Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, with limited success in traditional therapies due to the fibrotic, immunosuppressive, pro-metastatic tumor microenvironment (TME), which collectively impede the drug accumulation and accelerate the tumor progression. In this work, we developed a PDAC-customized nutrient-mimicking reconstituted high-density lipoprotein (rHDL) capable of efficiently co-encapsulate versatile TME regulating cannabidiol and cytotoxic gemcitabine to simultaneously reprogram TME while suppressing PDAC progression. Specifically, a small-sized, nutrient-like rHDL was constructed to realize deep PDAC parenchyma penetration and efficient intra-tumoral uptake. Next, natural herbal compound cannabidiol was screened and incorporated into rHDL to regulate TME via attenuating fibrosis, reliving immunosuppression and mitigating metastatic tendency. At last, gemcitabine, the PDAC gold standard first-line therapy was co-delivered by the PDAC-customized rHDL to overcome drug resistance and amplify its PDAC suppression. Our findings demonstrate the feasibility of an integrated multi-stage TME regulation strategy for improved PDAC therapy, and might represent a modality in promoting chemotherapy against PDAC.

Colorectal cancer (CRC) is an important public health issue and is the third most common cancer, accounting for approximately 10% of all cancer cases worldwide. CRC results from the accumulation of multiple genetic and epigenetic alterations in the normal epithelial cells of the colon and rectum, leading to the development of colorectal polyps and invasive carcinomas. The transforming growth factor-beta (TGF-β) pathway is regulated in many diseases, such as cancer. This factor can show tumor suppressant function in the early stages in healthy and cancer cells. It can be regulated and affected by different factors, including noncoding RNAs, which are the remarkable regulators for this pathway. The most prominent functions of this factor are cell cycle arrest and apoptosis in cancer cells. However, activating at the final stages of the cell cycle can cause tumor metastasis. Thus, the dual function of TGF-β and the pleiotropic nature of this signaling make it a crucial challenge for cancer treatment. Accurately studying the TGF-β signaling pathway is critical to determine its role. One of the roles of TGF-β signaling is its significant effect on colorectal polyp malignancy and cancer. In this article, we review the published scientific papers regarding the TGF-β signaling pathway, its related genes, and their contribution to precancerous conditions and colorectal cancer progression. The complex interaction of the TGF-β signaling pathway with noncoding RNAs, such as lncRNA TUG1 and miR-21, significantly influences colorectal polyp and cancer progression. Identifying dysregulated TGF-β-related noncoding RNAs offers promising therapeutic avenues for colorectal cancer. Comprehending TGF-β's connection to other molecular mechanisms is crucial for advancing effective therapeutic strategies.

Background: This study was aimed at elucidating the mechanisms underlying the development of treatment resistance in patients with acute myeloid leukemia (AML) other than M3 myeloid leukemia in order to devise ways to overcome treatment resistance and improve the treatment outcomes in these patients. Methods: For this study, we randomly selected 35 patients with AML who had received combined cytarabine plus idarubicin treatment for new-onset AML at our hospital. We performed immunohistochemical analysis of biopsy specimens obtained from the patients to investigate the expressions of 23 treatment-resistance-related proteins, and retrospectively analyzed the correlations between the expression profiles of the resistance proteins and the patient survival. Results: The following four proteins were identified as being particularly significant in relation to treatment resistance and patient prognosis: (1) p53; (2) multidrug resistance-associated protein 1 (MRP1; idarubicin extracellular efflux pump); (3) aldo-keto reductase family 1 member B10 (AKR1B10; idarubicin-inactivating enzyme); and (4) AKR1B1 (competitive inhibitor of AKR1B10). Based on our findings, we propose the following Urayasu classification for AML, which we believe would be very useful for accurately stratifying patients with AML according to the predicted prognosis: Group 1 (n = 22, 63%): p53(-)/MRP1(-) associated with AKR1B10(+)/AKR1B1(+) or AKR1B10(-)/AKR1B1(-); 5-year overall survival (OS), 82%-100%; Group 2 (n = 9, 26%): p53(-)/MRP1(-) associated with AKR1B10(+)/AKR1B1(-); 5-year OS, 68%; Group 3 (n = 4, 11%): p53(+) or MRP1(+); median survival, 12-14 months; 2-year OS, 0%. Conclusions: The Urayasu classification for AML is useful for predicting the prognosis of patients with AML. Group 1 in this classification included twice as many patients as that included in the Favorable prognosis group in the AML prognostic classification proposed by the European Leukemia Net. As the Urayasu classification for AML is based on the mechanisms of resistance to chemotherapy, it is not only useful for prognostic stratification of the patients, but also provides insights for developing more effective treatments for AML.

Cutaneous T-cell lymphoma (CTCL), characterized by malignant T-cell proliferation primarily in the skin, includes subtypes such as mycosis fungoides (MF) and Sézary syndrome (SS). The tumor microenvironment (TME) is central to their pathogenesis, with flow cytometry and histology being the gold standards for detecting malignant T cells within the TME. Alongside emerging molecular markers, particularly clonality analysis, these tools are indispensable for accurate diagnosis and treatment planning. Of note, adenosine signaling within the TME has been shown to suppress immune responses, affecting various cell types. The expression of CD39, CD73, and CD38, enzymes involved in adenosine production, can be elevated in MF and SS, contributing to immune suppression. Conversely, the expression of CD26, part of the adenosine deaminase/CD26 complex, that degrades adenosine, is often lost by circulating tumoral cells. Flow cytometry has demonstrated increased levels of CD39 and CD73 on Sézary cells, correlating with disease progression and prognosis, while CD38 shows a variable expression, with its prognostic significance remaining under investigation. Understanding these markers' roles in the complexity of TME-mediated immune evasion mechanisms might enhance diagnostic precision and offer new therapeutic targets in CTCL.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

