Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells.

Liver cancer, more specifically hepatocellular carcinoma (HCC), is a global health issue and one of the dominant causes of cancer death around the world. In the past few decades, remarkable advances have been achieved in the systemic therapy of HCC. Immune checkpoint inhibitors (ICIs) have become a therapy mainstay for advanced HCC and have shown promise in the neoadjuvant therapy before resection. Despite these significant advancements, the compositions and functions of the immune system occur various alterations with age, called "immunosenescence", which may affect the antitumor effects and safety of ICIs, thus raising concerns that immunosenescence may impair elderly patients' response to ICIs. Therefore, it is important to learn more about the immunosenescence characteristics of elderly patients. However, the real-world elderly HCC patients may be not accurately represented by the elderly patients included in the clinical trials, affecting the generalizability of the efficacy and safety profiles from the clinical trials to the real-world elderly patients. This review summarizes the characteristics of immunosenescence and its influence on HCC progression and immunotherapy efficacy as well as provides the latest progress in ICIs available for HCC and discusses their treatment efficacy and safety on elderly patients. In the future, more studies are needed to clarify the mechanisms of immunosenescence in HCC, and to find sensitive screening tools or biomarkers to identify the patients who may benefit from ICIs.

Head and neck squamous cell carcinoma (HNSCC) ranks among the most prevalent cancers globally, and despite improvements in treatment options such as surgery and radiotherapy, its survival rate remains low. With increased research in immunotherapy, antibodies against various immune checkpoints like programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have been shown to be effective against a wide range of tumors. Nonetheless, survival benefits gained by HNSCC patients remain limited. T-cell immunoglobulin mucin-3 (TIM-3), an emerging immune checkpoint molecule, is found to be expressed in HNSCC and is involved in shaping the tumor immune microenvironment (TIME). TIM-3 is significant in the initiation and progression of HNSCC by modulating effector T cells, innate immune cells, and other components of the immune system. Inhibiting TIM-3 can restore T cell function and enhance the immune response against HNSCC, making it a promising immunotherapeutic target for this disease. This article reviews the expression of TIM-3 in HNSCC and its immunomodulatory mechanism and briefly introduces the combined application and development prospects of TIM-3 as a potential immunotherapeutic target.

Immunosenescence is the dysfunction of the immune system that occurs with age, a process that is complex and characterized by several features, of which T-cell senescence is one of the key manifestations. In the tumor microenvironment, senescent T cells lead to the inability of tumor cells to be effectively eliminated, triggering immunosuppression, which in turn affects the efficacy of immunotherapy. This is a strong indication that T-cell senescence significantly weakens the immune function of the body, making individuals, especially elderly patients with cancer, more vulnerable to cancer attacks. Despite the many challenges, T-cell senescence is important as a potential therapeutic target. This review provides insights into the molecular mechanisms of T-cell senescence and its research advances in patients with cancer, especially in older adults, and systematically analyzes potential intervention strategies, including molecular mechanism-based interventions, the use of immune checkpoint inhibitors, and CAR-T cell therapy. It is hoped that this will establish a theoretical framework for T-cell senescence in the field of tumor immunology and provide a scientific and prospective reference basis for subsequent in-depth research and clinical practice on senescent T cells.

Immunotherapy using immune checkpoint inhibitors (ICIs) has become a prominent strategy for cancer treatment over the past ten years. However, the efficacy of ICIs remains limited, with certain cancers exhibiting resistance to these therapeutic approaches. Consequently, several immune checkpoint proteins are presently being thoroughly screened and assessed in both preclinical and clinical studies. Among these candidates, T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is considered a promising target. TIM-3 exhibits multiple immunosuppressive effects on various types of immune cells. Given its differential expression levels at distinct stages of T cell dysfunction in the tumor microenvironment (TME), TIM-3, along with programmed cell death protein 1 (PD-1), serves as indicators of T cell exhaustion. Moreover, it is crucial to carefully evaluate the impact of TIM-3 and PD-1 expression in cancer cells on the efficacy of immunotherapy. To increase the effectiveness of anti-TIM-3 and anti-PD-1 therapies, it is proposed to combine the inhibition of TIM-3, PD-1, and programmed death-ligand 1 (PD-L1). The efficacy of TIM-3 inhibition in conjunction with PD-1/PD-L1 inhibitors is being evaluated in a number of ongoing clinical trials for patients with various cancers. This study systematically investigates the fundamental biology of TIM-3 and PD-1, as well as the detailed mechanisms through which TIM-3 and PD-1/PD-L1 axis contribute to cancer immune evasion. Additionally, this article provides a thorough analysis of ongoing clinical trials evaluating the synergistic effects of combining PD-1/PD-L1 and TIM-3 inhibitors in anti-cancer treatment, along with an overview of the current status of TIM-3 and PD-1 antibodies.

