Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.

Immunotherapeutics targeting immune checkpoint receptors or their ligands (i.e., immune checkpoint inhibitors), have been groundbreaking in the field of oncology, radically changing the approach to treatment and improving the clinical outcomes of an ever-expanding list of solid tumors and hematological malignancies. However, immune checkpoint inhibitors (ICI) are not devoid of side effects, collectively regarded as immune-related adverse events (irAE); they are not easily uncovered in preclinical immunotoxicological investigations and are often due to the very low expression of their targets in immunologically-unchallenged non-clinical species. We have characterized expression of a broad range of immune checkpoint receptors in peripheral blood mononuclear cell (PBMC) subpopulations from cynomolgus monkeys and healthy human volunteers, under resting and T-cell stimulatory conditions by multicolor flow cytometry to inform appropriate species selection for modeling potential irAE in immunotherapeutic preclinical research. Focusing on the response of the main lymphocyte populations to interleukin (IL)-2 alone, or in combination with anti-CD3 and anti-CD28 antibodies, checkpoints with shared similarities and key differences between the two species were identified. The results of this first study provide a database for the expression and response to stimulation for immune checkpoint receptors and can help guide future model selection in the design of preclinical studies involving immunotherapeutics directed against these targets.

Sleeping disorders negatively affect cancer patient management, quality of life, and recovery. Immunotherapy, a rising cancer treatment, shows potential to improve sleep quality by reducing inflammation. This study analyzed 255 publications (2000-2024) from the Web of Science Core Collection using bibliometric methods. The US and China dominate research output, with The Mayo Clinic as a key contributor. Core topics are "immunotherapy," "quality of life," and "antibodies." Emerging keywords like "cancer," "encephalitis," and "depression" highlight a shift toward clinical psychology in treating tumors and rare diseases. It is noteworthy that with the rapid expansion of immunotherapy in cancer treatment, clinical trials have shown that it can improve sleep quality in cancer patients by reducing inflammation. As its application in cancer treatment expands, immunotherapy's potential for treating sleep disorders is promising. Future development is expected to improve sleep quality and address clinical issues, offering broad prospects for patient outcomes.

Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor that suppresses immune responses largely through its interaction with PD-L1. Tumors exploit this mechanism to evade immune surveillance, positioning immune checkpoint inhibitors targeting the PD-1/PD-L1 axis as groundbreaking advancements in cancer therapy. However, the overall effectiveness of these therapies is often constrained by an incomplete understanding of the underlying mechanisms. Recent research has uncovered the pivotal role of various post-translational modifications (PTMs) of PD-1, including ubiquitination, UFMylation, phosphorylation, palmitoylation, and glycosylation, in regulating its protein stability, localization, and protein-protein interactions. As much, dysregulation of these PTMs can drive PD-1-mediated immune evasion and contribute to therapeutic resistance. Notably, targeting PD-1 PTMs with small-molecule inhibitors or monoclonal antibodies (MAbs) has shown potential to bolster anti-tumor immunity in both pre-clinical mouse models and clinical trials. This review highlights recent findings on PD-1's PTMs and explores emerging therapeutic strategies aimed at modulating these modifications. By integrating these mechanistic insights, the development of combination cancer immunotherapies can be further rationally advanced, offering new avenues for more effective and durable treatments.

Invasive central nervous system (CNS) cancers are an area where the development of breakthrough therapies is urgently needed. For instance, conditions such as glioblastoma multiforme (GBM) are associated with poor clinical prognosis, with the majority of trials offering no improvement to marginally enhanced survival. Unleashing the potential of targeting the immune system in CNS cancers has gained attention in recent years. Inhibition of immune checkpoints such as CTLA-4, PD-1/PD-L1, TIM-3, and LAG-3 has been attempted in recent trials. While potentially offering a notable edge over other immunotherapies, multi-organ adverse events have been found with the administration of immune checkpoint inhibitors (ICIs). The present review captures the state-of-the-art evidence on ICI treatments in different CNS cancers. Also, we discuss the value of combinational therapies involving ICIs as well as next-generation therapeutics such as bispecific antibodies targeting PD-1/LAG-3/TIM-3 and CRISPR-Cas9-edited PD-1-knock-out checkpoint-resistant CAR T-cells.

Advanced 3D heterospheroids, composed of cancer, fibroblast, and immune cells, serve as more physiologically relevant models for anticancer drug screening and immunotherapy research compared to traditional 2D cultures. This study aimed to optimize the culturing, dissociation, and analysis of heterospheroids, addressing limitations that restrict their broader use in immunotherapy research. Our study revealed significant effects of Human Plasma-Like culture medium on cell viability, necrotic core formation, and the spatial organization of cancer and fibroblast cells within heterospheroids compared to DMEM and RPMI media. In HT-29 heterospheroids, cell viability decreased from 75 % in DMEM to 20 % in HPLM, which was accompanied by increased necrotic core formation and elevated PD-L1 expression. TrypLE™ effectively dissociated heterospheroids but compromised immune cell viability and surface marker detection. In comparison, Accutase™ significantly reduced cell yield, while collagenase I preserved immune cell markers but affected those on cancer cells. Furthermore, we developed a luciferase-based assay to measure immune-mediated cancer cell killing in heterospheroids, excluding signals from non-target cells, such as dying fibroblasts and immune cells, without requiring spheroid lysis or dissociation. Our findings highlight the importance of tailoring experimental conditions to reflect specific tumor characteristics, thus enhancing the utility of heterospheroids in drug discovery and immunotherapy research.

