In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

EMB-02 is a symmetric bispecific antibody targeting programmed cell death protein-1 and lymphocyte-activation gene 3 simultaneously. Here, we present the first-in-human study results of EMB-02 in patients with advanced solid tumors.

Patients were treated with intravenous infusions of EMB-02 at doses of 6-900 mg. The primary objective was to evaluate the safety and tolerability and to determine the maximum tolerated dose and/or recommended phase II dose(s). Secondary objectives included characterizing the pharmacokinetic (PK) profile, assessing preliminary antitumor activity and the immunogenicity.

A total of 47 patients were enrolled. All grade and grade 3/4 treatment-emergent and treatment related adverse events occurred in 97.9%, 48.9%, 68.1% and 12.8% patients, respectively. The objective response rate (ORR) was 6.4% and clinical benefit rate at 24 weeks (CBR-24) was 25.5% in overall population. The CBR-24 was 33.3% in checkpoint inhibitor (CPI)-naïve patients, and 15% in CPI-treated. No clear relationship was observed between the efficacy and PD-L1, LAG-3, or MHC II expression level. Doses 360 mg or higher resulted in sustained saturation of PD-1 receptors on circulating CD3 + T cells.

EMB-02 demonstrated a favorable safety profile and early efficacy signals in multiple solid tumors, warranting further development. (NCT04618393).

This study aimed to evaluate the predictive value of MHC class II (MHC-II) expression by melanoma cells in a large cohort of metastatic cutaneous melanoma patients treated with immune checkpoint inhibitors (ICIs). We conducted a single-center, retrospective study involving stage IV cutaneous melanoma patients who received ICI as first-line therapy. MHC-II expression in melanoma cells was quantified using dual-color anti-SOX10 and anti-MHC-II immunohistochemistry on tumor samples from 95 patients. The primary endpoint was event-free survival (EFS), with secondary endpoints including 1-year EFS, 1-year overall survival (OS), disease control rate (DCR), and the correlation between MHC-II expression and clinico-biological characteristics. The cohort had a median age of 67 years (range, 33-90), with a male-to-female ratio of 50 : 45. Thirty-three percent of patients received the ipilimumab-nivolumab combination. The median follow-up was 16.8 months. Disease progression occurred in 58 patients (61%), with a median time to progression of 4.8 months. Forty-six patients (48.4%) experienced an event within the first year, and 52 patients (54.7%) died during follow-up. MHC-II positivity was observed in ≥10% of melanoma cells in 6.3% of patients. MHC-II expression was significantly associated with 1-year EFS ( P  = 0.037) and DCR ( P  = 0.032), but not with EFS or 1-year OS. Age, phototype, and brain metastases were correlated with MHC-II expression status. Our findings suggest that MHC-II expression by melanoma cells may serve as a favorable predictive biomarker for survival in metastatic cutaneous melanoma patients treated with ICIs.

Esophageal squamous carcinoma (ESCC) is a common malignant tumor of the gastrointestinal tract with high morbidity and mortality rates. Lymphocyte activation gene-3 (LAG3), an important suppressive immune checkpoint in tumor immunity, exhibits a wobbling effect in the prediction of ESCC efficacy.

Tumor bite paraffin-embedded specimens from 84 patients diagnosed with ESCC, all of whom received radical concurrent chemoradiotherapy (CCRT) at our institution, were screened. For each tissue, we delineated the partitions and analyzed the spatial distribution of the tumor in an in situ immune microenvironment. The density and regional characteristics of immune factor-positive cells, together with the dynamics of various cells based on treatment regimens, were considered important factors influencing the prognostic significance of cancer.

Compared with baseline tissues, the density of CD4 + and CD8 + T cells in the tumor microenvironment of the on-treatment tissues decreased, but the expression of IFN-γ in CD4 + and CD8 + T cells increased. The density of LAG3 positive cells was correlated significantly with the density of CD4 + and CD8 + T cells in both baseline and on-treatment tissues. The density of LAG3 + T cells and the rate of LAG3 positivity in activated CD4 + and CD8 + T cells were associated with elevated Ki67 expression. There was a significant correlation between high LAG3 expression and active CD4 + and CD8 + T cells in tumor cells. Elevated densities and tighter spatial relationships of both CD4 + and CD8 + T cells were associated with longer overall survival with ESCC.

Concurrent chemoradiotherapy without combined immunotherapy inhibited tumor-infiltrating T cells to a certain extent, and elevated immune checkpoint LAG3 was closely associated with immune activation in the ESCC tumor microenvironment.