Cancer is characterized by unregulated cell proliferation, enabling it to invade and spread to different organs and tissues in the body. Cancer progression is intricately influenced by the complex dynamics within the tumor microenvironment (TME). The TME is a composite and dynamic network comprising cancer cells and various immune cells, including tumor-associated macrophages. Exosomes facilitate the communication between different cancer cells as well as other types of cells. This review particularly focuses on exosomal proteins derived from different cancer cells in mounting the complex crosstalk between cells of cancer and macrophages within the TME. Most cancer-derived exosomal proteins polarize macrophages towards M2 phenotype, promoting cancer aggressiveness, while a few have role switching towards the M1 phenotype, inhibiting cancer proliferation, respectively. In this review, we summarize, for the first time, the dual impact of cancer cell-derived exosomal proteins on macrophage polarization and the associated signaling pathways, offering valuable insights for developing innovative therapeutic strategies against diverse cancer types.

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

Clear cell renal cell carcinoma (ccRCC) poses a significant global health challenge as its incidence continues to rise, resulting in a substantial annual mortality rate. Major clinical challenges to current ccRCC treatments include high drug-resistance rates as well as dose-limiting adverse events; underlining the need to identify additional 'druggable' targets. TGF-β1, VEGF, and PD-L1 are potential therapeutic targets in ccRCC. This study analyzed their expression in human ccRCC cell lines and patient tumor biopsies. Data obtained from western blotting demonstrated higher levels of TGF-β1 and PD-L1 and lower levels of VEGF in sarcomatoid ccRCC cell lines compared to non-sarcomatoid ccRCC cell lines. In patient samples, TGF-β1 was significantly upregulated in both non-sarcomatoid and sarcomatoid ccRCC tumors. It was demonstrated through two assays (cellular thermal shift assay and a size exclusion assay) that methylseleninic acid (MSA) binds specifically and directly to TGF-β1. MSA treatment significantly downregulated TGF-β1, PD-L1, and VEGF in a dose- and time-dependent manner in both non-sarcomatoid and sarcomatoid ccRCC cell lines. Seleno-L-methionine (SLM) treatment in a nude mouse xenograft model showed a significant tumor growth inhibition and TGF-β1 downregulation at non-toxic doses. These findings suggest that selenium-mediated downregulation of TGF-β1, PD-L1, and VEGF could be a viable therapeutic strategy for ccRCC.

Radiation therapy (RT), a mainstay treatment for head and neck squamous cell carcinoma (HNSCC), kills cancer cells and modulates the tumor immune microenvironment. We sought to assess the effect of RT in combination with PD-L1/TGF-β dual blockade in squamous cell carcinomas (SCC) and analyze the underlying mechanisms. We transplanted mouse SCC cells derived from keratin-15 (K15) stem cells harboring KrasG12D/Smad4-/- mutations into syngeneic recipients and irradiated tumors followed by PD-L1/TGF-β dual blockade. We identified a responder line and a non-responder line to this combination therapy. Responder hosts eradicated SCCs by the combined therapy and rejected re-transplanted SCC cells 6 months post tumor eradication, which correlated with clonotype expansions of splenic CD8 T cells and effector memory gene expression identified by single cell sequencing of TCR and transcriptomes, respectively. Mechanistically, RT upregulated MHC-I (major histocompatibility complex I) and its transcriptional regulators including NLRC5, in SCCs of the responders but not non-responders. These data are consistent with the TCGA HNSCC database in which NLRC5 correlated to MHC-I genes and CD8 T cell gene expression. Functional contribution of MHC-I to PD-L1/TGF-β blockade response was confirmed by knocking out beta-2-microglobulin in responder cells that attenuated the response to the same therapy. Thus, the therapeutic effectiveness appeared to largely depend on cancer-cell MHC-I expression, triggering CD8 T cell effector memory-driven responses against tumor cell antigens. Identifying the differential RT response to MHC-I induction may serve as a predictive marker for stratifying patients that are most likely to benefit from this combination therapy.

Transforming Growth Factor-beta (TGF-β) is a multifunctional cytokine that exerts its biological effects through a complex process of activation and signaling. Initially synthesized in an inactive form bound to latency-associated peptide (LAP), TGF-β requires release from the extracellular matrix via proteolytic cleavage or integrin-mediated activation to engage with its receptors. Once active, TGF-β binds to type II receptor (TβRII), which then phosphorylates and activates type I receptor (TβRI), triggering downstream signaling cascades, including both Smad-dependent and non-Smad pathways. These signaling cascades regulate key processes like cell growth, differentiation, migration, and immune response modulation, thereby influencing tumor development, progression, and treatment outcomes. This review discusses the complex signaling pathways of TGF-β in cancer, including its interactions with other signaling molecules and its involvement in epithelial-mesenchymal transition (EMT) and in evading immune surveillance. Moreover, dysregulated TGF-β signaling due to alterations in receptor expression, mutations in key signaling proteins such as TβRII and Smads, and aberrant activation of non-canonical pathways, contributes significantly to tumor aggressiveness, metastasis, and therapy resistance. The article emphasizes the potential of TGF-β as a diagnostic biomarker for cancer, highlighting its use in early detection, prognosis assessment, and monitoring treatment response. Additionally, it underscores various therapeutic strategies targeting TGF-β, such as small molecule inhibitors, monoclonal antibodies, immunotherapies, and evaluates their efficacy and limitations in preclinical and clinical settings. Finally, the review provides a comprehensive analysis of TGF-β's role as both a diagnostic tool and a therapeutic target, while also discussing the challenges and opportunities in targeting TGF-β signaling for improving cancer treatment outcomes.