The benefits and harms of immune checkpoint inhibitor (ICI) therapy for lung cancer vary across groups, including those typically underrepresented in randomized clinical trials.

To quantify the harms and benefits of ICI-containing regimens in individuals with non-small cell lung cancer and assess heterogeneity across priority subgroups.

This retrospective cohort study conducted in 2024 used 2013 to 2019 Surveillance, Epidemiology, and End Results (SEER) Medicare data of individuals 66 years or older with non-small cell lung cancer who were exposed to any ICI.

ICI + chemotherapy, single ICI (reference group).

Severe immune-related adverse events (irAE; harm) and mortality (when delayed mortality was the benefit). Severe irAEs were defined using validated diagnosis and medication codes. Mortality was ascertained from Medicare data. Hazard ratios (HRs) were estimated and 95% CIs were stratified by whether an ICI was used as the first or second or later systemic anticancer treatment (SACT) and in subgroups defined by preexisting autoimmune disease, sex, and age. The harm-benefit tradeoff was described as excess severe irAEs per year of life gained in which the gain in survival time was assessed using restricted mean survival time.

Of 17 681 Medicare beneficiaries, 8797 (49.5%) were female, and the mean (SD) age was 74 (6.0) years. Compared with a single ICI (14 249 [80.6%]), individuals treated with ICI + chemotherapy (3432 [19.4%]) had an elevated risk of severe irAE in the first SACT setting (hazard ratio [HR], 1.18; 95% CI, 1.06-1.30) but not in the second or later SACT setting (HR, 1.04; 95% CI, 0.92-1.19); there was a decreased risk of mortality in the first SACT setting (HR, 0.66; 95% CI, 0.62-0.72) but not in the second or later SACT setting (HR, 0.94; 95% CI, 0.68-1.03). In the first SACT setting, ICI + chemotherapy delayed mortality more among patients with (vs without) autoimmune disease at baseline. For each 1 year of life gained, the risk of severe irAEs was 0.31 (95% CI, 0.09-0.53) and the tradeoff was also statistically significant in men and patients without autoimmune disease.

The results of this cohort study suggest that given both treatment-related harms and benefits, ICI + chemotherapy use in the first SACT setting requires informed decision-making; the potential benefits of ICI + chemotherapy vs single ICI in high-risk subgroups is encouraging.

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.

Extracellular vesicles (EVs), which are secreted by various cell types, hold significant potential for cancer therapy. However, there are several challenges and difficulties that limit their application in clinical settings. This review, which integrates the work of our team and recent advancements in this research field, discusses EV-based cancer treatment strategies to guide their clinical application. The following treatment strategies are discussed: 1) leveraging the inherent properties of EVs for the development of cancer treatments; 2) modifying EVs using EV engineering methods to improve drug loading and delivery; 3) targeting key molecules in tumor-derived EV (TDE) synthesis to inhibit their production; and 4) clearing TDEs from the tumor microenvironment. Additionally, on the basis of research into EV-based vaccines and bispecific antibodies, this review elaborates on strategies to enhance antitumor immunity via EVs and discusses engineering modifications that can improve EV targeting ability and stability and the research progress of AI technology in targeted delivery of EV drugs. Although there are limited strategies for enhancing EV targeting abilities, this review provides an in-depth discussion of prior studies. Finally, this review summarizes the clinical progress on the use of EVs in cancer therapy and highlights challenges that need to be addressed.

Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by poor immune cell infiltration and a strongly immunosuppressive microenvironment. Traditional treatments have often yielded unsatisfactory outcomes due to the insidious onset of the disease. Encouragingly, the introduction of immune checkpoint inhibitors (ICIs) has significantly transformed the approach to HCC treatment. Moreover, combining ICIs with other therapies or novel materials is considered the most promising opportunity in HCC, with some of these combinations already being evaluated in large-scale clinical trials. Unfortunately, most clinical trials fail to meet their endpoints, and the few successful ones also face challenges. This indicates that the potential of ICIs in HCC treatment remains underutilized, prompting a reevaluation of this promising therapy. Therefore, this article provides a review of the role of immune checkpoints in cancer treatment, the research progress of ICIs and their combination application in the treatment of HCC, aiming to open up avenues for the development of safer and more efficient immune checkpoint-related strategies for HCC treatment.

We explore the interaction between corneal immunity and mesenchymal stem/stromal cells (MSCs) and their potential in treating corneal and ocular surface disorders. We outline the cornea's immune privilege mechanisms and the immunomodulatory substances involved. In this realm, MSCs are characterized by their immunomodulatory properties and regenerative potential, making them promising for therapeutic application. Therefore, we focus on the role of MSCs in immune-mediated corneal diseases such as dry eye disease, corneal transplantation rejection, limbal stem cell deficiency, and ocular graft-versus-host disease. Preclinical and clinical studies demonstrate MSCs' efficacy in promoting corneal healing and reducing inflammation in these conditions. Overall, we emphasize the potential of MSCs as innovative therapies in ophthalmology, offering promising solutions for managing various ocular surface pathologies.