Lung cancer remains the second leading cause of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line therapy for advanced NSCLC with EGFR mutations, offering significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to chemotherapy alone. Recent studies suggest that their effectiveness decreased with the emergence of acquired resistance, such as C797S and T790M. Immunotherapy alone also shows enhanced PFS and OS over chemotherapy; however, its applicability can be limited in cases with low programmed cell death ligand 1 (PD-L1) expression and result in immune-related adverse effects like those observed in retrospective, non-randomized studies. Emerging fourth-generation EGFR-TKIs, currently under clinical trials, show promising potential to address these resistance mechanisms. Advanced inhibitors, including BBT-176, BLU-945, and BLU-701, have effectively targeted resistant mutations and reduced disease progression. Studies have suggested that combining fourth-generation EGFR-TKIs with immunotherapies targeting novel pathways like LAG-3 and TIM-3 may enhance patient outcomes. Such combination regimens aim to optimize PFS, OS, and ORR while minimizing adverse effects and addressing the limitations of current therapies. This study explores the landscape of EGFR mutations, their clinical significance, and the integration of innovative fourth-generation EGFR-TKIs with immunotherapies, emphasizing the potential of precision medicine in advancing the management of EGFR-mutated NSCLC.

V-set and immunoglobulin domain containing 4 (VSIG4) is a B7-family-related protein almost exclusively expressed on macrophages. The difference in its expression mediates the dynamic transformation of the polarization state of macrophages, but the underlying mechanism is still unclear. We sought to reveal the correlation between VSIG4 and the polarization of tumour-associated macrophages (TAMs) and the immune escape of tumour cells in colorectal cancer (CRC).

THP-1 monocyte-derived macrophages expressing different levels of VSIG4 were used for in vitro investigations. In addition, the co-culture system was used to verify the effect of tumour cells on the expression of VSIG4 in macrophages, and the effect of VSIG4 expression level on tumour cells in turn. Subcutaneous xenograft models evaluated the tumour growth inhibition efficacy of VSIG4 blockade as monotherapy and combined with immune checkpoint inhibitors (ICIs).

CRC cells secreted lactate to promote VSIG4 expression in macrophages. On the contrary, VSIG4 promoted macrophage M2 polarization and induced malignant progression of tumour cells by promoting M2 macrophage secretion of heparin-bound epidermal growth factor. In vivo experiments confirmed that knockdown VSIG4 inhibited tumour growth and improved the efficacy of ICIs therapy. Mechanistically, lactate secreted by CRC cells promoted its expression by influencing the epigenetic modification of VSIG4 in macrophages. In addition, VSIG4 enhanced the fatty acid oxidation (FAO) of macrophages and upregulated PPAR-γ expression by activating the JAK2/STAT3 pathway, which ultimately induced M2 polarization of macrophages. Downregulation of VSIG4 or blocking of FAO reversed the M2 polarization process of macrophages.

Our findings provide a molecular basis for VSIG4 to influence TAMs polarization by regulating the reprogramming of FAO, suggesting that targeting VSIG4 in macrophages could enhance the ICIs efficacy and represent a new combination therapy strategy for immunotherapy of CRC.

Colorectal cancer cells secrete lactate to upregulate VSIG4 in macrophages via the H3K18la-METTL14-m6A axis. VSIG4 promotes fatty acid oxidation of macrophages and drives its M2-type polarization. These VSIG4-expressing M2 macrophages promote tumour progression and an immunosuppressive microenvironment. Inhibition of VSIG4 expression can synergistically enhance the therapeutic effect of anti-PD-1 antibody.

The development of immune checkpoint inhibitors has revolutionized the treatment of patients with cancer. Targeting the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1(PD-L1) interaction using monoclonal antibodies has emerged as a prominent focus in tumor therapy with rapid advancements. However, the efficacy of anti-PD-1/PD-L1 treatment is hindered by primary or acquired resistance, limiting the effectiveness of single-drug approaches. Moreover, combining PD-1/PD-L1 with other immune drugs, targeted therapies, or chemotherapy significantly enhances response rates while exacerbating adverse reactions. Multispecific antibodies, capable of binding to different epitopes, offer improved antitumor efficacy while reducing drug-related side effects, serving as a promising therapeutic approach in cancer treatment. Several bispecific antibodies (bsAbs) targeting PD-1/PD-L1 have received regulatory approval, and many more are currently in clinical development. Additionally, tri-specific antibodies (TsAbs) and tetra-specific antibodies (TetraMabs) are under development. This review comprehensively explores the fundamental structure, preclinical principles, clinical trial progress, and challenges associated with bsAbs targeting PD-1/PD-L1.