The tumor microenvironment (TME) is critical for cancer initiation, growth, metastasis, and therapeutic resistance. The extracellular matrix (ECM) is a significant tumor component that serves various functions, including mechanical support, TME regulation, and signal molecule generation. The quantity and cross-linking status of ECM components are crucial factors in tumor development, as they determine tissue stiffness and the interaction between stiff TME and cancer cells, resulting in aberrant mechanotransduction, proliferation, migration, invasion, angiogenesis, immune evasion, and treatment resistance. Therefore, broad knowledge of ECM dysregulation in the TME might aid in developing innovative cancer therapies. This review summarized the available information on major ECM components, their functions, factors that increase and decrease matrix stiffness, and related signaling pathways that interplay between cancer cells and the ECM in TME. Moreover, mechanotransduction alters during tumorogenesis, and current drug therapy based on ECM as targets, as well as future efforts in ECM and cancer, are also discussed.

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.

Endometrial cancer (EC) is the most common gynecologic malignancy with increasing incidence and mortality. The tumor immune microenvironment significantly impacts cancer prognosis. Weighted Gene Co-Expression Network Analysis (WGCNA) is a systems biology approach that analyzes gene expression data to uncover gene co-expression networks and functional modules. This study aimed to use WGCNA to develop a prognostic prediction model for EC based on immune cell infiltration, and to identify new potential therapeutic targets. WGCNA was performed using the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma dataset to identify hub modules associated with T-lymphocyte cell infiltration. Prognostic models were developed using LASSO regression based on genes in these hub modules. The Search Tool for the Retrieval of Interacting Genes/Proteins was used for protein-protein interaction network analysis of the hub module. Gene Set Variation Analysis identified differential gene enrichment analysis between high- and low-risk groups. The relationship between the model and microsatellite instability, tumor mutational burden, and immune cell infiltration was analyzed using The Cancer Genome Atlas data. The model's correlation with chemotherapy and immunotherapy resistance was examined using the Genomics of Drug Sensitivity in Cancer and Cancer Immunome Atlas databases. Immunohistochemical staining of EC tissue microarrays was performed to analyze the relationship between the expression of key genes and immune infiltration. The green-yellow module was identified as a hub module, with 4 genes (ARPC1B, BATF, CCL2, and COTL1) linked to CD8+ T cell infiltration. The prognostic model constructed from these genes showed satisfactory predictive efficacy. Differentially expressed genes in high- and low-risk groups were enriched in tumor immunity-related pathways. The model correlated with EC-related phenotypes, indicating its potential to predict immunotherapeutic response. Basic leucine zipper activating transcription factor-like transcription factor(BATF) expression in EC tissues positively correlated with CD8+ T cell infiltration, suggesting BATF's crucial role in EC development and antitumor immunity. The prognostic model comprising ARPC1B, BATF, CCL2, and COTL1 can effectively identify high-risk EC patients and predict their response to immunotherapy, demonstrating significant clinical potential. These genes are implicated in EC development and immune infiltration, with BATF emerging as a potential therapeutic target for EC.

Human health is endangered by the occurrence and progression of urological cancers, including renal cell carcinoma, prostate cancer and bladder cancer, which are usually associated with the activation of oncogenic factors and inhibition of cancer suppressors. The primary mechanism for protein breakdown in cells is the ubiquitin-proteasome system, whilst deubiquitinases contribute to the reversal of this process. However, both are important for protein homeostasis. Deubiquitination may also be involved in the control of the cell cycle, proliferation and apoptosis, and dysregulated deubiquitination is associated with the malignant transformation, invasion and metastasis of urologic malignancies. Therefore, a comprehensive summary of the mechanisms underlying deubiquitination in urological cancers may provide novel strategies and insights for diagnosis and treatment. The present review aimed to methodically clarify the role of deubiquitinating enzymes in urinary system cancers as well as their prospective application prospects for clinical treatment.

Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model.

The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon-liver metastasis in an animal model, and to elucidate the underlying mechanisms.

Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100 mg/kg) for 21 days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R).

The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling.

In conclusion, berberine evidently possess an anti-colon-liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC.

Transforming growth factor beta (TGF-β) is a member of the growth factor superfamily that clinical studies address its association with bladder cancer invasion, progression, and metastasis. The present systematic review and meta-analysis aimed to explore the prognostic significance of TGF-β expression in bladder cancer patients.

The major international databases, including PubMed, Web of Science, Embase, and Scopus, were searched for full-text literature citations. The hazard ratio (HR) with a 95% CI as the effect size was applied as the appropriate summarized statistic. We used a random-effects model using the DerSimonian and Laird method to estimate the pooled effect size. To assess the heterogeneity among trials, the I-square (I 2 ) statistic and Cochran's Q test were used. Forest and funnel plots were drawn to respectively demonstrate the findings and detect any existing publication bias.

This meta-analysis included 3 studies that met the criteria and included 535 patients. The combined HR for the selected studies was 2.250 (95% CI=(1.411, 3.586), P< .001) and no significant heterogeneity was detected between trials (I 2=58.63, P=.089). Furthermore, no severe asymmetry was seen within the funnel plot, indicating a lack of potential publication bias.

Our findings suggest that TGF-β expression can remarkably predict a worse prognosis in patients with bladder cancer. The results of the present meta-analysis may be validated through further updated reviews and additional relevant investigations in future studies.

Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.

Biomaterials have potential applications in the treatment of myocardial infarction (MI). These biomaterials have the ability to mechanically support the ventricular wall and to modulate the inflammatory, metabolic, and local electrophysiological microenvironment. In addition, they can play an equally important role in promoting angiogenesis, which is the primary prerequisite for the treatment of MI. A variety of biomaterials are known to exert pro-angiogenic effects, but the pro-angiogenic mechanisms and functions of different biomaterials are complex and diverse, and have not yet been systematically described. This review will focus on the pro-angiogenesis of biomaterials and systematically describe the mechanisms and functions of different biomaterials in promoting angiogenesis in MI.

Transforming growth factor β (TGF-β) is a ubiquitous molecule that is extremely conserved structurally and plays a systemic role in human organism. TGF-β is a homodimeric molecule consisting of two subunits joined through a disulphide bond. In mammals, three genes code for TGF-β1, TGF-β2, and TGF-β3 isoforms of this cytokine with a dominating expression of TGF-β1. Virtually, all normal cells contain TGF-β and its specific receptors. Considering the exceptional role of fine balance played by the TGF-β in anumber of physiological and pathological processes in human body, this cytokine may be proposed for use in medicine as an immunosuppressant in transplantology, wound healing and bone repair. TGFb itself is an important target in oncology. Strategies for blocking members of TGF-β signaling pathway as therapeutic targets have been considered. In this review, signalling mechanisms of TGF-β1 action are addressed, and their role in physiology and pathology with main focus on carcinogenesis are described.

Mesenchymal stem cells (MSCs) exhibit multipotency, self-renewal, and immune-modulatory properties, making them promising in regenerative medicine, particularly in cardiovascular treatments. However, optimizing the MSC source and induction method of cardiac differentiation is challenging. This study compares the cardiomyogenic potential of bone marrow (BM)-MSCs and adipose-derived (AD)-MSCs using 5-Azacytidine (5-Aza) alone or combined with low doses of Fibroblast Growth Factor (FGF) and Insulin-like Growth Factor (IGF). BM-MSCs and AD-MSCs were differentiated using two protocols: 10 μmol 5-Aza alone and 10 μmol 5-Aza with 1 ng/mL FGF and 10 ng/mL IGF. Morphological, transcriptional, and translational analyses, along with cell viability assessments, were performed. Both the MSC types exhibited similar morphological changes; however, AD-MSCs achieved 70-80% confluence faster than BM-MSCs. Surface marker profiling confirmed CD29 and CD90 positivity and CD45 negativity. The differentiation protocols led to cell flattening and myotube formation, with earlier differentiation in AD-MSCs. The combined protocol reduced cell mortality in BM-MSCs and enhanced the expression of cardiac markers (MEF2c, Troponin I, GSK-3β), particularly in BM-MSCs. Immunofluorescence confirmed cardiac-specific protein expression in all the treated groups. Both MSC types exhibited the expression of cardiac-specific markers indicative of cardiomyogenic differentiation, with the combined treatment showing superior efficiency for BM-MSCs.

Severe trauma is an intractable problem in healthcare. Patients have a widespread immune system response that is complex and vital to survival. Excessive inflammatory response is the main cause of poor prognosis and poor therapeutic effect of medications in trauma patients. Cytokines are signaling proteins that play critical roles in the body's response to injuries, which could amplify or suppress immune responses. Studies have demonstrated that cytokines are closely related to the severity of injuries and prognosis of trauma patients and help present cytokine-based diagnosis and treatment plans for trauma patients. In this review, we introduce the pathophysiological mechanisms of a traumatic inflammatory response and the role of cytokines in trauma patients. Furthermore, we discuss the potential of cytokine-based diagnosis and therapy for post-traumatic inflammatory response, although further clarification to elucidate the underlying mechanisms of cytokines following trauma is warranted.

Voltage-gated sodium channels (VGSCs) initiate action potentials in electrically excitable cells and tissues. Surprisingly, some VGSC genes are aberrantly expressed in a variety of cancers, derived from "non-excitable" tissues that do not generate classic action potentials, showing potential as a promising pharmacological target for cancer. Most of the previous review articles on this topic are limited in scope, and largely unable to provide researchers with a comprehensive understanding of the role of VGSC in cancers. Here, we review the expression patterns of all nine VGSC α-subunit genes (SCN1A-11A) and their four regulatory β-subunit genes (SCN1B-4B). We reviewed data from the Cancer Genome Atlas (TCGA) database, complemented by an extensive search of the published papers. We summarized and reviewed previous independent studies and analyzed the VGSC genes in the TCGA database regarding the potential impact of VGSC on cancers. A comparison between evidence gathered from independent studies and data review was performed to scrutinize potential biases in prior research and provide insights into future research directions. The review supports the view that VGSCs play an important role in diagnostics as well as therapeutics of some cancer types, such as breast, colon, prostate, and lung cancer. This paper provides an overview of the current knowledge on voltage-gated sodium channels in cancer, as well as potential avenues for further research. While further research is required to fully understand the role of VGSCs in cancer, the potential of VGSCs for clinical diagnosis and treatment is promising.

Penile induration disease, commonly known as Peyronie's disease (PD), is a connective tissue disorder that affects the penis, leading to the development of fibrous plaques, penile curvature, and erectile dysfunction. PD is a common male reproductive system disease with a complex etiology involving multiple genes, signaling pathways, and different phenotypes.

The etiology and pathogenesis of PD remain poorly understood, hindering the development of effective treatment strategies. By understanding the underlying mechanisms of PD, we can pave the way for targeted therapies and improved patient outcomes.