Galectins are a family of β-galactosides-binding protein, crucial regulators of host-virus interactions. They achieve this by recognizing specific glycan patterns on viral surfaces or mediating interactions with intracellular viral or host proteins, subsequently influencing the critical phases of the viral life cycle, such as attachment, replication, immune evasion, and reactivation. Furthermore, galectins modulate host immune responses, shaping the progression and outcomes of viral infections. This review comprehensively examines the roles of both endogenous and exogenous galectins in viral infections, noting that only a few galectins, including Galectin-1, -3, -4, -7, -8, and -9, Have been identified as key players in viral infection. Notably, Galectin-1, -3, and -9 play diverse functions in both DNA and RNA viral infection. Emerging evidence highlights the potential of Galectin-4 and -8 as intracellular sensors and modulators of viral pathogenesis. Endogenous galectins, produced by host cells, act through both glycan-dependent and glycan-independent mechanisms, influencing viral processes and immune responses. Exogenous galectins, which are secreted by other cells or administered as recombinant proteins, can either enhance or counteract the actions of endogenous galectins. The functions of galectins are virus-specific and context-dependent, serving as either promoters or inhibitors of viral replication and reactivation. Dysregulation of galectin expression is often linked to disease progression, highlighting their potential as diagnostic and prognostic biomarkers, as well as therapeutic targets. The important and varied roles that galectins play in viral infections are highlighted in this review, which also provides fresh insights into host-pathogen interactions and the development of antiviral tactics.

The tumor microenvironment (TME) of hepatocellular carcinoma (HCC) has garnered significant attention, especially with the rise of immunotherapy as a treatment strategy. Radiomics, an innovative technique, offers valuable insights into the intricate structure of the TME. This review highlights recent advancements in radiomics for analyzing the HCC TME, identifies key areas that warrant further research, and explores comprehensive multi-omics approaches that extend the potential of radiomics to new frontiers.

The precise role of Galectin-9, an immune checkpoint protein involved in immune responses, in hepatocellular carcinoma (HCC) remains elusive. Importantly, the prognostic value of serum Galectin-9 has not been clarified, and its association with infiltrating immune characteristics was unclear.

The association between serum Galectin-9 concentration and HCC recurrence was analyzed in two cohorts of HCC patients (training 133; validation 97) who received curative resection during 2018 and 2019. Bioinformatic analyses, including WGCNA, GSEA, GO, KEGG, Hallmark, CIBERSORT, QUANTISEQ, ssGSEA and TISIDB, were performed to systematically demonstrate the expression pattern, immunomodulation role, and prognostic value of Galectin-9 in HCC. These findings were further validated by immunohistochemistry staining.

Patients with high serum Galectin-9 levels had significantly shorter time to tumor recurrence (TTR; P < 0.001) in both cohorts, and serum Galectin-9 was identified as an independent predictor of HCC recurrence, even in patients with low-AFP or early-stage. Bioinformatic analyzes revealed high Galectin-9 expression is involved in immune-evasive and inflammatory signaling pathways. It correlated with increased infiltration of exhausted CD8 + T cells, Tregs, TAMs and MDSCs. Interestingly, we found Galectin-9 was predominantly expressed on macrophages rather than malignant cells, and showed positively association with serum Galectin-9 concentration according to IHC results. Concordantly, high serum Galectin-9 levels also reflected an immune-evasive microenvironment composed by extensive CD163 + and FOXP3 + cell infiltrates.

Elevated serum Galectin-9 was a novel indicator for worse prognosis in HCC. The high expression of Galectin-9 may reflect the immunosuppressive environment by increasing CD163 + and FOXP3 + cell infiltrates.

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.

Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC.

We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023.

We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality.

IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.