Lymphocyte activation gene 3 (LAG3) has emerged as a promising cancer immunotherapy target, but the mechanism underlying LAG3 activation upon ligand engagement remains elusive. Here, LAG3 was found to undergo robust non-K48-linked polyubiquitination upon ligand engagement, which promotes LAG3's inhibitory function instead of causing degradation. This ubiquitination could be triggered by the engagement of major histocompatibility complex class II (MHC class II) and membrane-bound (but not soluble) fibrinogen-like protein 1 (FGL1). LAG3 ubiquitination, mediated redundantly by the E3 ligases c-Cbl and Cbl-b, disrupted the membrane binding of the juxtamembrane basic residue-rich sequence, thereby stabilizing the LAG3 cytoplasmic tail in a membrane-dissociated conformation enabling signaling. Furthermore, LAG3 ubiquitination is crucial for the LAG3-mediated suppression of antitumor immunity in vivo. Consistently, LAG3 therapeutic antibodies repress LAG3 ubiquitination, correlating with their checkpoint blockade effects. Moreover, patient cohort analyses suggest that LAG3/CBL coexpression could serve as a biomarker for response to LAG3 blockade. Collectively, our study reveals an immune-checkpoint-triggering mechanism with translational potential in cancer immunotherapy.

The introduction of immunotherapy and target therapy into clinical practice has become a chance for many patients with cancer to prolong their survival while maintaining optimal quality of life. Treatment of lung cancer is excellent evidence of the progress of medical therapies. An understanding of the mechanisms of tumor development has led to the evolution of new methods of treatment. Immunoreceptors of T cells with the immunoglobulin domain ITIM, TIM-3 (T-cell immunoglobulin- and mucin domain-3-containing molecule 3), and LAG-3 (lymphocyte activation gene-3) represent new interesting therapeutic targets. The combination of anti-PD-1 and anti-CTLA-4 blockade has proven the possibility of strengthening the anti-tumor response by acting via two separate mechanisms. Adding additional checkpoints to the PD-1 blockade offers hope for further improvements in the effects of the treatment of patients and expanding the group responding to immunotherapy. This paper presents new promising molecular targets along with studies demonstrating the treatment results using them.

Background/Objectives: Peripheral neuroblastic tumors (pNT) are a biologically heterogeneous group of embryonal tumors that derive from the neural crest and affect the sympathetic nervous system. So far, little is known about the complex immune landscape in these rare childhood cancers. Methods: We focused on the immune cell infiltrate of treatment-naïve pNT from 24 patients, including high-risk neuroblastoma (HR-NBL), non-high-risk neuroblastoma (NHR-NBL), ganglioneuroblastoma (GNBL), and rare ganglioneuroma (GN). To gain novel insights into the immune architecture of these pNT subtypes, we used multiplex immunohistochemistry, multispectral imaging, and algorithm-based data evaluation to detect and characterize T cells, B cells, neutrophils, macrophages, and tertiary lymphoid structures (TLS). Results: The majority of the investigated tumor-infiltrating immune cells were macrophages and T cells. Their detailed phenotypic characterization revealed high proportions of M2-like macrophages as well as activated GrzB+ CD8+ and PD-1+ T lymphocytes. Proportions of these T cell phenotypes were significantly increased in GN compared to HR-NBL, NHR-NBL, or GNBL. In addition, TLS occurred in 11 of 24 patients, independent of immune cell frequencies in the whole tissues. Interestingly, all GN, most GNBL, but only a few NBL contained TLS. We distinguished between three TLS maturation stages that were present irrespective of the pNT subtype. The majority belonged to mature TLS of the primary follicle state. Mature LAMP3+ dendritic cells were also found, predominantly in T cell zones of TLS. Furthermore, TLS presence identified pNT patients with significantly prolonged progression-free survival in contrast to all other analyzed immunological features. Conclusions: We propose TLS to be a potential prognostic marker for pNT to predict patient outcomes.