We reviewed the epidemiology and pathophysiology of PD. We performed database searches on Google Scholar, PubMed, Medline, and Web of Science from inception to September 2023. The literature reviewed included priapism guidelines, review articles, current trial studies, and various literature related to PD.

This article provides a comprehensive overview of the current research progress on the disease, focusing on its genetic factors, signaling pathways, cellular mechanisms, phenotypic manifestations, and therapeutic targets. It can help identify individuals at higher risk, aid in early detection and intervention, and provide insights into fibrosis and tissue remodeling. It can also reveal potential therapeutic targets, guide accurate diagnoses and treatment strategies, and address the impact of the disease on patients' quality of life.

By integrating insights from genomics, molecular pathways, clinical phenotypes, and therapeutic potentials, our research aims to achieve a deeper and more comprehensive understanding of PD, propelling the field toward innovative strategies that enhance the lives of those affected by PD. The complex manifestations and pathogenesis of PD necessitate the use of multiple treatment methods for personalized care.

The TGFβ type II receptor (TβRII) is a central player in all TGFβ signaling downstream events, has been linked to cancer progression, and thus, has emerged as an auspicious anti-TGFβ strategy. Especially its targeted degradation presents an excellent goal for effective TGFβ pathway inhibition. Here, cellular structure-activity relationship (SAR) data from the TβRII degrader chemotype 1 was successfully transformed into predictive ligand-based pharmacophore models that allowed scaffold hopping. Two distinct 3,4-disubstituted indoles were identified from virtual screening: tetrahydro-4-oxo-indole 2 and indole-3-acetate 3. Design, synthesis, and screening of focused amide libraries confirmed 2r and 3n as potent TGFβ inhibitors. They were validated to fully recapitulate the ability of 1 to selectively degrade TβRII, without affecting TβRI. Consequently, 2r and 3n efficiently blocked endothelial-to-mesenchymal transition and cell migration in different cancer cell lines while not perturbing the microtubule network. Hence, 2 and 3 present novel TβRII degrader chemotypes that will (1) aid target deconvolution efforts and (2) accelerate proof-of-concept studies for small-molecule-driven TβRII degradation in vivo.

Lung cancer is a malignant tumor that develops in the lungs due to the uncontrolled growth of aberrant cells. Heavy metals, such as arsenic, cadmium, mercury, and lead, are metallic elements characterized by their high atomic weights and densities. Anthropogenic activities, such as industrial operations and pollution, have the potential to discharge heavy metals into the environment, hence presenting hazards to ecosystems and human well-being. The TGF-β signalling pathways have a crucial function in controlling several cellular processes, with the ability to both prevent and promote tumor growth. TGF-β regulates cellular responses by interacting in both canonical and non-canonical signalling pathways. Research employing both in vitro and in vivo models has shown that heavy metals may trigger TGF-β signalling via complex molecular pathways. Experiments conducted in a controlled laboratory environment show that heavy metals like cadmium and arsenic may directly bind to TGF-β receptors, leading to alterations in their structure that enable the receptor to be phosphorylated. Activation of this route sets in motion subsequent signalling cascades, most notably the canonical Smad pathway. The development of lung cancer has been linked to heavy metals, which are ubiquitous environmental pollutants. To grasp the underlying processes, it is necessary to comprehend their molecular effect on TGF-β pathways. With a particular emphasis on its consequences for lung cancer, this abstract delves into the complex connection between exposure to heavy metals and the stimulation of TGF-β signalling.

Transforming Growth Factor-Beta (TGF-β) signalling pathway is of paramount importance in the processes of wound healing, epidermal integrity maintenance and development of skin cancer. The objective of this research endeavour was to clarify the impact of gene mutations and variations in expression within TGF-β family on mechanisms of tissue repair, as well as to identify potential targets for therapeutic purposes in non-melanoma skin cancer (NMSC). The methods utilized in this study involved obtaining RNA-seq data from 224 NMSC patients and paired normal skin tissues from the PRJNA320473 and PRJEB27606 databases. The purpose of the differential gene expression analysis was to identify genes whose expression had changed significantly. In order to evaluate the effects and interrelationships of identified gene variants, structural analysis with AlphaFold and PDB data and network analysis with the STRING database were both utilized. Critical gene expression was externally validated through the utilization of the GEPIA database. Tumour tissues exhibited a notable upregulation of genes associated with the TGF-β pathway, specifically MMP1, MMP3, MMP9, EGF, COL3A1 and COL1A2, in comparison with normal tissues. As indicated by the central node status of these genes in the network analysis, they play a crucial role in the progression of NMSCs. The results of the structural analysis suggested that mutations might cause functional disruptions. External validation of the upregulation confirmed the expression trends and emphasized the biomarker potential of the upregulated genes. In conclusion, this research offered thorough examination of molecular modifications that occur in TGF-β family genes, which are linked to cutaneous wound healing and NMSC. The modified expression of the identified hub genes may represent innovative targets for therapeutic intervention.