A major advance in cancer treatment has been the development and refinement of cancer immunotherapy. The discovery of immunotherapies for a wide range of cancers has revolutionized cancer treatment paradigms. Despite relapse or refractory disease, immunotherapy approaches can prolong the life expectancy of metastatic cancer patients. Multiple therapeutic approaches and agents are currently being developed to manipulate various aspects of the immune system. Oncolytic viruses, cancer vaccines, adoptive cell therapies, monoclonal antibodies, cytokine therapies, and inhibitors of immune checkpoints have all proven successful in clinical trials. There are several types of immunotherapeutic approaches available for treating cancer, and others are being tested in preclinical and clinical settings. Immunotherapy has proven successful, and many agents and strategies have been developed to improve its effectiveness. The purpose of this article is to present a comprehensive overview of current immunotherapy approaches used to treat cancer. Cancer immunotherapy advancements, emerging patterns, constraints, and potential future breakthroughs are also discussed.

The interaction between Tim-3 on T cells and its ligand Galectin-9 negatively regulates the cellular immune response. However, the regulation of Tim-3/Galectin-9 on CD4 T cell subsets in multiple myeloma (MM) remains unclear. The aim of this study was to investigate the relationship between the regulation of CD4 T cell subsets by the Tim-3/Galectin-9 pathway and clinical prognostic indicators in MM. Tim-3/Galectin-9 were detected by flow cytometry, PCR and ELISA in 60 MM patients and 40 healthy controls, and its correlation with clinical prognostic parameters was analyzed. The expressions of Tim-3 on CD4 T cells, Galectin-9 mRNA in PBMC and level of Galectin-9 protein in serum were significantly elevated in MM patients, especially those with poor prognostic indicators. In MM patients, Tim-3 was highly expressed on the surfaces of Th1, Th2, and Th17 cells, but lowly expressed on Treg. Moreover, level of cytokine IFN-γ in serum was negatively correlated with Tim-3+Th1 cell and Galectin-9mRNA, Galectin-9 protein level. In addition, cell culture experiments showed that the anti-tumor effect and the ability to secrete IFN-γ were restored by blocking the Tim-3/Galectin-9 pathway. In MM patients, Tim-3/Galectin-9 is elevated and associated with disease progression, by inhibiting the cytotoxic function of Th1, and also promoting Th2 and Th17 to be involved in immune escape of MM. Therefore, Tim-3/Galectin-9 may serve as a new immunotherapeutic target for MM patients.

Colorectal cancer (CRC) imposes a substantial worldwide health burden, necessitating innovative strategies to enhance therapeutic outcomes. T cell immunoglobulin-3 (Tim-3), an immune checkpoint, enhances immunological tolerance. Tim-3's role in CRC surpasses its conventional function as an indicator of dysfunction in T lymphocytes.

This review provides an all-inclusive summary of the structural and functional attributes of Tim-3's involvement in the case of CRC. It explores the implications of Tim-3 expression in CRC with regard to tumor progression, clinical characteristics, and therapeutic approaches. Furthermore, it delves into the intricate signaling pathways and molecular mechanisms through which Tim-3 exerts its dual function in both immunity against tumors and immune evasion.

Understanding Tim-3's complicated network of interactions in CRC has significant consequences for the development of novel immunotherapeutic strategies targeted toward restoring anti-tumor immune responses and improving patient survival. Tim-3 is an important and valuable target for CRC patient risk classification and treatment because it regulates a complex network of strategies for suppressing immune responses, including causing T cell exhaustion, increasing Treg (regulatory T-cell) proliferation, and altering antigen-presenting cell activity.

Immune checkpoint inhibitor (ICI) therapies can increase the risk of cardiovascular events in survivors of cancer by worsening atherosclerosis. Here we map the expression of immune checkpoints (ICs) within human carotid and coronary atherosclerotic plaques, revealing a network of immune cell interactions that ICI treatments can unintentionally target in arteries. We identify a population of mature, regulatory CCR7+FSCN1+ dendritic cells, similar to those described in tumors, as a hub of IC-mediated signaling within plaques. Additionally, we show that type 2 diabetes and lipid-lowering therapies alter immune cell interactions through PD-1, CTLA4, LAG3 and other IC targets in clinical development, impacting plaque inflammation. This comprehensive map of the IC interactome in healthy and cardiometabolic disease states provides a framework for understanding the potential adverse and beneficial impacts of approved and investigational ICIs on atherosclerosis, setting the stage for designing ICI strategies that minimize cardiovascular disease risk in cancer survivors.

