The breast cancer (BC)-related mortality is higher and the immunity is altered in women living with HIV (WLWH) compared to HIV-negative women. Therefore, tumor samples of 296 black BC patients from South Africa and Namibia with known age, HIV status, tumor stage, hormone receptor and HER2 status and overall survival (OS) are analyzed for components of the tumor microenvironment (TME). WLWH (n = 117), either with suppressed viral activity (HR = 1.25) or with immune suppression (HR = 2.04), have a shorter OS. HIV status is associated with increased numbers of CD8+ T cells in the TME compared to HIV-negative patients; no correlation is found with CD4+ T cell numbers in the blood. Moreover, an increased expression of CD276/B7-H3 and a more pronounced IFN-γ signaling in the tumors are found in WLWH, independent of age, stage, and BC subtypes. In conclusion, altered T cell composition and CD276 expression in WLWH may contribute to inferior survival and can be used for targeted treatment.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma, and immune checkpoint inhibitors (ICIs) are the only approved therapy; nonetheless, resistance is notable and there is a critical need for novel effective therapies. Recently, CD276 was identified as a promising therapeutic target in human cancers. In preclinical studies, a modified CD276 antibody-drug conjugate (ADC) with pyrrolobenzodiazepine (m276-SL-PBD) elicited more potent anti-tumor effects than two CD276 ADCs currently in clinical trials. Here, we uncover notable CD276 expression in MCC patient tumors, and demonstrate m276-SL-PBD efficacy against MCC preclinical models. Complete eradication is observed in all xenografts bearing CD276 expression, with 82% achieving 180-day tumor-free survival after 4 or 5 weekly doses, and m276-SL-PBD remained efficacious against relapsed tumors. Of clinical relevance, m276-SL-PBD retains its potency in MCC-bearing humanized mice. Importantly, no detectable adverse effects were observed. Thus, m276-SL-PBD is a promising therapy for patients unsuitable or resistant to ICIs.

Cancer is a leading cause of death worldwide, resulting in substantial economic costs. Because cancer is a complex, heterogeneous group of diseases affecting a variety of cells, its detection may sometimes be difficult. Herein we review a large group of the gastrointestinal cancers (oral, esophageal, stomach, pancreatic, liver, and bowel cancers) and the possibility of using glycans conjugated to protein backbones for less-invasive diagnoses than the commonly used endoscopic approaches. The reality of bacterial N-glycosylation and the effect of epithelial mucosa on gut microbiota are discussed. Current advantages, barriers, and advantages in the prospective use of selected glycomic approaches in clinical practice are also detailed.

Chimeric antigen receptor T cell (CAR-T) therapy has achieved great success and progress for treatment of hematological malignancy, but it still cannot overcome the obstacles in solid tumors. The hostile tumor microenvironment (TME), such as dense extracellular matrix, hypoxia, low pH, and tumor-derived metabolites, largely impedes CAR-T function. Oncolytic virus, as a form of immunotherapy, provides a way to antagonize the TME and improve the efficacy of CAR-T cells in solid tumors. In this study, the chemokine CXCL9 and interleukin 15 (IL15) genes were genetically integrated into adenoviral vector to construct oncolytic adenovirus (OAV) Ad-CXCL9-IL15, which could infect tumor cells to express and secrete CXCL9 and IL15. Ad-CXCL9-IL15 showed potent antitumor activity in xenografted prostate cancer model and augmented the tumor infiltration of CD45+CD3+ T and CD8+ T cells in immunocompetent mice. Moreover, Ad-CXCL9-IL15 treatment decreased Treg cells in tumor mass and increased CD44+CD62L+ T cells in spleen. Indicating that Ad-CXCL9-IL15 modified the TME and augmented antitumor immune responses in vivo. Furthermore, administration of Ad-CXCL9-IL15 dramatically promoted infiltration and survival of B7H3-targeting CAR-T cells, improved the therapeutic efficacy, and prolonged the survival time of prostate cancer-bearing mice. Therefore, cytokine-armored OAV Ad-CXCL9-IL15 could be used as a bioenhancer to modify TME and boost immunotherapy for solid tumors.

CNS tumors are the leading cause of cancer-related death in children, highlighting the dire need for new treatment strategies. CAR T cells represent a unique approach, distinct from the cytotoxic chemotherapies and small-molecule inhibitors that have dominated the clinical trial space for decades. Phase I CAR T-cell trials have shown feasibility and possible efficacy against pediatric CNS tumors; however, many challenges must be overcome if these therapeutics are going to be beneficial to most affected children. Although rapid translational development and early-phase trials have quickly evolved our understanding, the pediatric CNS CAR T-cell community now yearns for critical assessments and open dialogue about overcoming the remaining obstacles ahead.

Host immune responses to antigens are tightly regulated through the activation and inhibition of synergistic signaling networks that maintain homeostasis. Stimulatory checkpoint molecules initiate attacks on infected or tumor cells, while inhibitory molecules halt the immune response to prevent overreaction and self-injury. Multiple immune checkpoint proteins are grouped into families based on common structural domains or origins, yet the variability within and between these families remains largely unexplored. In this review, we discuss the current understanding of the mechanisms underlying the co-suppressive functions of CTLA-4, PD-1, and other prominent immune checkpoint pathways. Additionally, we examine the IgSF, PVR, TIM, SIRP, and TNF families, including key members such as TIGIT, LAG-3, VISTA, TIM-3, SIRPα, and OX40. We also highlight the unique dual role of VISTA and SIRPα in modulating immune responses under specific conditions, and explore potential immunotherapeutic pathways tailored to the distinct characteristics of different immune checkpoint proteins. These insights into the unique advantages of checkpoint proteins provide new directions for drug discovery, emphasizing that emerging immune checkpoint molecules could serve as targets for novel therapies in cancer, autoimmune diseases, infectious diseases, and transplant rejection.