Cancer is responsible for nearly one in six global fatalities, making it a major health issue worldwide. Despite advancements in early detection, surgery, and targeted therapies, effective treatment remains challenging due to the complexity and heterogeneity of the disease. A key factor in cancer progression and resistance to treatment is the tumor microenvironment (TME). It is a complex ecosystem comprising cancer cells, stromal cells, immune cells, extracellular matrix (ECM), and soluble factors like cytokines and chemokines. These components interact dynamically to influence tumor growth, metastasis, immune evasion, and treatment resistance. Cancer cells drive the formation of the TME by releasing signaling molecules, while stromal cells, such as fibroblasts and endothelial cells, support tumor metabolism, angiogenesis, and invasion. Immune cells within the TME can either suppress or promote tumor progression, depending on their activation state. Additionally, the TME can promote the growth of immunosuppressive cells that aid cancer cells in evading immune surveillance, such as regulatory T-cells and myeloid-derived suppressor cells. The TME also impedes drug delivery by creating defective blood vessels, contributing to drug resistance. Recent technological advancements have deepened our understanding of the TME, revealing its role in immune modulation, metabolism, and extracellular matrix remodeling. As a result, targeting the TME has become a promising strategy to overcome treatment resistance and improve cancer therapy outcomes.

Oral cancer, a prevalent form of head and neck malignancy, accounts for 4% of global cancer cases. The most common type, oral squamous cell carcinoma (OSCC), has a survival rate of about 50%. Even though emerging molecular therapies show promise for managing oral cancer, current treatments like surgery, radiotherapy, and chemotherapy have significant side effects. In addition, the complex tumor microenvironment (TME), involving the extracellular matrix (ECM) and cells like fibroblasts and stromal cells like immune cells, promotes tumor growth and inhibits immune responses, complicating treatment. Nonetheless, immunotherapy is crucial in cancer treatment, especially in oral cancers. Indeed, its effectiveness lies in targeting immune checkpoints such as PD-1 and CTLA-4 inhibitors, as well as monoclonal antibodies like pembrolizumab and cetuximab, adoptive cell transfer methods (including CAR-T cell therapy), cytokine therapy such as IL-2, and tumor vaccines. Thus, these interventions collectively regulate tumor proliferation and metastasis by targeting the TME through autocrine-paracrine signaling pathways. Immunotherapy indeed aims to stimulate the immune system, leveraging both innate and adaptive immunity to counteract cancer cell signals and promote tumor destruction. This review will explore how the TME controls tumor proliferation and metastasis via autocrine-paracrine signaling pathways. It will then detail the effectiveness of immunotherapy in oral cancers, focusing on immune checkpoints, targeted monoclonal antibodies, adoptive cell transfer, cytokine therapy, and tumor vaccines.

The widespread use of immune checkpoint inhibitors (anti-CTLA4 or PD-1) has opened a new chapter in tumor immunotherapy by providing long-term remission for patients. Unfortunately, however, these agents are not universally available and only a minority of patients respond to them. Therefore, there is an urgent need to develop novel therapeutic strategies targeting other co-inhibitory molecules. However, comprehensive information on the expression and prognostic value of co-inhibitory molecules, including co-inhibitory receptors and their ligands, in different cancers is not yet available.

We investigated the expression, correlation, and prognostic value of co-inhibitory molecules in different cancer types based on TCGA, UCSC Xena, TIMER, CellMiner datasets. We also examined the associations between the expression of these molecules and the extent of immune cell infiltration. Besides, we conducted a more in-depth study of VISTA.

The results of differential expression analysis, correlation analysis, and drug sensitivity analysis suggest that CTLA4, PD-1, TIGIT, LAG3, TIM3, NRP1, VISTA, CD80, CD86, PD-L1, PD-L2, PVR, PVRL2, FGL1, LGALS9, HMGB1, SEMA4A, and VEGFA are associated with tumor prognosis and immune cell infiltration. Therefore, we believe that they are hopefully to serve as prognostic biomarkers for certain cancers. In addition, our analysis indicates that VISTA plays a complex role and its expression is related to TMB, MSI, cancer cell stemness, DNA/RNA methylation, and drug sensitivity.

These co-inhibitory molecules have the potential to serve as prognostic biomarkers and therapeutic targets for a broad spectrum of cancers, given their strong associations with key clinical metrics. Furthermore, the analysis results indicate that VISTA may represent a promising target for cancer therapy.

Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade (ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified; some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration (FDA) for clinical treatment. However, limited responses and immune-related adverse events (irAEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.