This review explores some of the complex mechanisms underlying antitumor T-cell response, with a specific focus on the balance and cross-talk between selected co-stimulatory and inhibitory pathways. The tumor microenvironment (TME) fosters both T-cell activation and exhaustion, a dual role influenced by the local presence of inhibitory immune checkpoints (ICs), which are exploited by cancer cells to evade immune surveillance. Recent advancements in IC blockade (ICB) therapies have transformed cancer treatment. However, only a fraction of patients respond favorably, highlighting the need for predictive biomarkers and combination therapies to overcome ICB resistance. A crucial aspect is represented by the complexity of the TME, which encompasses diverse cell types that either enhance or suppress immune responses. This review underscores the importance of identifying the most critical cross-talk between inhibitory and co-stimulatory molecules for developing approaches tailored to patient-specific molecular and immune profiles to maximize the therapeutic efficacy of IC inhibitors and enhance clinical outcomes.

Background: Compared to other immune checkpoint molecules, T cell immunoglobulin domain and mucin domain-3 (TIM-3) is highly expressed on natural killer (NK) cells, but its functional role and prognostic significance in acute myeloid leukemia (AML) remains unclear. This study aims to evaluate the role of TIM-3 expression on the cytotoxic and killing capacity of NK cells and its prognostic significance in AML. Methods: AML public single-cell RNA sequencing (scRNAseq) data were used to analyze the correlation of transcript levels between HAVCR2 (encoding TIM-3) and cytotoxic molecules in NK cells. NK cells from the bone marrows of seven newly diagnosed AML patients and five healthy donors (HDs) were stimulated in vitro and cell-killing activity was evaluated. A total of one hundred and five newly diagnosed adult AML patients and seven HDs were tested the expression of TIM-3 and cytotoxic molecules on the bone marrow NK cells by multi-parameter flow cytometry (MFC). Results: Both scRNAseq and MFC analysis demonstrated that TIM-3 expression on NK cells was positively related to the levels of perforin (PFP) and granzyme B (GZMB) (all p < 0.05) in AML. It was PFP and GZMB but not the TIM-3 level that was related to NK-cell-killing activity against K562 cells (p = 0.027, 0.042 and 0.55). A high frequency of TIM-3+ NK cells predicted poorer relapse-free survival (RFS) and event-free survival (EFS) (p = 0.013 and 0.0074), but was not an independent prognostic factor, whereas low GZMB levels in TIM-3+ NK cells independently predicted poorer RFS (p = 0.0032). Conclusions: TIM-3 expression on NK cells is positively related to PFP and GZMB levels but has no relation to cell-killing activity in AML, and low GZMB levels in TIM-3+ NK cells in the diagnostic bone marrows predicts poor outcomes. This study lays a theoretical foundation for the clinical application of immune checkpoint inhibitor treatment.

Immune checkpoint inhibitors (ICIs) are important systemic therapeutic agents for hepatocellular carcinoma (HCC), among which T-cell immunoglobulin and mucin-domain containing protein 3 (Tim-3) is considered an emerging target for ICI therapy. This study aims to evaluate the prognostic value of Tim-3 expression and develop a predictive model for Tim-3 infiltration in HCC.

We collected data from 424 HCC patients in The Cancer Genome Atlas (TCGA) and data from 102 pathologically confirmed HCC patients from our center for prognostic analysis. Multivariate Cox regression analyses were performed on both datasets to determine the prognostic significance of Tim-3 expression. In radiomics analysis, we used the K-means algorithm to cluster regions of interest in arterial phase enhancement and venous phase enhancement images from patients at our center. Radiomic features were extracted from three subregions as well as the entire tumor using pyradiomics. Five machine learning methods were employed to construct Habitat models based on habitat features and Rad models based on traditional radiomic features. The predictive performance of the models was compared using ROC curves, DCA curves, and calibration curves.

Multivariate Cox analyses from both our center and the TCGA database indicated that high Tim-3 expression is an independent risk factor for poor prognosis in HCC patients. Higher levels of Tim-3 expression were significantly associated with worse prognosis. Among the ten models evaluated, the Habitat model constructed using the LightGBM algorithm showed the best performance in predicting Tim-3 expression status (training set vs. test set AUC 0.866 vs. 0.824).

This study confirmed the importance of Tim-3 as a prognostic marker in HCC. The habitat radiomics model we developed effectively predicted intratumoral Tim-3 infiltration, providing valuable insights for the evaluation of ICI therapy in HCC patients.