One of the main characteristics of tumor metabolite reprogramming is enhanced glycolysis, and Pyruvate Kinase M2(PKM2) is a crucial enzyme that limits the pace of glycometabolism. Although PKM2 has been proven to affect the development of some cancers, a pan-cancer analysis of PKM2 has not yet been performed. We analyzed the expression and prognosis of PKM2 in pan-cancer using multiple databases. We performed epigenetic, functional enrichment, immune cell infiltration, immune checkpoint, and drug sensitivity analyses of PKM2. PKM2 was found to be significantly upregulated in most malignancies and associated with a bad prognosis. In some cancers, the PKM2 DNA promoter was hypomethylated. The expression of PKM2 was positively linked with most m6A-methylation-related genes in pan-cancer. The functions of PKM2 were primarily associated with the regulation of the immune system, glycolysis, hypoxia, angiogenesis, and epithelial-mesenchymal transition. PKM2 was favorably associated with neutrophils and cancer-associated fibroblasts in the tumor microenvironment of most cancers. Importantly, PKM2 showed a strikingly high correlation with CD274 (PD-L1), CD276, TGF-β1, VEGFA, and HAVCR2 in most cancers. Finally, using experiments, it was confirmed that silencing PKM2 could increase the sensitivity of esophageal squamous cell carcinoma to cisplatin by regulating autophagy. PKM2 affects autophagy - regulated tumor cell tolerance to chemotherapy, providing future research directions for solving tumor chemotherapy resistance.

B7-H3, an immune checkpoint molecule, is prominently overexpressed in various solid tumors, correlating with poor clinical outcomes. Despite its critical role in promoting tumorigenesis, metastasis, and immune evasion, the regulatory mechanisms governing B7-H3 expression, particularly in cancer stem cells (CSCs), remain elusive. In this comprehensive study, we focused on breast CSCs to uncover the transcriptional regulators driving B7-H3 overexpression. Utilizing DNA affinity purification-mass spectrometry (DAP-MS) to analyze B7-H3 promoter regions, we identified a novel set of transcription factors, including DDB1, XRCC5, PARP1, RPA1, and RPA3, as key modulators of B7-H3 expression. Functional assays revealed that targeting DDB1 with nitazoxanide significantly downregulated B7-H3 expression, subsequently impairing tumor sphere formation and cell migration in breast CSCs. These findings not only elucidate the complex transcriptional network controlling B7-H3 expression but also open new avenues for developing targeted immunotherapies aimed at disrupting CSC-driven cancer progression.

The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, facilitating tumor cells to develop invasive traits and augmenting their migratory capabilities. EMT is primed by tumor microenvironment (TME)-derived signals, whereupon cancer cells undergoing EMT in turn remodel the TME, thereby modulating tumor progression and therapeutic response. This review discusses the mechanisms by which EMT coordinates TME dynamics, including secretion of soluble factors, direct cell contact, release of exosomes and enzymes, as well as metabolic reprogramming. Recent evidence also indicates that cells undergoing EMT may differentiate into cancer-associated fibroblasts, thereby establishing themselves as functional constituents of the TME. Elucidating the relationship between EMT and the TME offers novel perspectives for therapeutic strategies to enhance cancer treatment efficacy. Although EMT-directed therapies present significant therapeutic potential, the current lack of effective targeting approaches-attributable to EMT complexity and its microenvironmental context dependency-underscores the necessity for mechanistic investigations and translational clinical validation.

B7-H3 (CD276), a member of the B7 immune checkpoint family, plays a critical role in modulating immune responses and has emerged as a promising target in cancer therapy. It is highly expressed in various malignancies, where it promotes tumor evasion from T cell surveillance and contributes to cancer progression, metastasis, and therapeutic resistance, showing a correlation with the poor prognosis of patients. Although its receptors were not fully identified, B7-H3 signaling involves key intracellular pathways, including JAK/STAT, NF-κB, PI3K/Akt, and MAPK, driving processes crucial for supporting tumor growth such as cell proliferation, invasion, and apoptosis inhibition. Beyond immune modulation, B7-H3 influences cancer cell metabolism, angiogenesis, and epithelial-to-mesenchymal transition, further exacerbating tumor aggressiveness. The development of B7-H3-targeting therapies, including monoclonal antibodies, antibody-drug conjugates, and CAR-T cells, offers promising avenues for treatment. This review provides an up-to-date summary of the B7H3 mechanisms of action, putative receptors, and ongoing clinical trials evaluating therapies targeting B7H3, focusing on the molecule's role in gastrointestinal tumors.

This study was to investigate the clinical significance of soluble B7-dendritic cell (sB7-DC) concentration in bronchoalveolar lavage fluid (BALF) of children with Refractory Mycoplasma pneumoniae pneumonia (RMPP). A total of 298 patients with Mycoplasma pneumoniae pneumonia (MPP) were enrolled. Patients were divided into general MPP (GMPP) (n = 213) and RMPP groups (n = 85). Detection of sB7-DC and serum inflammatory factors in BALF was performed by ELISA. The relationship between sB7-DC and the risk of RMPP was assessed using restricted cubic spline (RCS) model. A base model for predicting RMPP was constructed using logistic regression analysis, and a compound model was created with the addition of sB7-DC in the base model. ROC curves were plotted to evaluate the predictive value of the model. Column line plots were plotted to assess the contribution of each variable to the outcome event. Calibration curves were plotted and the Hosmer-Lemeshow test (HL test) was performed to assess the calibration performance of the model. Decision curve analysis (DCA) plots were plotted to assess determine whether sB7-DC has clinical value. There was no statistical difference between sB7-H3 and sB7-H4 in the two groups (both p > 0.05). sB7-DC levels were higher in the RMPP group than in the GMPP group (91.66 [77.36, 122.5] pg/ml vs. 64.87 [47.07, 86.46] pg/ml, p < 0.001). RCS analysis showed that the risk of RMPP gradually increased with the increase of sB7-DC when sB7-DC > 76.505 pg/ml. Both the base model and the compound model constructed with independent correlates of RMPP had some predictive value, and the models were well-fitted. The column line graphs showed that the models had discriminative ability. Notably, the compound model had a higher predictive value, with a higher AUC value than the base model: 0.76 (0.65-0.87) versus 0.68 (0.54-0.81). The highest net benefit was close to 0.15 (only 0.1 in the base model). When the net benefit was >0, the high-risk threshold took on a wide range of values. sB7-DC in children with RMPP is an independent predictor of RMPP. sB7-DC helps to improve quantitative prediction of RMPP risk and accurately guide medical decisions.