Head and neck squamous cell carcinoma (HNSC) ranks among the most prevalent cancers worldwide, characterized by significant heterogeneity and a complex immune microenvironment. T cell exhaustion is pivotal in the pathogenesis of HNSC, where depleted T cells exhibit reduced proliferative capacity and diminished effector function, facilitating tumor immune escape and subsequent disease progression. A thorough understanding of the primary mechanisms driving T cell depletion within the tumor microenvironment is essential for enhancing the efficacy of immunotherapeutic approaches in HNSC, with profound implications for patient outcomes. In this study, a single-cell atlas of HNSC was constructed, enabling an in-depth analysis of T cell heterogeneity. The differentiation trajectory of T cells, transitioning from normal tissue to HNSC, was characterized, revealing a predisposition toward depletion in the C2 T cell subgroup. A subsequent cross-analysis of significantly upregulated differentially expressed genes in the C2 T cell subset identified five characteristics pertinent to T cell C2, which informed the development of a clinical prognostic model. Additionally, maximum half inhibitory concentration (IC50) values for various pharmacological agents were calculated, leading to the identification of eleven drugs relevant to the risk model, providing an intriguing starting point for further work in personalized cancer treatment. However, certain limitations of this study must be acknowledged. While T cell heterogeneity and differentiation trajectories were mapped, the interrelationships among these subpopulations remain poorly understood. Further research is required to elucidate the specific biological processes and molecular evolutionary mechanisms involved. The insights from this study provide a valuable foundation for future investigations into the molecular mechanisms and immune landscape associated with the progression from normal tissue to malignant squamous cell carcinoma.

In oncology drug development, measuring drug concentrations at the tumor site and at the targeted receptor remains an ongoing challenge. Positron emission tomography (PET)-imaging is a promising noninvasive method to quantify intratumor exposure of a radiolabeled drug (biodistribution data) and target saturation by treatment doses in vivo. Here, we present the development and application of a minimal physiologically-based pharmacokinetic (mPBPK) modeling approach to integrate biodistribution data in a quantitative platform to characterize and predict intratumor exposure and receptor occupancy (RO) of BI 754111, an IgG-based anti-lymphocyte-activation gene 3 (LAG-3) monoclonal antibody (mAb). Specifically, calibration and qualification of the predictions were performed using 89Zr-labeled BI 754111 biodistribution data, that is, PET-derived intratumor drug concentration data, tumor-to-plasma ratios, and data from Patlak analyses. The model predictions were refined iteratively by the inclusion of additional biological processes into the model structure and the use of sensitivity analyses to assess the impact of model assumptions and parameter uncertainty on the predictions and model robustness. The developed mPBPK model allowed an adequate description of observed tumor radioactivity concentrations and tumor-to-plasma ratios leading to subsequent adequate prediction of LAG-3 RO at different dose levels. In the future, the developed model could be used as a platform for the prediction and analysis of biodistribution data for other mAbs and may ultimately support dose optimization by identifying dosages resulting in saturated RO.

Colorectal cancer (CRC) is known for its high heterogeneity, with liver metastases significantly impairing survival outcomes. Understanding the tumor microenvironment (TME) and genomic alterations in metastatic sites is crucial for developing personalized therapies that overcome drug resistance and improve prognosis.

We profiled 54 CRC liver metastases, comparing them with 198 other metastatic lesions and normal liver tissues. By analyzing immune cell infiltration, stromal interactions, and key genomic alterations, we constructed an 11-gene prognostic model to predict survival and immunotherapy outcomes.

CRC liver metastases with high-risk profiles demonstrated enriched follicular helper T cells, activated dendritic cells, and M2 macrophages in the TME. Frequent mutations in APC, TP53, KRAS, and PIK3CA were identified, alongside altered EGFR signaling. The 11-gene model effectively stratified patients by prognosis and predicted immunotherapy responses, emphasizing the therapeutic potential of targeting resistance mechanisms.

This study reveals how genomic and TME-driven factors contribute to drug resistance in CRC liver metastases. Integrating these insights with clinical data could advance precision therapies, addressing the evolving challenge of tumor drug resistance in CRC.

The Golgi apparatus (GA) serves as the center of protein and lipid synthesis and modification within cells, playing a crucial role in regulating diverse cellular processes as a signaling hub. Dysregulation of GA function can give rise to a range of pathological conditions, including tumors. Notably, mutations in Golgi-associated genes (GARGs) are frequently observed in various tumors, and these mutations have been implicated in promoting tumor metastasis. However, the precise relationship between GARGs and glioma, a type of brain tumor, remains poorly understood. Therefore, the objective of this investigation was to assess the prognostic significance of GARGs in glioma and evaluate their impact on the immune microenvironment.