Found in many fruits and plants, Ursolic acid (UA), a pentacyclic triterpene that occurs naturally, is recognized for its anti-cancer effects, especially in combating glioblastoma. However, the intricate molecular mechanisms underpinning its anti-tumor actions are still not fully understood, despite the recognition of these effects. By examining the functions of epithelial-mesenchymal transition (EMT) and angiogenesis, crucial for glioblastoma progression, and their regulation through Transforming Growth Factor Beta (TGFβ) - a key marker for glioblastoma, our research aims to fill this knowledge gap. This study explores how ursolic acid can block the progression of glioblastoma by precisely targeting TGFβ-triggered EMT and angiogenesis. The findings show that UA successfully blocks the spread, movement, and invasion of glioblastoma cells. Accompanying this, there is a significant reduction in the expression of TGFβ and crucial EMT indicators like snail and vimentin. Furthermore, UA shows a reduction in angiogenesis that depends on the dosage, highlighted by decreased vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs). Interestingly, increased TGFβ expression in U87 and U251 glioblastoma cell lines was found to weaken UA's anti-tumor properties, shedding more light on TGFβ's critical function in glioblastoma's pathology. Supporting these laboratory results, UA also showed considerable inhibition of tumor growth in a glioblastoma xenograft mouse model. Overall, our research emphasizes Ursolic acid's promise as a new treatment for glioblastoma and clarifies its action mechanism, mainly by inhibiting TGFβ signaling and thereby EMT and angiogenesis.

This study aimed to explore novel tumor immune microenvironment (TIME)-associated biomarkers in prostate adenocarcinoma (PRAD).

PRAD RNA-sequencing data were obtained from UCSC Xena database as the training dataset. The ESTIMATE package was used to evaluate stromal, immune, and tumor purity scores. Differentially expressed genes (DEGs) related to TIME were screened using the immune and stromal scores. Gene functions were analyzed using DAVID. The LASSO method was performed to screen prognostic TIME-related genes. Kaplan-Meier curves were used to evaluate the prognosis of samples. The correlation between the screened genes and immune cell infiltration was explored using Tumor IMmune Estimation Resource. The GSE70768 dataset from the Gene Expression Omnibus was used to validate the expression of the screened genes.

The ESTIMATE results revealed that high immune, stromal, and ESTIMATE scores and low tumor purity had better prognoses. Function analysis indicated that DEGs are involved in the cytokine-cytokine receptor interaction signaling pathway. In TIME-related DEGs, METTL7B, HOXB8, and TREM1 were closely related to the prognosis. Samples with low expression levels of METTL7B, HOXB8, and TREM1 had better survival times. Similarly, both the validation dataset and qRT-PCR suggested that METTL7B, HOXB8, and TREM1 were significantly decreased. The three genes showed a positive correlation with immune infiltration.

This study identified three TIME-related genes, namely, METTL7B, HOXB8, and TREM1, which correlated with the prognosis of patients with PRAD. Targeting the TIME-related genes might have important clinical implications when making decisions for immunotherapy in PRAD.

Physiological embryogenesis and adult tissue homeostasis are regulated by transforming growth factor-β (TGF-β), an evolutionarily conserved family of secreted polypeptide factors, acting in an autocrine and paracrine manner. The role of TGF-β in inflammation, fibrosis, and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, especially fibrosis and cancer, overexpressed TGF-β causes extracellular matrix deposition, epithelial-mesenchymal transition, cancer-associated fibroblast formation, and/or angiogenesis. In this review article, we have tried to dive deep into the mechanism of action of TGF-β in inflammation, fibrosis, and carcinogenesis. As TGF-β and its downstream signaling mechanism are implicated in fibrosis and carcinogenesis blocking this signaling mechanism appears to be a promising avenue. However, targeting TGF-β carries substantial risk as this pathway is implicated in multiple homeostatic processes and is also known to have tumor-suppressor functions. There is a need for careful dosing of TGF-β drugs for therapeutic use and patient selection.

The myogenic differentiation potential of MSCs is a key factor in their potential use as a cell source for muscle tissue repair and regeneration. Additionally, evaluating the immunomodulatory properties of MSCs is important to highlight their potential for regulating inflammation and supporting tissue regeneration. Given the limited literature on muscle differentiation potential and immunomodulatory properties, this study aims to characterize rat ADP MSCs for treating muscle disease. We isolated MSCs from adipose tissues around the periscapular region of the rats. We used a monoculture method for the myogenic differentiation and modified the myogenic induction medium by supplementing it with the growth factors FGF, HGF, and IGF. In rat ADP MSCs, expression of the MSC-specific marker, CD90, was 87.7%, while CD44 was 42.8%. For genes involved in immunomodulation, IGF1 and TGFB1 were highly expressed, while IL6 was poorly expressed. In addition to their trilineage differentiation potential, ADP MSCs exhibited the capacity to differentiate into myogenic cell lines, as evidenced by changes in cell morphology, leading to elongated and aligned structures and the expression of the MyoD and MYOG antibodies. The study found that ADP MSCs show great clinical promise for muscle regeneration.

Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.