B7H3 (CD276), an immunoregulatory molecule known for its role in immune evasion by transmitting inhibitory signals to T lymphocytes, has garnered significant attention in recent years as a promising target for cancer immunotherapy. This interest is largely due to its high expression in various types of solid tumors, coupled with low protein levels in normal tissues. However, studies examining the impact of B7H3 on survival outcomes have shown inconsistent results, leaving its prognostic significance not fully clarified. Therefore, this meta-analysis aimed to assess the relationship between B7H3 expression and various prognostic parameters in patients with solid malignancies. PubMed, Web of Science (WOS), Cochrane, SCOPUS, and Embase databases were searched for eligible articles published until November 2024. Statistical analysis was performed using R studio (version 4.3.2). The analysis included a total of 51 eligible studies comprising 11,135 patients. Results showed that overexpression of B7H3 is a negative predictor for all examined survival outcomes: OS (HR = 1.71, 95% CI = 1.44-2.03, p < 0.0001), DFS (HR = 2.02, 95% CI = 1.49-2.73, p < 0.0001), PFS (HR = 2.10, 95% CI = 1.44-3.06, p < 0.0001), RFS (HR = 1.66, 95% CI = 1.11-2.48, p = 0.01), and DSS (HR = 1.70, 95% CI = 1.24-2.32, p < 0.01). Despite the high heterogeneity observed across the studies, the sensitivity analysis confirmed the robustness of these results. This research suggests that B7H3 may serve as an effective biomarker for prognosis in solid tumors.

Glioblastoma remains one of the most lethal malignancies, largely due to its resistance to standard chemotherapy such as temozolomide. This study investigates a novel resistance mechanism involving glioblastoma stem cells (GSCs) and the polarization of M2-type macrophages, mediated by the extracellular vesicle (EV)-based transfer of Clusterin. Using 6-week-old male CD34+ humanized huHSC-(M-NSG) mice (NM-NSG-017) and glioblastoma cell lines (T98G and U251), we demonstrated that GSC-derived EVs enriched with Clusterin induce M2 macrophage polarization, thereby enhancing temozolomide resistance in glioblastoma cells. Single-cell and transcriptome sequencing revealed close interactions between GSCs and M2 macrophages, highlighting Clusterin as a key mediator. Our findings indicate that Clusterin-rich EVs from GSCs drive glioblastoma cell proliferation and resistance to temozolomide by modulating macrophage phenotypes. Targeting this pathway could potentially reverse resistance mechanisms, offering a promising therapeutic approach for glioblastoma. This study not only sheds light on a critical pathway underpinning glioblastoma resistance but also lays the groundwork for developing therapies targeting the tumor microenvironment. Our results suggest a paradigm shift in understanding glioblastoma resistance, emphasizing the therapeutic potential of disrupting EV-mediated communication in the tumor microenvironment.

Prostate cancer (PCa) continues to pose substantial clinical challenges, with molecular heterogeneity significantly impacting therapeutic decision-making and disease trajectories. Emerging evidence implicates protein lactylation-a novel epigenetic regulatory mechanism-in oncogenic processes, though its prognostic relevance in PCa remains underexplored. Through integrative bioinformatics interrogation of lactylation-associated molecular signatures, we established prognostic correlations using multivariable feature selection methodologies. Initial screening via differential expression analysis (limma package) coupled with Cox proportional hazards modeling revealed 11 survival-favorable regulators and 16 hazard-associated elements significantly linked to biochemical recurrence. To enhance predictive precision, ensemble machine learning frameworks were implemented, culminating in a 10-gene lactylation signature demonstrating robust discriminative capacity (concordance index = 0.738) across both primary (TCGA-PRAD) and external validation cohorts (DKFZ). Multivariable regression confirmed the lactylation score's prognostic independence, exhibiting prominent associations with clinicopathological parameters including tumor staging and metastatic potential. The developed clinical-molecular nomogram achieved superior predictive accuracy (C - index > 0.7) through the synergistic integration of biological and clinical covariates. Tumor microenvironment deconvolution uncovered distinct immunological landscapes, with high-risk stratification correlating with enriched stromal infiltration and immunosuppressive phenotypes. Pathway enrichment analyses implicated chromatin remodeling processes and cytokine-mediated inflammatory cascades as potential mechanistic drivers of prognostic divergence. Therapeutic vulnerability profiling demonstrated differential response patterns: low-risk patients exhibited enhanced immune checkpoint inhibitor responsiveness, whereas high-risk subgroups showed selective chemosensitivity to docetaxel and mitoxantrone. Functional validation in PC-3 models revealed AK5 silencing induced proapoptotic effects, suppressed metastatic potential of migration and invasion, and modulated immune checkpoint regulation through CD276 coexpression. These multimodal findings position lactylation dynamics, particularly AK5-mediated pathways, as promising therapeutic targets and stratification biomarkers in PCa management.

The immune checkpoint protein B7-H3 (CD276) is overexpressed in various cancers and is an attractive target for the treatment of malignant tumors. Radionuclide molecular imaging of B7-H3 expression using engineered scaffold proteins such as Affibody molecules is a promising strategy for the selection of potential responders to B7-H3-targeted therapy. Feasibility of B7-H3 imaging was demonstrated using two 99mTc-labeled probes, AC12 and an affinity-matured SYNT179 using a [99mTc]Tc-GGGC label. This study aimed to evaluate whether the use of a residualizing 111In-based label provides better imaging contrast compared with a nonresidualizing label. To do that, SYNT179 and AC12-GGGC Affibody molecules were labeled with 111In using (4,10-bis-carboxymethyl-7-{[2-(2,5-dioxo-3-thioxo-pyrrolidin-1-yl)-ethylcarbamoyl]-methyl}-1,4,7,10-tetraaza-cyclododec-1-yl)-acetic acid (maleimide-DOTA) chelator, site-specifically coupled to the C-terminus of Affibody molecules. The binding affinities of the 111In-labeled conjugates to B7-H3-expressing living cells were higher compared with the affinities of the 99mTc-labeled variants. In mice with B7-H3-expressing xenografts, the tumor uptake of 111In-labeled proteins (3.6 ± 0.3 and 1.8 ± 0.5%ID/g for [111In]In-SYNT179-DOTA and [111In]In-AC12-DOTA, respectively) was significantly (p < 0.05, ANOVA) higher than those for 99mTc-labeled counterparts (1.6 ± 0.2%ID/g and 0.8 ± 0.2%ID/g for [99mTc]Tc-SYNT179 and [99mTc]Tc-AC12-GGGC, respectively). The best variant, [111In]In-SYNT179-DOTA, provided a tumor-to-blood ratio of 31.1 ± 2.9, which was twice higher than that for [99mTc]Tc-SYNT179 and 7-fold higher than that for [99mTc]Tc-AC12-GGGC. Both 111In-labeled Affibody molecules had higher renal retention compared with 99mTc-labeled ones, but the hepatobiliary excretion of 111In-labeled proteins was appreciably lower, potentially improving the imaging of abdominal metastases. Overall, [111In]In-SYNT179-DOTA is the most promising tracer for visualization of B7-H3 expression.