The expression of GARGs was obtained from the TCGA and CGGA databases, encompassing a total of 1564 glioma samples (598 from TCGA and 966 from CGGA). Subsequently, a risk prediction model was constructed using LASSO regression and Cox analysis, and its efficacy was assessed. Additionally, qRT-PCR was employed to validate the expression of GARGs in relation to glioma prognosis. Furthermore, the association between GARGs and immunity, mutation, and drug resistance was investigated.

A selection of GARGs (SPRY1, CHST6, B4GALNT1, CTSL, ADCY3, GNL1, KIF20A, CHP1, RPS6, CLEC18C) were selected through differential expression analysis and Cox analysis, which were subsequently incorporated into the risk model. This model demonstrated favorable predictive efficiency, as evidenced by the area under the curve (AUC) values of 0.877, 0.943, and 0.900 for 1, 3, and 5-year predictions, respectively. Furthermore, the risk model exhibited a significant association with the tumor immune microenvironment and mutation status, as well as a diminished sensitivity to chemotherapy drugs. qRT-PCR analysis confirmed the up-regulation or down-regulation of the aforementioned genes in glioma.

The utilization of GARGs in our constructed model exhibits a high level of accuracy in prognosticating glioma and offers promising avenues for the development of therapeutic interventions targeting glioma.

Cancer immunotherapy, leveraging antibodies, excels in targeting efficacy but faces hurdles in tissue penetration, oral delivery, and prolonged half-life, with costly production and risk of adverse immunogenic effects. In contrast, small molecule immuno-oncology agents provide favorable pharmacokinetic properties and benign toxicity profiles. These agents are well-positioned to address the limitations of antibody-based immunotherapies, augment existing treatment modalities, and achieve synergistic effects when combined with antibodies. This review, for the first time, summarizes the recent advances (2020-2024) in small molecule inhibitors targeting PD-1/PD-L1, CTLA4, VISTA, TIM-3, and LAG3, highlighting rational design, benefits, and potential limitations. It also outlines the prospects for small-molecule immunotherapy.

Despite the high response rate to PD-1 blockade therapy in metastatic melanoma (MM) patients, a significant proportion of patients do not respond. Identifying biomarkers to predict patient response is crucial, ideally through non-invasive methods such as liquid biopsy.

Soluble forms of PD1, PD-L1, LAG-3, CTLA-4, CD4, CD73, and CD74 were quantified using ELISA assay in plasma of a cohort of 110 MM patients, at baseline, to investigate possible correlations with clinical outcomes. A clinical risk prediction model was applied and validated in pilot studies.

No biomarker showed statistically significant differences between responders and non-responders. However, high number of significant correlations were observed among certain biomarkers in non-responders. Through univariate and multivariate Cox analyses, we identified sPD-L1, sCTLA-4, sCD73, and sCD74 as independent biomarkers predicting progression-free survival and overall survival. According to ROC analysis we discovered that, except for sCD73, values of sPD-L1, sCTLA-4, and sCD74 lower than the cut-off predicted lower disease progression and reduced mortality. A comprehensive risk score for predicting progression-free survival was developed by incorporating the values ​​of the two identified independent factors, sCTLA-4 and sCD74, which significantly improved the accuracy of outcome prediction. Pilot validations highlighted the potential use of the risk score in treatment-naive individuals and long responders.

In summary, risk score based on circulating sCTLA-4 and sCD74 reflects the response to immune checkpoint inhibitor (ICI) therapy in MM patients. If confirmed, through further validation, these findings could assist in recommending therapy to patients likely to experience a long-lasting response.

Immune checkpoint inhibitor (ICI) therapy represents a ground-breaking paradigm in cancer treatment, harnessing the immune system to combat malignancies by targeting checkpoints such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). The use of ICI therapy generates distinctive immune-related adverse events (irAEs) including cardiovascular toxicity, necessitating targeted research efforts. This comprehensive review explores preclinical models dedicated to ICI-mediated cardiovascular complications including myocarditis. Tailored preclinical models of ICI-mediated myocardial toxicities highlight the key role of CD8+ T cells, emphasizing the profound impact of immune checkpoints on maintaining cardiac integrity. Cytokines and macrophages were identified as possible driving factors in disease progression, and at the same time, initial data on possible cardiac antigens responsible are emerging. The implications of contributing factors including thoracic radiation, autoimmune disorder, and the presence of cancer itself are increasingly understood. Besides myocarditis, mouse models unveiled an accelerated progression of atherosclerosis, adding another layer for a thorough understanding of the diverse processes involving cardiovascular immune checkpoint signalling. This review aims to discuss current preclinical models of ICI cardiotoxicity and their potential for improving enhanced risk assessment and diagnostics, offering potential targets for innovative cardioprotective strategies. Lessons from ICI therapy can drive novel approaches in cardiovascular research, extending insights to areas such as myocardial infarction and heart failure.