Pancreatic cancer is a highly aggressive and lethal disease, characterized by a limited response to chemotherapy and overall poor prognosis. Pancreatic cancers with a distinct mismatch repair deficiency, although relatively rare, have been shown to be associated with markedly better outcomes in comparison. Furthermore, whereas pancreatic cancers are generally unresponsive to current immunotherapy, this specific group of tumors has been shown to have a notable susceptibility to immune checkpoint inhibitors.

In this review, we aim to summarize the relevant literature regarding mismatch-repair associated pancreatic cancers, the impacted biological mechanisms, and the resulting vulnerabilities for potential opportunistic immunotherapeutic treatment approaches. We will also review the current clinical studies assessing survival outcomes of mismatch repair deficient pancreatic cancers and ongoing clinical trials in this emerging field.

Patients with dMMR/MSI-H pancreatic cancers harbor a distinct phenotype that has increased immune activation, greater responsiveness to immune checkpoint inhibitor therapy and better overall survival when compared to other pancreatic cancers. Although this molecular subtype makes up a small minority of cases, emerging data suggest immunotherapy may offer benefit to these patients.

The potent antitumor effects of interleukin 12 (IL12) gene therapy in glioblastoma (GBM) are significantly attenuated by the highly immunosuppressive microenvironment and the upregulation of the PD-1/PD-L1 immune checkpoint. However, combining IL12 gene therapy with PD-1/PD-L1 inhibitors failed to improve efficacy. This study aims to assess the effects of silencing the immunosuppressive long noncoding RNA INCR1 when combined with IL12 therapy.

RNAscope in situ hybridization was performed to analyze INCR1 and PD-L1 expression in tumor tissues from GBM patients pre- and post-IL12 gene therapy. Quantitative PCR was used to analyze immunosuppressive gene expression in patient-derived GBM cells co-cultured with immune cells stimulated with IL12. The effects of INCR1 and PD-L1 silencing on the expression of immunosuppressive genes were evaluated by RNA sequencing. 3D-cytotoxicity assays were performed to assess the activity of immune cells against GBM tumor cells.

INCR1 and PD-L1 expression was upregulated in tumor tissue from GBM patients treated with IL12 gene therapy compared to the tumor tissue of the same patients before the IL12 treatment. Co-culture of patient-derived GBM cells with IL12-stimulated immune cells increased the expression of several immunosuppressive genes. Knocking down INCR1 was more effective than silencing PD-L1 in reducing the expression of multiple immunosuppressive genes. INCR1 silencing improved IL12-mediated immune cell antitumor activity compared to monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint signaling.

INCR1 silencing affects more immune evasive pathways than PD-L1. Targeting INCR1 may represent a valid approach to improve the efficacy of IL12 therapy in GBM.

Cancer is one of the leading causes of death worldwide. In recent years, immune checkpoint inhibitor therapies, in addition to standard immuno- or chemotherapy and surgical approaches, have massively improved the outcome for cancer patients. However, these therapies have their limitations and improved strategies, including access to reliable cancer vaccines, are needed. Here, we describe the use of self-assembling artificial cell membrane (ACM) polymersomes to deliver tumour-specific peptides to trigger sustainable and efficient anti-tumour immune responses. We found that ACM polymersomes were highly efficient in targeting and activating mononuclear phagocytes (MNP) including dendritic cells (DC), while providing long-term reservoirs of antigens for continued immune cell priming. Subcutaneous injection of ACM-encapsulated tumour-antigen-peptides into tumour-bearing mice resulted in improved priming of CD8+ T cells and increased generation of tumour-antigen-peptide specific CD8+ effector T cells. Prophylactic and therapeutic immunisation with ACM-encapsulated peptides resulted in changes to the MNP composition in the tumour microenvironment, tumour regression and improved survival of immunised mice. Combining anti-PD-1 immune checkpoint inhibitor therapy with ACM polymersome peptide delivery further boosted anti-tumour immunity. Our results show that ACM polymersome nanocarriers efficiently instruct anti-tumour immune responses offering a promising new approach for vaccination and cancer immunotherapy. Trial Registration: NCT05385991.

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.

The global incidence of melanoma, the most lethal form of skin cancer, continues to escalate, emphasizing the urgent need for more effective therapeutic strategies. This review assesses the latest advancements in topical and transdermal drug delivery systems, positioning them as promising alternatives. These systems allow for the direct application of therapeutic agents to tumor sites, enhancing drug effectiveness, improving patient compliance, and reducing systemic toxicity. Specifically, innovations such as nanoparticles, microneedles, and vesicular systems are explored for their potential to optimize topical and localized drug delivery. By incorporating a graphical overview of these drug delivery vehicles, we visually underscore their roles in enhancing therapeutic outcomes across various treatment categories such as chemotherapy, immunotherapy, phototherapy, phytotherapy, and targeted therapy. This article critically evaluates recent breakthroughs, addresses the current challenges faced by researchers, and explores the future directions of topical and transdermal approaches in melanoma management. By presenting a summary of the latest research and predicting future trends, this review aims to inform ongoing developments and encourage further innovation in strategies for treating melanoma.

Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.

Despite current technological advancements in the treatment of glioma, immediate alleviation of symptoms can be catered by therapeutic modalities, including surgery, chemotherapy, and combinatorial radiotherapy that exploit aberrations of glioma. Additionally, a small number of target antigens, their heterogeneity, and immune evasion are the potential reasons for developing targeted therapies. This oncologic milestone has catalyzed interest in developing immunotherapies against Glioblastoma to improve overall survival and cure patients with high-grade glioma. The next-gen CAR-T Cell therapy is one of the effective immunotherapeutic strategies in which autologous T cells have been modified to express receptors against GBM and it modulates cytotoxicity.

In this review article, we examine preclinical and clinical outcomes, and limitations as well as present cutting-edge techniques to improve the function of CAR-T cell therapy and explore the possibility of combination therapy.

To date, several CAR T-cell therapies are being evaluated in clinical trials for GBM and other brain malignancies and multiple preclinical studies have demonstrated encouraging outcomes.

CAR-T cell therapy represents a promising therapeutic paradigm in the treatment of solid tumors but a few limitations include, the blood-brain barrier (BBB), antigen escape, tumor microenvironment (TME), tumor heterogeneity, and its plasticity that suppresses immune responses weakens the ability of this therapy. Additional investigation is required that can accurately identify the targets and reflect the similar architecture of glioblastoma, thus optimizing the efficiency of CAR-T cell therapy; allowing for the selection of patients most likely to benefit from immuno-based treatments.

To develop and assess an ethiodized oil (Lipiodol) Pickering emulsion containing anti-programmed cell death ligand 1 (PD-L1) antibodies through in vitro experiments.

The emulsion was created by combining ethiodized oil with poly (lactic-co-glycolic acid) (PLGA) nanoparticles and anti-PD-L1 antibodies. Confocal laser microscopy was used to evaluate the encapsulation of the antibodies within the Pickering emulsion. To assess the stability, the emulsion was visually examined, and droplet sizes were measured under a light microscope. For the sustained release evaluation, the emulsion was introduced into saline and incubated in a shaking bath, after which the supernatant was collected over time. The concentration of anti-PD-L1 antibodies in the supernatant was determined using a bicinchoninic acid assay. Western blotting and flow cytometry were employed to confirm the functionality of the released antibodies. A conventional ethiodized oil emulsion was used as a control for comparison.

The anti-PD-L1 antibodies were encapsulated within the layer of PLGA nanoparticles, positioned at the interface between the water and oil phases, as confirmed by confocal laser microscopy. The ethiodized oil Pickering emulsion demonstrated long-term stability with significantly smaller droplet sizes (P < .001). Moreover, the emulsion facilitated a gradual and sustained release of the anti-PD-L1 antibodies over an 8-week period (P < .001). The antibodies released from the emulsion specifically targeted PD-L1.

This study demonstrated that ethiodized oil Pickering emulsions effectively encapsulate anti-PD-L1 antibodies and enable their sustained release, highlighting their potential as a therapeutic agent for primary and secondary liver cancers.

The tuberous sclerosis complex (TSC1/TSC2/TBC1D7) primarily functions to inhibit the mechanistic target of rapamycin complex 1 (mTORC1), a crucial regulator of cell growth. Mutations in TSC1 or TSC2 cause tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder marked by benign tumors in multiple organs that rarely progress to malignancy. Traditionally, TSC proteins are considered tumor suppressive due to their inhibition of mTORC1 and other mechanisms. However, more recent studies have shown that TSC proteins can also promote tumorigenesis in certain cancer types. In this review, we explore the composition and function of the TSC protein complex, the roles of its individual components in cancer biology, and potential future therapeutic targeting strategies.

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

Dengue virus (DENV) infection imposes a significant global health burden, driven by its ability to manipulate host cellular processes to facilitate replication and evade immune defenses. This review explores the complex interplay between DENV, host immunometabolism, and signaling pathways. DENV induces metabolic reprogramming, including glycolytic upregulation, lipid droplet utilization through lipophagy, and alterations in amino acid metabolism, to fulfill its energy and biosynthetic needs. The virus also disrupts mitochondrial dynamics, leading to increased reactive oxygen species (ROS) production, which modulates immune responses but may also contribute to oxidative stress and severe pathology. Concurrently, DENV hijacks host signaling pathways, including PI3K/Akt, NF-κB, and JAK/STAT, to suppress apoptosis, evade type I interferon responses, and drive pro-inflammatory cytokine production. The interplay between these signaling and metabolic pathways highlights a dual role of host processes: enabling viral replication while activating antiviral immune responses. The review also examines potential therapeutic strategies targeting metabolic and signaling pathways to combat DENV infection, including glycolysis inhibitors, lipid metabolism modulators, and host-directed therapies. While significant progress has been made in understanding DENV-induced immunometabolism, further research is needed to elucidate the precise molecular mechanisms and translate these findings into clinical applications. This study underscores the importance of integrating metabolic and signaling insights to identify novel therapeutic targets against DENV and related flaviviruses, addressing the critical need for effective antiviral interventions.