In recent years, there has been a growing trend towards the utilization of immunotherapy techniques for the treatment of cancer. Some malignancies have acquired significant progress with the use of cancer vaccines, immune checkpoint inhibitors, and adoptive cells therapy. Scholars are exploring the aforementioned methods as potential treatments for advanced prostate cancer (PCa) due to the absence of effective adjuvant therapy to improve the prognosis of metastatic castration-resistant prostate cancer (mCRPC). Immunotherapy strategies have yet to achieve significant advancements in the treatment of PCa, largely attributed to the inhibitory tumor microenvironment and low mutation load characteristic of this malignancy. Hence, researchers endeavor to address these challenges by optimizing the design and efficacy of immunotherapy approaches, as well as integrating them with other therapeutic modalities. To date, studies have also shown potential clinical benefits. This comprehensive review analyzed the utilization of immunotherapy techniques in the treatment of PCa, assessing their advantages and obstacles, with the aim of providing healthcare professionals and scholars with a comprehensive understanding of the progress in this field.

Recent studies have highlighted the potential contribution of CD4+ T cells with cytotoxic activity (CD4 CTLs) to anti-tumor immunity. However, their precise roles remain elusive, partly due to the absence of specific markers defining CD4 CTLs with target-killing potential in humans. We previously demonstrated that Epstein-Barr virus (EBV)-driven immortalized B cell lines efficiently induce human CD4 CTLs with cytotoxic functions comparable to cytotoxic CD8+ T cells (CD8 CTLs). Here we show that EBV-driven CD4 CTLs exhibit prolonged proliferation and sustained cytotoxicity compared with CD8 CTLs, although their cytotoxic function markedly decreased during long-term culture. Comparative transcriptomic analysis of CD4 CTLs with varying cytotoxic activities identified B7-H3 and LAG3 as surface molecules associated with highly cytotoxic CD4 CTLs. Co-expression of B7-H3 and LAG3 correlated with CD107a expression and was observed on CD4+ T cells with enhanced cytotoxic potential in a target-dependent manner but not on CD8 CTLs. Furthermore, B7-H3+LAG3+ CD4+ T cells were induced during co-culture with bone marrow cells from pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL). These findings suggest that B7-H3 and LAG3 co-expression represents a characteristic feature of functional CD4 CTLs in humans, providing valuable insights into the role of CD4 CTLs in tumor immunity.

Isocitrate dehydrogenase (IDH) wild-type (wt) glioblastoma is an aggressive malignancy associated with poor clinical outcomes, marked by high heterogeneity and resistance to treatment. This study aims to investigate the prognostic significance of B7-H3 expression in IDH wt glioblastoma and its potential association with clinical outcomes, including overall survival (OS) and progression-free survival (PFS). Additionally, the relationship between B7-H3 and PD-L1 expression was explored.

A retrospective cohort of 86 IDH wt glioblastoma patients, all of whom underwent surgery, radiotherapy, and temozolomide treatment, was analyzed. B7-H3 expression was quantified using an immunoreactivity score (IRS), classifying samples as low (IRS ≤ 4) or high (IRS > 4). PD-L1 expression was evaluated based on tumor and immune cell staining, with >5% positivity indicating significant expression.

High B7-H3 expression was significantly associated with poorer OS and PFS. Co-expression of B7-H3 and PD-L1 was prevalent, particularly among younger male patients with unifocal tumors; however, PD-L1 expression did not show a significant correlation with clinical outcomes.

B7-H3 appears to be a promising prognostic biomarker in IDH wt glioblastoma and may serve as a target for developing combination therapies, integrating B7-H3-targeting treatments with immune checkpoint inhibitors. Further prospective studies are necessary to validate these findings and to explore potential therapeutic strategies.

Targeting cytotoxic T lymphocytes (CTLs), as chimeric antigen T cells (CAR-T), T cell receptor-engineered (TCR)-T cells or adoptive cell transfer of tumor infiltrating T cells (TILs) to solid tumors is a major therapeutic challenge. We describe a new strategy to confer these lymphocytes with de novo adhesiveness to surface proteins enriched in the tumor microenvironment. This approach is based on decorating CTLs with monoclonal antibodies (mAbs) specific to any surface protein of interest within the stroma and the extracelullar matrix of solid tumors. For efficient mAb decoration, we have introduced a mAb binding Fc receptor (FcR) scaffold, FcγRIIB1 (CD32B1), which we found to be enriched on B lymphocyte microvilli (MV). This isoform contains an inhibitory ITIM motif within a cytoplasmic tail anchored to the cortical cytoskeleton. We thus generated a non-signaling CD32B1 mutant lacking the ITIM motif (termed ITIM-less CD32B1, or ILCD32B1) and successfully expressed it in human T cells which normally do not express this FcR. The ILCD32B1 expressing lymphocytes bound multiple IgG1 mAbs whose Fc domain was engineered with a 5-residue substitution to reach a nM range of Fc-FcγCR dissociation constants. The mAb decorated ILCD32B1 expressing T cells could readily adhere to a surface-bound cognate antigen. To broaden the utility of this scaffold, we have also generated a new fusion protein in which the entire Fc binding domain was truncated (tILCD32B1) and replaced with a monomeric streptavidin variant, mSA2, via a CD8 hinge. The molecule, termed mSA2-CD8h-tILCD32B1, was also successfully expressed in T cells, readily and stably bound biotinylated IgG mAbs in vitro and once decorated with the biotin labeled mAbs, conferred the T cells with high adhesiveness to multiple surface-coated antigens. mSA2-CD8h-tILCD32B1 expressing human T cells decorated ex vivo with a biotin-labeled mAb retained the antibody for hours after accumulation inside breast tumors implanted in immunodeficient recipient mice. Our results collectively suggest that a non-signaling CD32B1 can be used as a versatile scaffold for mAb decoration of T cells. Our mAb decoration approach can confer new cell adhesive reactivities to improve tumor CTL (CAR-T and TIL) accumulation and retention inside solid tumors.