Background: Cytokines modulate the glioma tumor microenvironment, influencing occurrence, progression, and treatment response. Strategic cytokine application may improve glioma immunotherapy outcomes. Gliomas remain refractory to standard therapeutic modalities, but immunotherapy shows promise given the integral immunomodulatory roles of cytokines. However, systematic evaluation of cytokine glioma immunotherapy research is absent. Bibliometric mapping of the research landscape, recognition of impactful contributions, and elucidation of evolutive trajectories and hot topics has yet to occur, potentially guiding future efforts. Here, we analyzed the structure, evolution, trends, and hotspots of the cytokine glioma immunotherapy research field, subsequently focusing on avenues for future investigation. Methods: This investigation conducted comprehensive bibliometric analyses on a corpus of 1529 English-language publications, from 1 January 2000, to 4 October 2023, extracted from the Web of Science database. The study employed tools including Microsoft Excel, Origin, VOSviewer, CiteSpace, and the Bibliometrix R package, to systematically assess trends in publication, contributions from various countries, institutions, authors, and journals, as well as to examine literature co-citation and keyword distributions within the domain of cytokines for glioma immunotherapy. The application of these methodologies facilitated a detailed exploration of the hotspots, the underlying knowledge structure, and the developments in the field of cytokines for glioma immunotherapy. Results: This bibliometric analysis revealed an exponential growth in annual publications, with the United States, China, and Germany as top contributors. Reviews constituted 17% and research articles 83% of total publications. Analysis of keywords like "interleukin-13," "TGF-beta," and "dendritic cells" indicated progression from foundational cytokine therapies to sophisticated understanding of the tumor microenvironment and immune dynamics. Key research avenues encompassed the tumor microenvironment, epidermal growth factor receptor, clinical trials, and interleukin pathways. This comprehensive quantitative mapping of the glioma immunotherapy cytokine literature provides valuable insights to advance future research and therapeutic development. Conclusion: This study has identified remaining knowledge gaps regarding the role of cytokines in glioma immunotherapy. Future research will likely focus on the tumor microenvironment, cancer vaccines, epidermal growth factor receptor, and interleukin-13 receptor alpha 2. Glioma immunotherapy development will continue through investigations into resistance mechanisms, microglia and macrophage biology, and interactions within the complex tumor microenvironment.

Continuous exposure to UVB is the main extrinsic cause of skin photodamage, which is associated with oxidative stress, DNA damage, apoptosis and degradation of collagen. Rapamycin, a mechanistic target inhibitor of rapamycin complex 1 (mTORC1), has been shown to play a crucial role anti-tumor and aging retardation, but its mechanism of action in UVB-induced photodamage still remains unknown. In this study, we investigated the role of rapamycin and Hspb2 (also known as Hsp27) in UVB-induced photodamage in mice.

We constructed skin acute photodamage models on the ears of WT and Hspb2 KO mice, respectively, and administered rapamycin treatment. Histological results showed that knockout of the hspb2 exacerbated the skin damage, as evidenced by thickening of the epidermis, breakage and disruption of collagen fibers and reduction in their number, which is reversed by rapamycin treatment. In addition, hspb2 knockout promoted UVB-induced apoptosis and reduced autophagy levels, with a significant increase in p53 levels and Bax/Bcl-2 ratio, a reduction in LC3II/I ratio and an increase in p62 levels in the KO mice compared to those in WT mice after the same dose of UVB irradiation. Rapamycin was also found to inhibit collagen degradation induced by hspb2 knockdown through activation of the TGF-β/Smad signaling pathway.

Rapamycin can alleviate skin photodamage from Hspb2 knockout to some extent. It may be a potential therapeutic drug for skin photodamage. In this study, we investigated the role of rapamycin and Hspb2 in UVB-induced photodamage in mice. Histological results showed that knockout of the hspb2 exacerbated the skin damage, as evidenced by thickening of the epidermis, breakage and disruption of collagen fibers and reduction in their number, which is reversed by rapamycin treatment. In addition, hspb2 knockout promoted UVB-induced apoptosis and reduced autophagy levels. Rapamycin was also found to inhibit collagen degradation induced by hspb2 knockdown through activation of the TGF-β/Smad signaling pathway. We conclude that rapamycin and Hspb2 exert a synergistic protective effect in skin photodamage.

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with a poor prognosis. Novel vascular-related therapeutic targets and prognostic markers remain urgently needed.

To investigate the role and mechanism of CLCA1 in hepatocellular carcinoma.

Immunofluorescence, Co-immunoprecipitation and rescue experiment were used to determine the specific mechanisms of CLCA1. Chemosensitivity assay was used to measure the impact of CLCA1 on Sorafenib.

CLCA1 was dramatically downregulated in hepatocellular carcinoma cell lines and tissues. Ectopic expression of CLCA1 induced cell apoptosis and G0/G1 phase arrest while suppressed cell growth, inhibited migration and invasion, reversal of epithelial mesenchymal transition in vitro and reduced xenograft tumor growth in vivo. Mechanistically, CLCA1 could co-localize and interact with TGFB1, thereby suppressing HCC angiogenesis through the TGFB1/SMAD/VEGF signaling cascade in vitro and in vivo. Moreover, CLCA1 also enhanced the sensitivity of HCC cells to the first-line targeted therapy, Sorafenib.

CLCA1 sensitizes HCC cells to Sorafenib and suppresses hepatocellular carcinoma angiogenesis through downregulating TGFB1 signaling cascade. This newly identified CLCA1 signaling pathway may help guide the anti-angiogenesis therapies for hepatocellular carcinoma. We also support the possibility of CLCA1 being a prognostic biomarker for hepatocellular carcinoma.

Transforming growth factor beta (TGF-β) initiates epithelial-mesenchymal transition (EMT) in tubular and glomerular epithelial cells, resulting in excessive production and deposition of extracellular matrix through its interaction with TGF-β receptors, which play a crucial role in TGF-β signaling involving two receptor types, namely TGF-β type I (TβRI) and type II (TβRII). EMT contributes to the pathogenesis of interstitial renal fibrosis, a marker of end-stage kidney disease. This study aimed to identify the bioactive compounds in the active fraction of P. angulata and evaluate their ability to inhibit the TGF-β activity and their potential as drug candidates. The active components in the active fraction of P. angulata were analyzed using gas chromatography-mass spectrometry (GC-MS). The bioactive compound structures were obtained from the PubChem database, while the protein targets, TβRI and TβRII, were retrieved from the Protein Data Bank (PDB). The molecular docking analyses were performed using PyRx 0.8 and Discovery Studio. SwissADME was used to evaluate ligand properties and druglikeness. Three dominant active compounds were identified, namely palmitic acid, campesterol, and stigmasterol. In silico studies demonstrated strong energy bonds existed between TβRI and palmitic acid, campesterol, stigmasterol, and SB431542 with binding energy values of -5.7, -10, -9.4, and -10.9 kcal/mol, respectively. Similarly, they strongly bound to TβRII with binding energy values of -5.2, -7.1, -7.5, and -6.1 kcal/mol, respectively. All compounds meet Lipinski's criteria for druglikeness. Among the identified active compounds, campesterol exhibited the highest affinity for TβRI, while stigmasterol exhibited a strong affinity for TβRII. These findings suggested that the three compounds have potential as drug candidates.