Ovarian cancer is a serious disease that is a danger to a woman's life and health and is currently being extensively studied worldwide. TNFAIP8L3, a member of the tumor necrosis family, plays a significant role in tumor immune regulation; however, its role in ovarian cancer has not been fully studied and reported.

This study used data from 381 cases of ovarian cancer (OVCA) from The Cancer Genome Analysis (TCGA)-OV to analyze the clinical phenotype and immune phenotype of TNFAIP8L3. Pearson correlation coefficients and protein-protein interaction (PPI) network analyses were used to identify potential biological functions and the genes co-expressed with TNFAIP8L3. The Gene Set Enrichment Analysis (GSEA) method was used to evaluate the relevant regulatory pathways of TNFAIP8L3. Gene Set Variation Analysis was performed to evaluate the proportions of 24 immune cell types in OVCA. Finally, a nomogram and multivariate COX regression analysis were performed to prove the independent prognostic value of TNFAIP8L3 in OVCA.

A total of 181 genes were co-expressed with TNFAIP8L3, including 163 positively correlated and 18 negatively correlated genes. The co-expressed genes associated with TNFAIP8L3 were significantly enriched in biological processes such as cell activation involved in immune response and leukocyte activation involved in immune response. Pathway analysis of TNFAIP8L3 further revealed the association of TNFAIP8L3 with the TGF-β signaling pathway and antigen processing and presentation pathways, especially with macrophages and neutrophils in the antigen presentation process. Moreover, the expression of TNFAIP8L3 was significantly high in OVCA and other solid tumors to function as an independent risk factor for the prognosis of OVCA, with important research value for the prognosis of patients with OVCA.

Those findings indicate that TNFAIP8L3 is correlated with antigen processing and presentation pathways in macrophages and neutrophils and affects prognosis and immune infiltration in OVCA.

Programmed cell death protein 1 (PD-1) is frequently detected in certain subsets of tumor cells, and our understanding of PD-1 signaling consequences has expanded to include control of tumor growth, stemness and drug resistance. Nonetheless, tumor cell-intrinsic PD-1 has been comparatively underexplored in relation to PD-1 expressed on the surface of immune cells as an immune checkpoint, despite the imperative need to comprehensively elucidate the underlying mechanisms of action for achieving optimal responses in tumor immunotherapy. Here, we review the roles of the regulation and function of tumor-intrinsic PD-1 from its expression to degradation processes. Our primary focus is on unraveling its enigmatic influence on tumorigenesis and progression as proposed by recent findings, while navigating the labyrinthine network of regulatory mechanisms governing its expression and intricate functional interplay. We also discuss how the elucidation of the mechanistic underpinnings of tumor-intrinsic PD-1 expression holds the potential to explain the divergent therapeutic outcomes observed with anti-PD-1-based combination therapies, thereby furnishing indispensable insights crucial for synergistic anti-tumor strategies.

Enhancer of zeste homolog 2 (EZH2) catalyzes H3K27me3, an epigenetic modification linked to gene silencing, and its overexpression contributes to the progression of hematological malignancies. This study compares the efficacy of a conventional EZH2 inhibitor with a PROTAC-based EZH2 degrader in human lymphoma cell lines. Furthermore, we investigate the anti-tumor effects of combining EZH2 degrader with anti-PD-1, an immune checkpoint inhibitor, focusing on immune cell interactions and underlying mechanisms.

The cytotoxic effects of the EZH2 degrader and EZH2 inhibitor were evaluated in Burkitt's, B-cell, cutaneous T-cell, and Hodgkin's lymphoma cell lines. Additionally, the combination therapy of the EZH2 degrader and anti-PD-1 was assessed both in vitro and in a hu-PBMC-CDX mouse model.

We evaluated the effects of an EZH2 degrader on seven lymphoma cell lines and observed significant reductions in cell viability compared to EZH2 inhibitor, particularly in Burkitt's lymphoma cell lines. EZH2 degrader treatment reduced EZH2 and c-Myc expression, induced G2/M cell cycle arrest, and increased apoptosis markers, including cleaved caspase-3 and cleaved PARP. Furthermore, Burkitt's lymphoma is a PD-L1 negative tumor; however, treatment with the EZH2 degrader resulted in a slight increase in PD-L1 expression. Combining EZH2 degrader with anti-PD-1 significantly enhanced anti-tumor effects compared to monotherapy. In vivo studies using a humanized lymphoma mouse model demonstrated a synergistic anti-tumor effect of EZH2 degrader and anti-PD-1, which was attributed to apoptosis-related pathways.

These findings aim to provide insights into the therapeutic potential of targeting EZH2 in combination with immune checkpoint inhibitors for improved treatment of lymphomas.