Advanced triple-negative breast cancer (TNBC) is prone to brain metastasis (BrM). The precise molecular mechanism responsible for this phenomenon has not yet been completely established, so it is vital to comprehend the molecular mechanism behind it.

The protein chip analysis was conducted to identify any abnormal UBE2T protein expression in TNBC, especially BrM. Here, we used public databases and bioinformatics analysis as well as clinical samples from different cohorts to investigate the interrelationship between UBE2T/CDC42/CD276. This predicted relationship was then repeatedly validated using different in vivo and in vitro experimental methods. Additionally, multiple experimental approaches were implemented, encompassing western blotting, Co-IP, GST pull-down, flow cytometry, mass spectrometry, immunofluorescence, immunohistochemistry, and qRT-PCR to reveal the molecular mechanism of UBE2T-mediated immune escape and BrM.

Our results indicate that expressed at elevated levels in breast cancer, UBE2T is negatively linked to patient prognosis, especially in BrM of TNBC. Data from clinical samples from our different cohorts and TCGA indicate a significant correlation between UBE2T and immunosuppression. Mechanistically, UBE2T directly interacts with CDC42, promoting its K48-linked polyubiquitination and proteasomal degradation, thereby inhibiting CDC42 from degrading CD276 via the autophagy-lysosomal pathway, indirectly upregulating CD276 and thereby impairing the CD8+ T cells function, ultimately mediating tumor immune escape and BrM. Finally, animal experimental results also showed that inhibition of UBE2T elevated the TNBC sensitivity to immune checkpoint CD276 blockade and inhibited BrM of TNBC.

In conclusion, our results indicate a new mechanism whereby UBE2T-mediated ubiquitination positively controls the UBE2T/CDC42/CD276 axis to upregulate tumor cell expression of CD276 and thereby impair CD8+ T cells function, ultimately leading to tumor cell immune escape and BrM.

CD276 (B7-H3) is an immunoregulatory protein that plays an important role in the inhibition of T-cell function. CD276 is overexpressed on a variety of human solid cancer cells with limited expression in normal tissues, making it an appealing target for innovative cancer immunotherapy approaches. Pleural mesothelioma (PM) is a highly aggressive disease with a need for new treatment options. Our objective was to investigate the expression of CD276 in the multicenter PM cohort of the European Thoracic Oncology Platform Mesoscape project and correlate the results with annotated clinical data.

Using tissue microarrays (TMAs), the expression of CD276, assessed using a semiquantitative aggregate H-score method on the membrane (and secondarily in the cytoplasm), was correlated with clinicopathologic characteristics and survival outcome.

CD276 immunohistochemistry results were available for 353 patients, with mostly epithelioid histology (71%). Membranous CD276 expression was present in 86%. High membranous CD276 expression (H-score ≥the median H-score of 120) was significantly more common in females (P = .0029; 71% v 47%) and in epithelioid histology (P < .001; 59% v 29%), whereas no significant association in clinical outcome (overall survival [OS]/progression-free survival) was found. Cross-validation of the TMA method using whole sections revealed a moderate agreement for membranous assessment (Cohen's kappa = 0.47) and a lower agreement for cytoplasm assessment (Cohen's kappa = 0.37). In an exploratory analysis, high cytoplasmic CD276 expression was associated with worse prognosis (OS, log-rank P = .043), but was not significant when adjusting for other clinical variables.

Although no prognostic value of CD276 expression was found, its high membranous expression (86%) in the PM samples of the study supports further research of its potential as a therapeutic target for this disease.

Immunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood.

Data for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry.

We were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors.

In this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy.

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous immune checkpoints, particularly those within the B7 family. Elucidating the mechanisms that govern the induction of B7 family molecules is crucial for the advancement of immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, is suggested may play a role in reshaping the tumor microenvironment and facilitating immune evasion. Methods: We analyzed the glycolysis pathway's enrichment in patients with immune-evading tumors and assessed the impact of lactate treatment on the antitumor immunity of CD8+ T cells in the tumor microenvironment. We interrupted glycolysis using lactate dehydrogenase A (LDHA) knockdown and sodium oxamate, and evaluated its effects on CD8+ T cell cytotoxicity. Additionally, we investigated the correlation between B7-H3 expression and the glycolysis pathway, and explored the molecular mechanisms underlying lactate-induced B7-H3 expression. Results: Our findings revealed that the glycolysis pathway was highly enriched in immune-evading tumors. Lactate treatment inhibited the antitumor immunity of CD8+ T cells, whereas interruption of glycolysis via LDHA knockdown or treatment with sodium oxamate augmented the cytotoxicity of CD8+ T cells, effectively counteracting tumor immune evasion. B7-H3 expression was found to be closely linked with the glycolysis pathway. Mechanistically, lactate-upregulated H3K18la directly bound to the B7-H3 promoter in conjunction with the transcription factor Creb1 and its co-activator Ep300, leading to increased B7-H3 expression and contributing to tumor progression by compromising the proportion and cytotoxicity of tumor-infiltrating CD8+ T cells. In mouse tumor bearing models, inhibiting glycolysis and B7-H3 expression suppressed tumor cell growth, activated tumor-infiltrating CD8+ T cells, and demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced the efficacy of anti-PD-1 treatment. Conclusions: This study uncovers a novel mechanism by which lactate modulates the immune microenvironment through the glycolysis pathway and B7-H3 expression, providing new avenues for lactate metabolism-targeted tumor immunotherapy.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic challenges, including antigen heterogeneity and immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview of recent advances in CAR T cell therapy aimed at overcoming these obstacles. We discuss the importance of antigen identification by emphasizing the identification of tumor-specific and tumor-associated antigens and the development of CAR T therapies targeting these antigens. Furthermore, we highlight key structural innovations, including cytokine-armored CARs, protease-regulated CARs, and CARs engineered with chemokine receptors, to enhance tumor infiltration and activity within the immunosuppressive microenvironment. Additionally, novel manufacturing approaches, such as the Sleeping Beauty transposon system, mRNA-based CAR transfection, and in vivo CAR T cell production, are discussed as scalable solution to improve the accessibility of CAR T cell therapies. Finally, we address critical therapeutic limitations, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and suboptimal persistence of CAR T cells. An examination of emerging strategies for countering these limitations reveals that CRISPR-Cas9-mediated genetic modifications and combination therapies utilizing checkpoint inhibitors can improve CAR T cell functionality and durability. By integrating insights from preclinical models, clinical trials, and innovative engineering approaches, this review addresses advances in CAR T cell therapies and their performance in solid tumors.