Brain metastasis leads to poor outcomes and CNS injury, significantly reducing quality of life and survival rates. Advances in understanding the tumor immune microenvironment have revealed the promise of immunotherapies, which, alongside surgery, chemotherapy, and radiation, offer improved survival for some patients. However, resistance to immunotherapy remains a critical challenge. This review explores the immune landscape of brain metastases, current therapies, clinical trials, and the need for personalized, biomarker-driven approaches to optimize outcomes.

Skin cancer is the most common new cancer among Caucasians. This cancer has different types, of which non-melanoma skin cancer is the most common type. Various factors affect this disease, one of which is viral infections, including HPV. This virus plays an important role in skin cancer, especially cSCCs. There are various options for the treatment of skin cancer, and today special attention has been paid to treatments based on therapeutic goals, immunotherapy and combination therapy. In this study, we have investigated treatments based on immunotherapy and virotherapy and the effect of HPV virus on the effectiveness of these treatments in skin cancer. Treatments based on virotherapy are performed for a long time in combination with other common treatments such as radiotherapy and chemotherapy in order to have a greater effect and lower its side effects, which include: shortness of breath, tachycardia, lowering blood pressure in the patient. Also, the most important axis of immunotherapy is to focus on PD1-PDL1, despite abundant evidence on the importance of immunotherapy, many studies investigate the use of immunotherapy inhibitors in the adjuvant and neoadjuvant setting in various cancers. Also, previous findings show conflicting evidence of the effect of HPV status on the response to immunotherapy.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly half of all patients diagnosed at an advanced stage. Immune checkpoint inhibitors (ICIs) harness the host immune system to combat malignant cells. ICIs, which target programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), and cytotoxic T-cell lymphocyte-4 (CTLA-4), have transformed the treatment landscape for advanced NSCLC. While a subset of patients experiences a long-term durable response, most patients will develop disease progression. New drugs targeting novel pathways are being tested in clinical trials to improve the efficacy of immunotherapy and overcome resistance patterns. This review aims to summarize the currently available ICIs for advanced NSCLC and describe emerging immunotherapies with recently published data from phase I/II clinical trials.

Cancer immunotherapy-including immune checkpoint inhibition (ICI) and adoptive cell therapy (ACT)-has become a standard, potentially curative treatment for a subset of advanced solid and liquid tumors. However, most patients with cancer do not benefit from the rapidly evolving improvements in the understanding of principal mechanisms determining cancer immune responsiveness (CIR); including patient-specific genetically determined and acquired factors, as well as intrinsic cancer cell biology. Though CIR is multifactorial, fundamental concepts are emerging that should be considered for the design of novel therapeutic strategies and related clinical studies. Recent advancements as well as novel approaches to address the limitations of current treatments are discussed here, with a specific focus on ICI and ACT.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Cancer treatment has entered the age of immunotherapy. Immune checkpoint inhibitor (ICI) therapy has shown robust therapeutic potential in clinical practice, with significant improvements in progression-free survival (PFS) and overall survival (OS). Recently, checkpoint blockade of the lymphocyte activation gene 3 (LAG3) inhibitory receptor (IR) in combination with programmed death protein 1 (PD1) inhibition has been FDA approved in patients with advanced melanoma. This has encouraged the clinical evaluation of new LAG3-directed biologics in combination with other checkpoint inhibitors. Several of these studies are evaluating bispecific antibodies that target exhausted T (TEX) cells expressing multiple IRs. This review discusses the current understanding of LAG3 in regulating antitumor immunity and the ongoing clinical testing of LAG3 inhibition in cancer.

Distant metastasis occurs in the majority of adrenocortical carcinoma (ACC), leading to an extremely poor prognosis. However, the key genes driving ACC metastasis remain unclear.