The tumor microenvironment (TME) is a complex, dynamic ecosystem where tumor cells interact with diverse immune and stromal cell types. This review provides an overview of the TME's evolving composition, emphasizing its transition from an early pro-inflammatory, immune-promoting state to a later immunosuppressive milieu characterized by metabolic reprogramming and hypoxia. It highlights the dual roles of key immunocytes-including T lymphocytes, natural killer cells, macrophages, dendritic cells, and myeloid-derived suppressor cells-which can either inhibit or support tumor progression based on their phenotypic polarization and local metabolic conditions. The article further elucidates mechanisms of immune cell plasticity, such as the M1/M2 macrophage switch and the balance between effector T cells and regulatory T cells, underscoring their impact on tumor growth and metastasis. Additionally, emerging therapeutic strategies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T and NK cell therapies, as well as approaches targeting metabolic pathways, are discussed as promising avenues to reinvigorate antitumor immunity. By integrating recent molecular insights and clinical advancements, the review underscores the importance of deciphering the interplay between immunocytes and the TME to develop more effective cancer immunotherapies.

Immune checkpoint inhibitors (ICIs) have improved outcomes of patients with many different cancers. These antibodies target molecules such as programmed cell death 1 (PD-1) or cytotoxic T lymphocyte associated protein 4 (CTLA-4) which normally function to limit immune activity. Treatment with ICIs reactivates T cells to destroy tumor cells in a highly specific manner, which in some patients, results in dramatic remissions and durable disease control. Over the last decade, much effort has been directed at characterizing factors that drive efficacy and resistance to ICI therapy. Food and Drug Administration (FDA)-approved biomarkers for ICI therapy have facilitated more judicious treatment of cancer patients and transformed the field of precision oncology. Yet, adaptive immunity against cancers is complex, and newer data have revealed the potential utility of other biomarkers. In this review, we discuss the utility of currently approved biomarkers and highlight how emerging biomarkers can further improve the identification of patients who benefit from ICIs.

Combination radiotherapy (RT) and αPD-L1 therapy has potential to enhance local and distant (abscopal) tumor control, however, clinical results in humans have been variable. Using murine melanoma models, we found RT + αPD-L1 increases intra-tumor progenitor CD8+ PD-1+ TCF-1+ T cells. This increase depends on trafficking of the PD-1+ TCF-1+ cells from the tumor-draining lymph node (TdLN) to the tumor. RT alone promotes the expansion and differentiation of the TdLN derived PD-1+ TCF-1+ cells into TIM-3+ GZMB+ TCF-1- effector-like cells in the tumor with further enhancement after the addition of αPD-L1. In the TdLN, combination therapy enriches for a novel PD-1+ TCF-1+ TOX- LY6A+ subset with expression of a type I interferon and migratory signature. This subset is able to traffic to the tumor and differentiate into TIM-3+ TCF-1- cells. Finally, we found that ablation of the PD-1+ TCF-1+ T cell population attenuates the enhanced tumor control observed with combination RT + αPD-L1. These results suggest that abscopal response failures may be secondary to impaired stimulation of TdLN CD8+ PD-1 + TCF-1+ T cells or an inability of PD-1+ TCF-1+ cells in the TdLN to traffic to the tumor.

Since the first approval of an immune checkpoint inhibitor, we have witnessed the clinical success of cancer immunotherapy. Adoptive T-cell therapy with chimeric antigen receptor T (CAR-T) cells has shown remarkable efficacy in hematological malignancies. Concurrently with these successes, the cancer immunoediting concept that refined the cancer immunosurveillance concept underpinned the scientific mechanism and reason for past failures, as well as recent breakthroughs in cancer immunotherapy. Now, we face the next step of issues to be solved in this field, such as tumor heterogeneity, the tumor microenvironment, the metabolism of tumors and the immune system, and personalized approaches for patients, aiming to expand the population benefitted by the therapies.

Cancer treatment has long been hindered by the complexity of the tumor microenvironment (TME) and the mechanisms that tumors employ to evade immune detection. Recently, the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies has emerged as a promising approach to improve cancer treatment outcomes. This review delves into the role of immunostimulatory molecules and ICIs in enhancing anti-tumor immunity, while also discussing the therapeutic potential of anti-angiogenic strategies in cancer. In particular, we highlight the critical role of endoplasmic reticulum (ER) stress in angiogenesis. Moreover, we explore the potential of macrophage reprogramming to bolster anti-tumor immunity, with a focus on restoring macrophage phagocytic function, modulating hypoxic tumor environments, and targeting cytokines and chemokines that shape immune responses. By examining the underlying mechanisms of combining ICIs with anti-angiogenic therapies, we also review recent clinical trials and discuss the potential of biomarkers to guide and predict treatment efficacy.

Metastasis-related disease is a major cause of death in canine mammary tumours (CMTs). Immunotherapy has been investigated due to the less successful outcomes of systemic therapy. This study aims to examine the expression of Programmed Cell Death Ligand-1 (PD-L1) in canine mammary tumours in dogs of Chiang Mai, Thailand, and determine the relationship between the level of mRNA expression and clinicopathologic characteristics. A total of 28 CMT samples were collected at the Small Animal Hospital, Chiang Mai University. Quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot assays were performed. The results revealed that all CMTs in this study expressed PD-L1 mRNA and PD-L1 protein. The mean relative mRNA expression showed no significant differences between groups categorized by age, tumour size, or histopathological findings. However, the mean relative mRNA expression in tumours with a TNM stage >3 was significantly lower compared to those with TNM stage ≤2. In conclusion, this study investigates the expression of PD-L1 mRNA and PD-L1 protein, particularly in malignant CMTs. The findings strongly support the potential for developing effective immunotherapy methods targeting the PD-1/PD-L1 pathway for advanced CMTs in the future. For further conclusive assessment, future studies should focus on refining immunotherapy strategies for CMT cases expressing PD-L1.