Numerous preclinical studies have demonstrated the inhibitory function of T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) on T cells as an inhibitory receptor, leading to the clinical development of anti-Tim-3 blocking antibodies. However, recent studies have shown that Tim-3 is expressed not only on T cells but also on multiple cell types in the tumor microenvironment (TME), including dendritic cells (DCs), natural killer (NK) cells, macrophages, and tumor cells. Therefore, Tim-3 blockade in the immune microenvironment not only affect the function of T cells but also influence the functions of other cells. For example, Tim-3 blockade can enhance the ability of DCs to regulate innate and adaptive immunity. The role of Tim-3 blockade in NK cells function is controversial, as it can enhance the antitumor function of NK cells under certain conditions while having the opposite effect in other situations. Additionally, Tim-3 blockade can promote the reversal of macrophage polarization from the M2 phenotype to the M1 phenotype. Furthermore, Tim-3 blockade can inhibit tumor development by suppressing the proliferation and metastasis of tumor cells. In summary, increasing evidence has shown that Tim-3 in other cell types also plays a critical role in the efficacy of anti-Tim-3 therapy. Understanding the function of anti-Tim-3 therapy in non-T cells can help elucidate the diverse responses observed in clinical patients, leading to better development of relevant therapeutic strategies. This review aims to discuss the role of Tim-3 in the TME and emphasize the impact of Tim-3 blockade in the tumor immune microenvironment beyond T cells.

Galectin-9 (gal-9) is a protein that belongs to the galectin family. Gal-9 is expressed in cells of the innate and adaptive immune system, including lymphocytes, dendritic cells, giant salivary cells, eosinophils and T cells, etc. In different immune cells, the role of gal-9 is different. Gal-9 can induce the proliferation and activation of immune cells, and also promote the apoptosis of immune cells. This effect of gal-9 affects the occurrence and development of a variety of immune-related diseases, such as the invasion of pathogenic microorganisms, immune escape of tumor cells, and inflammatory response. Thus, understanding the biological roles of gal-9 in innate and adaptive immunity may be essential for autoimmune diseases treatment and diagnosis to improve patient quality of life. In this review, we aim to summarize current research on the regulatory roles of gal-9 in human immune system and potential inducers and inhibitors of gal-9, which may provide new strategies for immune diseases therapies.

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway.

Deregulating cellular metabolism is one of the prominent hallmarks of malignancy, with a critical role in tumor survival and growth. However, the role of reprogramming aspartate metabolism in hepatocellular carcinoma (HCC) are largely unknown.

The multi-omics data of HCC patients were downloaded from public databases. Univariate and multivariate stepwise Cox regression were used to establish an aspartate metabolism-related gene signature (AMGS) in HCC. The Kaplan-Meier and receiver operating characteristic curve analyses were performed to evaluate the predictive ability for overall survival (OS) in HCC patients. Gene set enrichment analysis and immune infiltration analysis were operated to determine the potential mechanisms underlying the AMGS. Single-cell RNA sequencing (scRNA-seq) data of liver cancer stem cells were visualized by t-SNE algorithm. In vivo and in vitro experiments were implemented to investigate the biological function of CAD in HCC. In addition, a nomogram based on the AMGS and clinicopathologic characteristics was constructed by univariate and multivariate Cox regression analyses.

Patients in the high-AMGS subgroup exerted advanced tumor status and poor prognosis. Mechanistically, the high-AMGS subgroup patients had significantly enhanced proliferation and stemness-related pathways, increased infiltration of regulatory T cells and upregulated expression levels of suppressive immune checkpoints in the tumor immune microenvironment. Notably, scRNA-seq data revealed CAD, one of the aspartate metabolism-related gene, is significantly upregulated in liver cancer stem cells. Silencing CAD inhibited proliferative capacity and stemness properties of HCC cells in vitro and in vivo. Finally, a novel nomogram based on the AMGS showed an accurate prediction in HCC patients.

The AMGS represents a promising prognostic value for HCC patients, providing a perspective for finding novel biomarkers and therapeutic targets for HCC.

