1 inhibitor in mouse models. Evaluation of SHR-1806 in rhesus monkeys indicates a favorable safety profile and typical pharmacokinetic characteristics. Thus, SHR-1806 emerges as a robust OX40 agonist with promising therapeutic potential.