Biomarkers of responsiveness to immune checkpoint blockade (ICB) are heavily sought given the breadth and depth of the use of ICB in cancer. PD-L1 expression was among the first biomarkers identified, but multiple factors have precluded more widespread use. In this issue, Galsky and colleagues utilize two separate PD-L1 assays to study urothelial carcinoma specimens and observe that SP142 (relative to 22C3) preferentially stains dendritic cells. These observations may help reconcile the discordant performance of the two PD-L1 assays in ICB-treated urothelial carcinoma while underscoring the role of dendritic cells in orchestrating ICB response. See related article by Galsky et al., p. 476 .

With low early detection rates and high incidence and mortality, Gastrointestinal cancer (GIC) imposes a significant global health burden. Emerging evidence indicates that periodontitis may be a potential risk factor for GIC development; however, epidemiological data remains inconclusive.

This study aimed to examine the impact of periodontitis on the incidence, recurrence, and metastasis of GIC in Southwest China, thereby offering epidemiological evidence to support GIC prevention and management.

Between September 2022 and August 2024, a case-control study was conducted at the Affiliated Hospital of North Sichuan Medical College. Five hundred GIC patients were included as the case group based on the predefined inclusion and exclusion criteria, while 1005 healthy individuals were recruited for the control group. Multivariate analyses were performed to examine the associations between periodontitis and GIC incidence, recurrence, and metastasis while controlling for potential confounding factors.

The results of this study demonstrated that periodontitis was significantly associated with the incidence of esophageal, gastric, and colorectal cancer. Even after adjusting for potential confounders, it remained a significant risk factor for esophageal cancer (OR = 2.810, 95% CI 1.032-7.649, P = 0.043), colon cancer (OR = 2.330, 95% CI 1.072-5.067, P = 0.033), and rectal cancer (OR = 2.730, 95% CI 1.247-5.379, P = 0.012). Compared to non-periodontitis subjects, periodontitis showed a significant association with distant metastasis of rectal cancer (aHR = 5.332, 95% CI 1.406-20.220, P = 0.014). Moreover, severe periodontitis was identified as an risk factor for distant metastasis in rectal cancer (aHR = 10.138, 95% CI 1.824-56.354, P = 0.008).

This study highlights significant associations between periodontitis and an increased risk of esophageal and colorectal cancers. Additionally, patients with rectal cancer and periodontitis exhibited an increased risk of distant metastasis compared to those without periodontitis.

Today, treating cancer patients with monoclonal antibodies (mAbs), by targeting immune checkpoints, is one of the most outstanding immunotherapeutic methods. Immune checkpoints are special molecules having regulatory role in immune system responses. Once these molecules are presented on cancer cells, these cells will be capable of evading the immune system through their own specific pathways. This Evasion can be prevented by counterbalancing immune system responses with immune checkpoints related antibodies.

The current study aimed to highlight immunotherapy and its methods, describe the immune checkpoints pathways, outline the immune checkpoint inhibitors (ICIs), and recent advances in this field, and sketch an outlook on the best treatment options for the most prevalent cancers.

This research implemented a narrative review method. A comprehensive literature review on the history, molecular and cellular biology, and the clinical aspects of immune checkpoint molecules was performed to illustrate the pathways involved in various cancers. Also, currently-available and future potential immunotherapies targeting these pathways were extracted from the searched studies.

The immune checkpoint family consists of many molecules, including CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, and TIGIT. Attempts to modify these molecules in cancer treatment led to the development of therapeutic monoclonal antibodies. Most of these antibodies have entered clinical studies and some of them have been approved by the Food and Drug Administration (FDA) to be used in cancer patients' treatment plans.

With these novel treatments and the combination therapies they offer, there is also hope for better treatment outcomes for the previously untreatable metastatic cancers. In spite of the beneficial aspects of immune checkpoint therapy, similar to other treatments, they may cause side effects in some patients. Therefore, more studies are needed to reduce the probable side effects and uncover their underlying mechanism.

Based on the data shown in this review, there is still a lack of knowledge about the complete properties of ICIs and the possible combination therapies that we may be able to implement to achieve a better treatment response in cancer patients.