Natural Killer (NK) cells play a crucial role as effector cells within the tumor immune microenvironment, capable of identifying and eliminating tumor cells through the expression of diverse activating and inhibitory receptors that recognize tumor-related ligands. Therefore, harnessing NK cells for therapeutic purposes represents a significant adjunct to T cell-based tumor immunotherapy strategies. Presently, NK cell-based tumor immunotherapy strategies encompass various approaches, including adoptive NK cell therapy, cytokine therapy, antibody-based NK cell therapy (enhancing ADCC mediated by NK cells, NK cell engagers, immune checkpoint blockade therapy) and the utilization of nanoparticles and small molecules to modulate NK cell anti-tumor functionality. This article presents a comprehensive overview of the latest advances in NK cell-based anti-tumor immunotherapy, with the aim of offering insights and methodologies for the clinical treatment of cancer patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Its high recurrence rate and lack of effective control drugs result in a 5-year survival rate of only about 10%. HCC is a tumor regulated by the immune system. Significant breakthroughs have occurred in treating solid tumors with immunotherapy in recent years. Various immunotherapies, such as immune checkpoint inhibitors (ICIs), including combination therapies, have demonstrated promising therapeutic effects in both clinical applications and research. Other immunotherapies, such as adoptive cell therapies and oncolytic viruses, are also emerging, offering hope for addressing long-term survival issues in HCC. This article reviews current commonly used immunotherapy strategies and the latest research findings for reference.

Layilin (LAYN) represents a valuable prognostic biomarker across various tumor types, while also serving as an innovative indicator of dysfunctional or exhausted CD8+ T cells and exhibiting correlation with immune context. However, the immune function and prognostic significance of LAYN in hepatocellular carcinoma (HCC) remain unexplored. Therefore, our objective is to investigate the role of LAYN in CD8+ T cell exhaustion, clinical prognosis, and the tumor microenvironment within HCC.

TIMER or GEPIA databases were used to analyze LAYN expression level and its correlation with immune infiltration in HCC. Bioinformatics analysis was conducted on TCGA and scRNA-seq cohorts. The evaluation of LAYN expression level in fresh specimens was performed through IF, IHC, and ELISA assays. Flow cytometry and mRNA-seq were employed to investigate co-expressed genes of LAYN, the LAYN+CD8+ T cell exhaustion signature and immune function. Cell proliferation ability and killing activity were assessed using CCK8 and CFSE/PI.

The expression level of LAYN in HCC tumors was significantly higher compared to peri-tumors. Patients with high levels of LAYN exhibited poorer OS. GO or KEGG analysis confirmed that LAYN was involved in immune response and was positively associated with CD8+ T cell immune infiltration levels. Furthermore, LAYN negatively regulated the immune function of CD8+ T cells, leading to dysfunctional phenotypes characterized by elevated levels of CD39, TIM3 and reduced levels of perforin, TNF-α, Ki-67. CFSE/PI assays demonstrated that LAYN+CD8+ T cells displayed decreased cytotoxic activity. Additionally, there was a positive correlation between LAYN and CD146 levels, which are involved in adhesion and localization processes of CD8+ T cells. Interestingly, blocking LAYN partially restored the exhaustion properties of CD8+ T cells.

LAYN exhibits a strong correlation with immune infiltration in the TME and represents a novel biomarker for predicting clinical prognosis in HCC. Moreover, targeting LAYN may hold promise as an effective strategy for HCC immunotherapy.

Tumor-infiltrating CD4+ T cells orchestrate the adaptive immune response through remarkable plasticity, and the expression patterns of exhaustion-related inhibitory receptors in these cells differ significantly from those of CD8+ T cells. Thus, a better understanding of the molecular basis of CD4+ T cell exhaustion and their responses to immune checkpoint blockade (ICB) is required. Here, we integrated multiomics approaches to define the phenotypic and molecular profiles of exhausted CD4+ T cells in oropharyngeal squamous cell carcinoma (OPSCC). Two distinct immune-promoting (Module 1) and immunosuppressive (Module 2) functional modules in tumor-infiltrating CD4+ T cells were identified, and both the immune-promoting function of Module 1 cells and immunosuppressive function of Module 2 cells were positively associated with their corresponding exhaustion states. Furthermore, the application of ICBs targeting effector CD4+ T cells in Module 1 (αPD-1) and Treg cells in Module 2 (αCTLA-4) in mouse models could help reinvigorate the effector function of Module 1-exhausted CD4+ T cells and reduce the immunosuppressive function of Module 2-exhausted CD4+ T cells, ultimately promoting OPSCC tumor regression. Taken together, our study provides a crucial cellular basis for the selection of optimal ICB in treating OPSCC.

Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

TIM-3 was originally identified as a negative regulator of helper T cells and is expressed on dendritic cells (DCs). Since the inhibition of TIM-3 on DCs has been suggested to enhance T cell-mediated anti-tumor immunity, we examined its expression on DCs within the tumor microenvironment (TME) in colorectal cancer (CRC) using transcriptomic data from a public database (n = 592) and immunohistochemical evaluations from our cohorts of CRC (n = 115). The expression of TIM-3 on DCs in vitro was examined by flow cytometry, while the expression of its related molecules, cGAS and STING, on immature and mature DCs was assessed by Western blotting. The expression of HAVCR2 (TIM-3) was strongly associated with the infiltration of DCs within the TME of CRC. Immunohistochemical staining of clinical tissue samples revealed that tumor-infiltrating DCs expressed TIM-3; however, their number at the tumor-invasive front significantly decreased with stage progression. TIM-3 expression was higher on immature DCs than on mature DCs from several different donors (n = 6). Western blot analyses showed that the expression of STING was higher on mature DCs than on immature DCs, which was opposite to that of TIM-3. We demonstrated that TIM-3 was highly expressed on tumor-infiltrating DCs of CRC and that its expression was higher on immature DCs than on mature DCs.

Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.

This systematic review investigates the immunosuppressive environment in HBV-associated hepatocellular carcinoma (HCC), characterized by dysfunctional and exhausted HBV-specific T cells alongside an increased infiltration of HBV-specific CD4+ T cells, particularly regulatory T cells (Tregs). Heightened expression of checkpoint inhibitors, notably PD-1, is linked with disease progression and recurrence, indicating its potential as both a prognostic indicator and a target for immunotherapy. Nevertheless, using PD-1 inhibitors has shown limited effectiveness. In a future perspective, understanding the intricate interplay between innate and adaptive immune responses holds promise for pinpointing predictive biomarkers and crafting novel treatment approaches for HBV-associated HCC.

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease widespread in Europe and Asia. HFRS is caused by negative-sensed single-stranded RNA orthohantaviruses transmitted to humans through inhaling aerosolized excreta of infected rodents. Symptoms of HFRS include acute kidney injury, thrombocytopenia, hemorrhages, and hypotension. The immune response raised against viral antigens plays an important role in the pathogenesis of HFRS. Inhibitory co-receptors are essential in regulating immune responses, mitigating immunopathogenesis, and reducing tissue damage. Our research showed an increased soluble form of inhibitory co-receptors TIM-3, LAG-3, and PD-1 in HFRS patients associated with disease severity. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient's serum and the potential correlation with key clinical parameters. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient's serum and their possible association with relevant clinical parameters. Using multiplex immunoassay, we found elevated levels of TIM-3, LAG-3, and PD-1 proteins in the serum of HFRS patients. Furthermore, increased levels were associated with creatinine, urea, lactate dehydrogenase concentrations, and platelet count. These findings suggest that these proteins play a role in regulating the immune response and disease progression.

The T cell immunoglobulin and mucin-domain containing-3 (TIM-3) receptor has gained significant attention as a promising target for cancer immunotherapy. The inhibitory effect of T cells by TIM-3 is mediated through the interaction between TIM-3 and its ligands. Ligand-blocking anti-TIM-3 antibodies possess the potential to reactivate antigen-specific T cells and augment anti-tumor immunity. However, the precise ligand-receptor interactions disrupted by the administration of TIM-3 blocking Abs have yet to be fully elucidated. In this study, we have developed a panel of monoclonal antibodies targeting human TIM-3, namely MsT001, MsT065, MsT229, and MsT286. They exhibited high sensitivities (10 pg/mL) and affinities (3.70 × 10-9 to 4.61 × 10-11 M) for TIM-3. The TIM-3 antibodies recognized distinct epitopes, including linear epitopes (MsT001 and MsT065), and a conformational epitope (MsT229 and MsT286). Additionally, the MsT229 and MsT286 displayed reactivity towards cynomolgus TIM-3. The interactions between TIM-3/Gal-9, TIM-3/HMGB-1, and TIM-3/CEACAM-1 disrupt the binding of MsT229 and MsT286, while leaving the binding of MsT001 and MsT065 unaffected. The inhibitory effect on the interaction between Gal-9 and TIM-3 was found to be dose-dependently in the presence of either MsT229 or MsT286. The findings suggested that the involvement of conformational epitopes in TIM-3 is crucial for its interaction with ligands, and we successfully generated novel anti-TIM-3 Abs that exhibit inhibitory potential. In conclusion, our finding offers valuable insights -on the comprehension and targeting of human TIM-3.