Vaccines for the deadliest brain tumor - glioblastoma (GBM) - are generally based on targeting growth factors or their receptors, often using antibodies. The vaccines described in the review were prepared to suppress the principal cancer growth factor - IGF-I, using anti-gene approaches either of antisense (AS) or of triple helix (TH) type. Our objective was to increase the median survival of patients treated with AS and TH cell vaccines.

The cells were transfected in vitro by both constructed IGF-I AS and IGF-I TH expression episomal vectors; part of these cells was co-cultured with plant phytochemicals, modulating IGF-I expression. Both AS and TH approaches completely suppressed IGF-I expression and induced MHC-1 / B7 immunogenicity related to the IGF-I receptor signal.

This immunogenicity proved to be stronger in IGF-I TH than in IGF-I AS-prepared cell vaccines, especially in TH / phytochemical cells. The AS and TH vaccines generated an important TCD8+ and TCD8+CD11b- immune response in treated GBM patients and increased the median survival of patients up to 17-18 months, particularly using TH vaccines; in some cases, 2- and 3-year survival was reported. These clinical results were compared with those obtained in therapies targeting other growth factors.

The anti-gene IGF-I vaccines continue to be applied in current GBM personalized medicine. Technical improvements in the preparation of AS and TH vaccines to increase MHC-1 and B7 immunogenicity have, in parallel, allowed to increase in the median survival of patients.

Transforming growth factor β (TGF-β) is a pleiotropic cytokine expressed by a wide range of cell types and is known for hampering the effectiveness of cancer immune cell therapeutic approaches. We have designed a novel construct containing the extracellular domain of the TGF-β receptor II linked to a glycosylphosphatidylinositol (GPI) anchor (GPI-ecto-TβRII) lacking the transmembrane and cytoplasmic signaling domain of TGF-β receptor II (TβRII). T cells transduced with lentivirus expressing the GPI-ecto-TβRII construct show 5 to 15 times higher membrane expression compared with a previously established dominant-negative receptor carrying a truncated signaling domain. GPI-ecto-TβRII expression renders T cells unresponsive to TGF-β-induced signaling seen by a lack of SMAD phosphorylation upon exogeneous TGF-β treatment. Transduced T cells continue to express high levels of IFNγ and granulocyte-macrophage colony-stimulating factor (GM-CSF), among other cytokines, in the presence of TGF-β while cytokine expression in untransduced T cells is being markedly suppressed. Furthermore, T cells expressing GPI-ecto-TβRII constructs have been shown to efficiently capture and inactivate TGF-β from their environment. These results indicate the potential benefits of GPI-ecto-TβRII expressing cytotoxic T cells (CTLs) in future cell therapies.

Ovarian cancer (OC) is an aggressive malignancy characterized by a complex immunosuppressive tumor microenvironment (TME). Immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy by reactivating the antitumor immune response suppressed by tumor cells. However, in the case of OC, these inhibitors have failed to demonstrate significant improvements in patient outcomes, and existing biomarkers have not yet identified promising subgroups. Consequently, there remains a pressing need to understand the interplay between OC tumor cells and their surrounding microenvironment to develop effective immunotherapeutic approaches. This review aims to provide an overview of the OC TME and explore its potential as a therapeutic strategy. Tumor-infiltrating lymphocytes (TILs) are major actors in OC TME. Evidence has been accumulating regarding the spontaneous TILS response against OC antigens. Activated T-helpers secrete a wide range of inflammatory cytokines with a supportive action on cytotoxic T-cells. Simultaneously, mature B-cells are recruited and play a significant antitumor role through opsonization of target antigens and T-cell recruitment. Macrophages also form an important subset of innate immunity (M1-macrophages) while participating in the immune-stimulation context. Finally, OC has shown to engage a significant natural-killer-cells immune response, exerting direct cytotoxicity without prior sensitization. Despite this initial cytotoxicity, OC cells develop various strategies to induce an immune-tolerant state. To this end, multiple immunosuppressive molecules are secreted to impair cytotoxic cells, recruit regulatory cells, alter antigen presentation, and effectively evade immune response. Consequently, OC TME is predominantly infiltrated by immunosuppressive cells such as FOXP3+ regulatory T-cells, M2-polarized macrophages and myeloid-derived suppressor cells. Despite this strong immunosuppressive state, PD-1/PD-L1 inhibitors have failed to improve outcomes. Beyond PD-1/PD-L1, OC expresses multiple other immune checkpoints that contribute to immune evasion, and each representing potential immune targets. Novel immunotherapies are attempting to overcome the immunosuppressive state and induce specific immune responses using antibodies adoptive cell therapy or vaccines. Overall, the OC TME presents both opportunities and obstacles. Immunotherapeutic approaches continue to show promise, and next-generation inhibitors offer exciting opportunities. However, tailoring therapies to individual immune characteristics will be critical for the success of these treatments.