Cellular senescence is considered a new marker of cancer. It has been suggested that long non-coding RNA (lncRNA) can be used to predict the prognosis of cancers. However, it remains to be seen whether the lncRNAs associated with cellular senescence can be used to predict the prognosis of gastric cancer (GC). The present study aimed to develop a novel senescence-related lncRNA signature (SenLncSig) to predict GC prognosis. The SenLncSig model holds promise for enhancing patient stratification, enabling more precise prognostic predictions and facilitating immunotherapy strategies.

Senescence-associated lncRNAs were identified from RNA expression profiles in The Cancer Genome Atlas (TCGA) database through the construction of a co-expression network linking senescence genes and lncRNAs. A prognostic signature for GC (334 patients from TCGA-STAD data set), comprising the senescence-related lncRNAs, was developed through univariate and multivariate Cox proportional hazards regression analyses. By using the median SenLncSig risk score, the GC patients were categorized into high- and low-risk groups. A Kaplan-Meier analysis and gene set enrichment analysis were conducted, and immune infiltration, the tumor mutation burden (TMB), and pharmacological treatments were compared between the high- and low-risk groups. We used an independent GC cohort (an external cohort of 30 pairs of tumor and non-tumor tissues from the GC patients) and three GC cell lines to conduct a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis to validate the results.

We established a SenLncSig, a prognostic risk model comprising the following five senescence-associated lncRNAs; AP000695.2, LINC02381, AC005586.1, AP003392.1, and AP001528.2. According to the SenLncSig, high-risk scores were associated with poor overall survival (multivariate Cox proportional hazard ratio: 1.498, 95% confidence interval: 1.294-1.735; P<0.001). The time-dependent receiver operating characteristic curve indicated that the model performed (area under the curve: 0.711). We developed a nomogram incorporating age, gender, grade, stage, T stage, M stage, N stage, and SenLncSig risk score to estimate 1-year, 3-year, and 5-year survival rates. Further, according to the results of the mutation analysis, patients with a high TMB in the high-risk group had the worst prognosis. Interestingly, the high-risk group had a stronger infiltration of regulatory T cells (P<0.001) and M2 macrophage cells (P<0.001), as well as higher tumor immune dysfunction and exclusion scores than the low-risk group. These results might explain why the high-risk group had a worse prognosis. Finally, the qRT-PCR validation revealed that the AP000695.2 and AP003392.1 expression levels were significantly higher in the tumor tissues and GC cell lines than the normal tissues and normal human gastric epithelial cell line, whereas the opposite pattern was found for LINC02381.

The development of the SenLncSig provided a potential tool for improving patient prognosis predictions and offered preliminary insights into predicting the efficacy of GC immunotherapy.

B7-H3 (CD276), a member of the B7-family of immune checkpoint proteins, has been shown to have immunological and non-immunological effects promoting tumorigenesis [1, 2] and expression correlates with poor prognosis for many solid tumors, including cervical, ovarian and breast cancers [3-6]. We recently identified a tumor-cell autochthonous tumorigenic role for dimerization of the 4Ig isoform of B7-H3 (4Ig-B7-H3) [7], where 4Ig-B7-H3 dimerization in cis activated tumor-intrinsic cellular proliferation and tumorigenesis pathways, providing a novel opportunity for therapeutic intervention. Herein, a live cell split-luciferase complementation strategy was used to visualize 4Ig-B7-H3 homodimerization in a high-throughput small molecule screen (HTS) to identify modulators of this protein-protein interaction (PPI). Notably, the HTS identified several compounds that converged on lipid metabolism (including HMG-CoA reductase inhibitors, also known as statins) as significant inhibitors of 4Ig-B7-H3 dimerization (p < 0.01). In vitro and in vivo murine studies provided evidence that statin-mediated disruption of 4Ig-B7-H3 dimerization was associated with anti-tumor effects. Statin-mediated anti-cancer efficacy was selective for B7-H3-expressing tumors and retrospective analysis of clinical tumor specimens supported the hypothesis that concurrent statin use enhanced clinical outcomes for patients in a B7-H3 restricted manner. Thus, disruption of 4Ig-B7-H3 dimerization provides an unanticipated molecular mechanism linking statin use in cancer therapy and prevention with immune checkpoint.

Sperm-associated antigen 5 (SPAG5) is a mitotic spindle protein crucial for coordinating the separation of sister chromatids into daughter cells. Increasing evidence suggests that SPAG5 is overexpressed in various malignancies, functioning as an oncogene. However, research specifically examining SPAG5 in esophageal cancer remains limited.

In this research, we leveraged bioinformatics techniques to evaluate the expression and prognostic significance of SPAG5 in a variety of cancer types. We conducted Gene Set Enrichment Analysis (GSEA) to elucidate the relationship between SPAG5 and cancer characteristics. Additionally, we investigated the correlation between SPAG5 expression and immune cell infiltration utilizing the TIMER2.0 platform. The TIDE platform was used to assess the impact of SPAG5 on the effectiveness of immunotherapy and to screen for potential therapeutic drugs. We employed qRT-PCR and immunohistochemistry staining to ascertain the expression of SPAG5 in esophageal cancer tissue. Through cellular functional experiments, we examined the influence of SPAG5 expression on the proliferation, apoptosis, invasion, and migration of esophageal cancer cells. The Pathscan Stress Signaling Antibody Array was utilized to probe the potential molecular mechanisms of SPAG5.

SPAG5 exhibits high levels of expression in various cancers, encompassing esophageal cancer, and its presence indicates an unfavorable prognosis. SPAG5 is primarily enriched in pathways associated with cellular proliferation and demonstrates a correlation with immune gene expression as well as the infiltration of immune cells. Suppression of SPAG5 expression in esophageal cancer cells not only inhibits cell proliferation, but also attenuates cell invasion and migration while inducing cellular apoptosis. The depletion of SPAG5 results in a decline in the levels of critical signaling proteins.