Weighted gene co-expression network analysis (WGCNA) and functional enrichment analysis were conducted to identify ACC metastasis-related genes. Data from RNA-seq and microarray were analyzed to reveal correlations of the CENPM gene with cancer, metastasis, and survival in ACC. Immunohistochemistry was used to assess CENPM protein expression. The impact of CENPM on metastasis behaviour was verified in ACC (H295R and SW-13) cells and xenograft NPG mice. DIA quantitative proteomics analysis, western blot, immunofluorescence, and co-immunoprecipitation assay were performed to identify the downstream target of CENPM.

Among the 12 035 analyzed genes, 363 genes were related to ACC metastasis and CENPM was identified as the hub gene. CENPM was upregulated in ACC samples and associated with metastasis and poor prognosis. Knockdown of CENPM inhibited proliferation, invasion, and migration of ACC cells and suppressed liver metastasis in xenograft NPG mice. Collagen-containing extracellular matrix signalling was primarily downregulated when CENPM was knocked down. FGL1, important components of ECM signalling and immune checkpoint ligand of LAG3, were downregulated following CENPM silence, overexpressed in human advanced ACC samples, and colocalized with CENPM. Physical interaction between CENPM and FGL1 was identified. Overexpression of FGL1 rescued migration and invasion of CENPM knockdown ACC cells.

CENPM is a key gene in driving ACC metastasis. CENPM promotes ACC metastasis through physical interaction with the immune checkpoint ligand FGL1. CENPM can be used as a new prognostic biomarker and therapeutic target for metastatic ACC.

CENPM is the key gene that drives ACC metastasis, and a robust biomarker for ACC prognosis. Silencing CENPM impedes ACC metastasis in vitro and in vivo by physical interaction with immune checkpoint ligand FGL1. FGL1 is overexpressed in ACC and promotes ACC metastasis.

Alcohol-associated hepatitis (AH) has a short-term mortality rate of up to 40% primarily related to impaired hepatocyte regeneration and uncontrolled liver inflammation. The acute phase protein fibrinogen-like protein 1 (FGL-1) produced by hepatocytes stimulates hepatocyte proliferation by autocrine signaling. FGL-1 also is a ligand for the inhibitory T cell receptor lymphocyte activation gene 3 (LAG-3). In these ways, FGL-1 and LAG-3 have beneficial interactions that could be interrupted in AH.

We aimed to characterize FGL-1 and LAG-3 in patients with AH and describe their relationship with the disease state and course.

Thirty-two patients with AH were included at diagnosis and followed up for 3 years. We measured the hepatic gene expression of FGL-1 and LAG-3 using RNA sequencing, plasma FGL-1 and soluble (s)LAG-3 using ELISA, and LAG-3+CD8+ T cells using flow cytometry. Healthy persons (HC) and patients with stable alcohol-associated cirrhosis served as controls.

At diagnosis of AH, liver FGL-1 mRNA was increased when compared to HC, whereas plasma FGL-1 was unchanged. In contrast, liver LAG-3 mRNA was reduced in AH. Plasma sLAG-3 levels and the frequency of LAG-3+CD8+ T cells were as in HC. However, those patients who had the lowest plasma FGL-1 and the lowest frequency of LAG-3+CD8+ T cells at diagnosis had the highest disease severity and mortality.

Our data suggest that an impaired FGL-1/LAG-3 axis may be involved in the pathogenesis and course of AH.

LAG3 plays a regulatory role in immunity and emerged as an inhibitory immune checkpoint molecule comparable to PD-L1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. We generated 3D cancer cultures as a model to identify novel molecular biomarkers for the selection of patients suitable for α-LAG3 treatment and simultaneously the possibility to perform an early diagnosis due to its higher presence in breast cancer, also to achieve a theragnostic approach. Our data confirm the extreme dysregulation of LAG3 in breast cancer with significantly higher expression in tumor tissue specimens, compared to non-cancerous tissue controls. LAG3 blockade inhibited proliferation of in vitro and ex vivo 3D human organoids and immune micro-environment through both a decrease of PD-L1, TIM-3 and CTLA4 expression and an increased production of several pro-inflammatory cytokines (IFNγ, IL-12, IL-6, IL-1β, TNFα) and EMT markers. These effects trigger a more permissive anti-tumor immune reaction, recruiting immune cells to the tumor sites, boosting the anti-tumor response. LAG3 acts as an immunosuppressive molecule in breast cancer, inhibiting T CD8 + cell proliferation and cytokine production by T cells. We proposed the modulation of a novel checkpoint molecule, such as LAG3, as potential biomarkers associated to a rapid diagnosis.

Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.