Immunotherapies blocking cell surface signaling of the immune checkpoint PD-L1 have shown great promise in several cancers, but the results have been disappointing in ovarian cancer (OC). One of the main underlying mechanisms likely consists of the cell-intrinsic intracellular functions of PD-L1, which are incompletely understood. The expression of PD-L1 in OC cells is induced by interferon-γ (IFNγ), a pleiotropic cytokine produced in response to chemotherapy or immune checkpoint blockade. We have recently shown that IFNγ induces expression of the proto-oncogene Bcl3, the proangiogenic chemokine interleukin-8 (IL-8)-CXCL8, and the transcription factor STAT1, resulting in increased OC cell proliferation and migration. Here, we report that IFNγ-induced expression of PD-L1 results in PD-L1 recruitment to IL-8, Bcl3, and STAT1 promoters. The occupancy of PD-L1 at IL-8, Bcl3, and STAT1 promoters is associated with increased histone acetylation and RNA polymerase II recruitment to these promoters. Suppression of IFNγ-induced PD-L1 decreases the expression of IL-8, Bcl3, and PD-L1 and increases apoptosis in OC cells. Together, these findings demonstrate that PD-L1 promotes transcription of IL-8, Bcl3, and STAT1, thus providing a novel function of PD-L1 in cancer cells, and suggesting that the increased IL-8, Bcl3, and STAT1 expression mediated by PD-L1 might contribute to the limited effectiveness of cancer immunotherapies targeting the surface expression of PD-L1 in OC.

Resistance to BRAF plus MEK inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives rebound, progression, and high mortality, yet it remains poorly understood. This study addresses the urgent need to develop treatments for BRAFi+MEKi-resistant glioma in novel mouse models and patient-derived materials. BRAFi+MEKi reveals glioma plasticity by heightening cell state transitions along glial differentiation trajectories, giving rise to astrocyte- and immunomodulatory oligodendrocyte (OL)-like states. PD-L1 upregulation in OL-like cells links cell state transitions to tumor evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi induces interferon response signatures, tumor infiltration, and suppression of T cells. Combining BRAFi+MEKi with immune checkpoint inhibition enhances survival in a T cell-dependent manner, reinvigorates T cells, and outperforms individual or sequential therapies in mice. Elevated PD-L1 expression in BRAF-mutant versus BRAF-wildtype glioblastoma supports the rationale for PD-1 inhibition in patients. These findings underscore the potential of targeting glioma plasticity and highlight combination strategies to overcome therapy resistance in BRAFV600E-mutant HGG.

The arachidonic acid (AA) pathway promotes tumor progression by modulating the complex interactions between cancer and immune cells within the microenvironment. In this Review, we summarize the knowledge acquired thus far concerning the intricate mechanisms through which eicosanoids either promote or suppress the antitumor immune response. In addition, we will discuss the impact of eicosanoids on immune cells and how they affect responsiveness to immunotherapy, as well as potential strategies for manipulating the AA pathway to improve anticancer immunotherapy. Understanding the molecular pathways and mechanisms underlying the role played by AA and its metabolites in tumor progression may contribute to the development of more effective anticancer immunotherapies.

Targeting immune checkpoint proteins (ICPs) via small molecules open a new window for cancer immunotherapy. Herein, we summarize recent advances of small molecules with novel chemical structures targeting ICPs, discusses their anti-tumor efficacies, which are important for the development of novel small molecules for cancer immunotherapy.

In this review, the latest patents and literature were gathered through the comprehensive searches in the databases of European Patent Office (EPO), Cortellis Drug Discovery Intelligence (CDDI), PubMed and Web of Science using ICPs and compounds as key words.

To develop novel weapons to fight against cancer, small molecules targeting ICPs including CTLA-4, LAG-3, PD-L1, Siglec-9, TIM-3, TIGIT, and VISTA have been synthesized and evaluated in succession. Chief among them are the small molecules targeting PD-L1, which have been intensively investigated in recent years. Various in vitro assays such as ALPHA, HTRF binding assay, NFAT assay have been successfully developed to screen novel IPCs inhibitors. However, the in vivo assay, for example, using double-humanized PD-1/PD-L1 (hPD-1/hPD-L1) mouse as evaluation model, are seldom reported. Novel pharmacophores with new working mechanisms such as proteolysis targeting chimeras (PROTACs) and peptides are needed to enhance the therapeutic efficacy.

The use of cancer vaccines represents a promising avenue in cancer immunotherapy. Advances in next-generation sequencing (NGS) technology, coupled with the development of sophisticated analysis tools, have enabled the identification of somatic mutations by comparing genetic sequences between normal and tumor samples. Tumor neoantigens, derived from these mutations, have emerged as potential candidates for therapeutic cancer vaccines. In this study, raw NGS data from two melanoma patients (NCI_3903 and NCI_3998) were analyzed using publicly available SRA datasets from NCBI to identify patient-specific neoantigens. A comprehensive pipeline was employed to select candidate peptides based on their antigenicity, immunogenicity, physicochemical properties, and toxicity profiles. These validated epitopes were utilized to design multi-epitope chimeric vaccines tailored to each patient. Peptide linkers were employed to connect the epitopes, ensuring optimal vaccine structure and function. The two-dimensional (2D) and three-dimensional (3D) structures of the chimeric vaccines were predicted and refined to ensure structural stability and immunogenicity. Furthermore, molecular docking simulations were conducted to evaluate the binding interactions between the vaccine chimeras and the HLA class I receptors, confirming their potential to elicit a robust immune response. This work highlights a personalized approach to cancer vaccine development, demonstrating the feasibility of utilizing neoantigen-based immunoinformatics pipelines to design patient-specific therapeutic vaccines for melanoma.