SPAG5 plays a pivotal role in esophageal cancer cell proliferation, apoptosis, and metastasis within the tumor microenvironment, making it a promising therapeutic target.

Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, most clinically tested "Armed" OAds show limited antitumor effects in patients with various solid tumors even with increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), in which tumors are coinfected with an OAd and a non-replicating helper-dependent Ad (HDAd). We recently demonstrated that a single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker, and HSV thymidine kinase safety switch (CAdTrio) induces significant antitumor effects in patients, including complete response. Similar to previous OAd studies, all patients primarily amplified Ad-specific T cells after treatment however, CAdVEC was still able to induce clinical responses even given at a 100-fold lower dose.

To address the mechanisms of CAdTrio-mediated antitumor effect in patients, we analyzed patients' samples using Enzyme-linked immunosorbent spot (ELISpot) to measure T-cell specificity and quantitative polymerase chain reaction (qPCR) to measure CAdVEC viral genome copies at tumor sites. We then evaluated potential mechanisms of CAdVEC efficacy in vitro using live-cell imaging. Based on those results, we developed a new CAdVEC additionally expressing a T-cell engager molecule targeting CD44v6 to redirect tumor-infiltrating irrelevant T cells against cancer stem cell populations (CAdTetra) for further improvement of local CAdVEC treatment. We tested its efficacy against different cancer types both in vitro and in vivo including Ad pre-immunized humanized mice.

We found that HDAd-infected cells escape Ad-specific T-cell recognition with enhanced tumor-specific T-cell activity through immunomodulatory transgenes. Since CAdVEC treatment initially amplified Ad-specific T cells in patients, we re-direct these virus-specific T cells to target tumor cells by additionally expressing CD44v6.BiTE from CAdTetra. CAdTetra significantly controlled tumor growth, repolarizing local and systemic responses against cancer cells in both immunologically "hot" and "cold" tumor models and also induced immunologic memory against rechallenged tumors.

Our results indicate that CAdTetra effectively induces adaptive T-cell responses against cancer cells by using tumor-infiltrating irrelevant T cells.

The immune system serves as a fundamental defender against the initiation and progression of cancer. Failure of the immune system augments immunosuppressive action that leading to cancer manifestation. This immunosuppressive effect causes from significant alterations in immune checkpoint expression associated with tumoral progression. The tumor microenvironment promotes immune escape mechanisms that further amplifying immunosuppressive actions. Notably, substantial targeting of immune checkpoints has been pragmatic in the advancement of cancer research. This study highlights a comprehensive review of emerging druggable targets aimed at modulating immune checkpoint co-inhibitory as well as co-stimulatory molecules in response to immune system activation. This modulation has prompted to the development of newer therapeutic insights, eventually inducing immunogenic cell death through immunomodulatory actions. The study emphasizes the role of immune checkpoints in immunogenic regulation of cancer pathogenesis and explores potential therapeutic avenues in cancer immunotherapy.Modulation of Immunosuppressive and Immunostimulatory pathways of immune checkpoints in cancer immunotherapy.

Objectives: B7 homolog 3 protein (B7-H3, also known as CD276) is a member of the B7 family that has been found to be associated with the growth and progression of a variety of tumors, but no pan-cancer evaluations of CD276 have been performed so far. In this study, we aimed to perform a pan-cancer analysis of the oncogenic role of CD276 in human tumors; Methods: We used a series of databases to perform a pan-cancer analysis of CD276, including the expression level of CD276 in pan-cancer and its relationship to tumor progression, patient survival duration, the immune cell infiltration within the tumor, and the potential signaling pathways and molecular mechanisms associated with CD276; Results: We found that CD276 was a potential biomarker for the prognosis of most cancers. The high expression of CD276 was associated with tumor progression, leading to poor survival. Notably, the up-regulation of CD276 expression in tumors increased the tumor infiltration of cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs) and decreased the CD8+ T cells; Conclusions: Our study demonstrates that CD276 might promote tumor progression via the promotion of an immunosuppressive microenvironment.

Cancer has emerged as the second most prevalent disease and the leading cause of death, claiming the lives of 10 million individuals each year. The predominant varieties of cancer encompass breast, lung, colon, rectal, and prostate cancers. Among the more aggressive malignancies is glioblastoma, categorized as WHO stage 4 brain cancer. Following diagnosis, the typical life expectancy ranges from 12 to 15 months, as current established treatments like surgical intervention, radiotherapy, and chemotherapy using temozolomide exhibit limited effectiveness. Beyond conventional approaches, the exploration of immunotherapy for glioblastoma treatment is underway. A methodology involves CAR-T cells, monoclonal antibodies, ADCC and nanobodies sourced from camelids. Immunotherapy's recent focal point is the cellular ligand B7-H3, notably abundant in tumor cells while either scarce or absent in normal ones. Its expression elevates with cancer progression and serves as a promising prognostic marker. In this article, we delve into the essence of B7-H3, elucidating its function and involvement in signaling pathways. We delineate the receptors it binds to and its significance in glioblastoma and other cancer types. Lastly, we examine its role in immunotherapy and the utilization of nanobodies in this domain.

Glioblastoma is the most common lethal primary brain tumor, urging evaluation of new treatment options. Chimeric antigen receptor (CAR)-T cells targeting B7 homolog 3 (B7-H3) are promising because of the overexpression of B7-H3 on glioblastoma cells but not on healthy brain tissue. Nanobody-based (nano)CARs are gaining increasing attention as promising alternatives to classical single-chain variable fragment-based (scFv)CARs, because of their single-domain nature and low immunogenicity. Still, B7-H3 nanoCAR-T cells have not been extensively studied in glioblastoma.

B7-H3 nanoCAR- and scFvCAR-T cells were developed and evaluated in human glioblastoma models. NanoCAR-T cells targeting an irrelevant antigen served as control. T cell activation, cytokine secretion and killing capacity were evaluated in vitro using ELISA, live cell imaging and flow cytometry. Antigen-specific killing was assessed by generating B7-H3 knock-out cells using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-genome editing. The tumor tracing capacity of the B7-H3 nanobody was first evaluated in vivo using nuclear imaging. Then, the therapeutic potential of the nanoCAR-T cells was evaluated in a xenograft glioblastoma model.