Cancer progression is continuously controlled by the immune system which can identify and destroy nascent tumor cells or inhibit metastatic spreading. However, the immune system and its deregulated activity in the tumor microenvironment can also promote tumor progression favoring the outgrowth of cancers capable of escaping immune control, in a process termed cancer immunoediting. This process, which has been classified into three phases, i.e. "elimination", "equilibrium" and "escape", is influenced by several cancer- and microenvironment-dependent factors. Senescence is a cellular program primed by cells in response to different pathophysiological stimuli, which is based on long-lasting cell cycle arrest and the secretion of numerous bioactive and inflammatory molecules. Because of this, cellular senescence is a potent immunomodulatory factor promptly recruiting immune cells and actively promoting tissue remodeling. In the context of cancer, these functions can lead to both cancer immunosurveillance and immunosuppression. In this review, the authors will discuss the role of senescence in cancer immunoediting, highlighting its context- and timing-dependent effects on the different three phases, describing how senescent cells promote immune cell recruitment for cancer cell elimination or sustain tumor microenvironment inflammation for immune escape. A potential contribution of senescent cells in cancer dormancy, as a mechanism of therapy resistance and cancer relapse, will be discussed with the final objective to unravel the immunotherapeutic implications of senescence modulation in cancer.

Immune checkpoints (ICPs) can promote tumor growth and prevent immunity-induced cancer cell apoptosis. Fortunately, targeting ICPs, such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4), has achieved great success in the past few years and has gradually become an effective treatment for cancers, including hepatocellular carcinoma (HCC). However, many patients do not respond to ICP therapy due to acquired resistance and recurrence. Therefore, clarifying the specific mechanisms of ICP in the development of HCC is very important for enhancing the efficacy of anti-PD-1 and anti-CTLA-4 therapy. In particular, antigen presentation and interferon-γ (IFN-γ) signaling were reported to be involved in the development of resistance. In this review, we have explained the role and regulatory mechanisms of ICP therapy in HCC pathology. Moreover, we have also elaborated on combinations of ICP inhibitors and other treatments to enhance the antitumor effect. Collectively, recent advances in the pharmacological targeting of ICPs provide insights for the development of a novel alternative treatment for HCC.

As integral components of the immune microenvironment, tissue resident macrophages (TRMs) represent a self-renewing and long-lived cell population that plays crucial roles in maintaining homeostasis, promoting tissue remodeling after damage, defending against inflammation and even orchestrating cancer progression. However, the exact functions and roles of TRMs in cancer are not yet well understood. TRMs exhibit either pro-tumorigenic or anti-tumorigenic effects by engaging in phagocytosis and secreting diverse cytokines, chemokines, and growth factors to modulate the adaptive immune system. The life-span, turnover kinetics and monocyte replenishment of TRMs vary among different organs, adding to the complexity and controversial findings in TRMs studies. Considering the complexity of tissue associated macrophage origin, macrophages targeting strategy of each ontogeny should be carefully evaluated. Consequently, acquiring a comprehensive understanding of TRMs' origin, function, homeostasis, characteristics, and their roles in cancer for each specific organ holds significant research value. In this review, we aim to provide an outline of homeostasis and characteristics of resident macrophages in the lung, liver, brain, skin and intestinal, as well as their roles in modulating primary and metastatic cancer, which may inform and serve the future design of targeted therapies.

Galectin-9 (Gal-9) is a vital member of the galectin family, functioning as a multi-subtype galactose lectin with diverse biological roles. Recent research has revealed that Gal-9's interaction with tumors is an independent factor that influences tumor progression. Furthermore, Gal-9 in the immune microenvironment cross-talks with tumor-associated immune cells, informing the clarification of Gal-9's identity as an immune checkpoint. A thorough investigation into Gal-9's role in various cancer types and its interaction with the immune microenvironment could yield novel strategies for subsequent targeted immunotherapy. This review focuses on the latest advances in understanding the direct and indirect cross-talk between Gal-9 and hematologic malignancies, in addition to solid tumors. In addition, we discuss the prospects of Gal-9 in tumor immunotherapy, including its cross-talk with the ligand TIM-3 and its potential in immune-combination therapy.