We showed that B7-H3 nanoCAR-T cells were most efficient in lysing B7-H3pos glioblastoma cells in vitro. Lack of glioblastoma killing by control nanoCAR-T cells and lack of B7-H3neg glioblastoma killing by B7-H3 nanoCAR-T cells showed antigen-specificity. We showed in vivo tumor targeting capacity of the B7-H3 nanobody-used for the nanoCAR design-in nuclear imaging experiments. Evaluation of the nanoCAR-T cells in vivo showed tumor control in mice treated with B7-H3 nanoCAR-T cells in contrast to progressive disease in mice treated with control nanoCAR-T cells. However, we observed limiting toxicity in mice treated with B7-H3 nanoCAR-T cells and showed that the B7-H3 nanoCAR-T cells are activated even by low levels of mouse B7-H3 expression.

B7-H3 nanoCAR-T cells showed promise for glioblastoma therapy following in vitro characterization, but limiting in vivo toxicity was observed. Off-tumor recognition of healthy mouse tissue by the cross-reactive B7-H3 nanoCAR-T cells was identified as a potential cause for this toxicity, warranting caution when using highly sensitive nanoCAR-T cells, recognizing the low-level expression of B7-H3 on healthy tissue.

Melanoma is an aggressive tumor with a high mortality rate. Metformin, a commonly prescribed diabetes medication, has shown promise in cancer prevention and treatment. Long noncoding RNAs (lncRNAs) are non-protein-coding RNA molecules that play a key role in tumor development by interacting with cellular chromatins. Despite the benefits of metformin, the anticancer mechanism underlying its effect on the regulation of lncRNAs in melanoma remains unclear.

We investigated the lncRNA profiles of human melanoma cells with and without metformin treatment using a next-generation sequencing approach (NGS). Utilizing public databases, we analyzed the expression levels and clinical impacts of LINC00094 and miR-1270 in melanoma. The expression levels of LINC00094 and miR-1270 were verified in human cell lines and clinical samples by real-time PCR and in situ hybridization. The biological roles of LINC00094 and miR-1270 in cell growth, proliferation, cell cycle, apoptosis, and motility were studied using in vitro assays.

We identify a novel long noncoding RNA, namely LINC00094, whose expression considerably decreased in melanoma cells after metformin treatment. In situ hybridization analysis revealed substantially higher expression of LINC00094 in cutaneous melanoma tissue compared with adjacent normal epidermis and normal control tissues (P < 0.001). In nondiabetic patients with melanoma, the overall survival of high LINC00094 expression group was shorter than the low LINC00094 expression group with borderline statistical significance (log-rank test, P = 0.057). Coexpression analysis of LINC00094 indicated its involvement in the mitochondrial respiratory pathway, with its knockdown suppressing genes associated with mitochondrial oxidative phosphorylation, glycolysis, antioxidant production, and metabolite levels. Functional analysis revealed that silencing-LINC00094 inhibited the proliferation, colony formation, invasion, and migration of melanoma cells. Cell cycle analysis following LINC00094 knockdown revealed G1 phase arrest with reduced cell cycle protein expression. Combined TargetScan and reporter assays revealed a direct link between miR-1270 and LINC00094. Ectopic miR-1270 expression inhibited melanoma cell growth and motility while inducing apoptosis. Finally, through in silico analysis, we identified two miR-1270 target genes, CD276 and centromere protein M (CENPM), which may be involved in the biological functions of LINC00094.

Overall, LINC00094 expression may regulate melanoma cell growth and motility by modulating the expression of miR-1270, and targeting genes of CD276 and CENPM indicating its therapeutic potential in melanoma treatment.

Bacterial and viral infections cause a huge burden to healthcare settings worldwide, and mortality rates associated with infectious microorganisms have remained high in recent decades. Despite tremendous efforts and resources worldwide to explore diagnostic biomarkers, rapid and easily assayed indicators for the diagnosis of bacterial and viral infections remain a challenge. B7 homolog 3 (B7-H3), a member of the B7 family of immunoregulatory proteins, is overexpressed in patients with septicemia, meningitis, pneumonia, and hepatitis. Therefore, B7-H3 could be used as a potential clinical indicator and therapeutic target for bacterial and viral infections caused by H. pylori, S. pneumoniae, M. pneumoniae, hepatitis B virus (HBV), viral hemorrhagic septicemia virus (VHSV), respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). Moreover, the interplay between infectious microorganisms and B7-H3 and exploration of the functional roles of the B7-H3 molecule could aid in the development of novel strategies for disease diagnosis and immunotherapy.

Integrin β5 (ITGB5) is a pivotal player in the pathogenesis of gastric cancer (GC). We aimed to explore the potential value of ITGB5 as a predictor of diagnosis and immunotherapy in gastric cancer.

The expression of ITGB5 in GC was assessed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and verified through quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Kaplan-Meier curves were conducted to evaluate the prognostic significance. The immune cells infiltration, tumor mutational burden (TMB), and immunophenoscore (IPS) were examined using CIBERSORT, TIMER, and TISIDB. In addition, colony formation, scratch assays, and transwell assays were employed to determine the impact on tumor progression and metastasis. CD276 expression was detected by western blotting following the knockdown of ITGB5. ELISA was utilized to measure serum ITGB5 levels.

The expression of ITGB5 in GC tissue surpassed that in normal tissue, it might contribute to GC pathogenesis through pathways including PI3K-AKT, ECM-receptor interaction, and TGF-beta. The elevated ITGB5 expression is associated with poor prognosis in GC patients. In addition, a strong positive association between ITGB5 overexpression and the infiltration levels of macrophages and monocytes, and it significantly influenced immune response. Moreover, lower expression of ITGB5 was associated with better immunotherapy efficacy. Subsequent investigation demonstrated that silencing of ITGB5 suppressed the proliferation and migration of GC cell lines in vitro. ITGB5 expression was positively correlated with CD276 expression and the knockdown of ITGB5 resulted a notable decrease CD276 expression. Futhermore, a significantly high level of serum ITGB5 was observed in GC patients. The combined assessment of ITGB5, CEA, and CA19-9 improved the diagnostic accuracy.

ITGB5 potentially serve as both a diagnostic biomarker and therapeutic target in managing GC.