Transforming growth factor-β (TGF-β) is a multifunctional molecule with a dual role in carcinogenesis. Recent studies have demonstrated its various effects on cancer-related processes. However, the identification of TGF-β and TGF-β signaling pathway regulators in extracellular vesicles (EVs) appears promising for targeting them to control cancer progression associated with drug resistance. Exosomal TGF-β has been shown to be implicated in cancer cell phenotypic plasticity, a dynamic feature of cancer cells, and an evasive process hampering treatment efficacy. Additionally, EVs can influence the metastatic cascade through mechanisms, including their effects on the immune system and their binding to extracellular matrix (ECM) proteins. These processes collaborate to provide a supportive microenvironment for the development and growth of metastatic tumors. A deeper understanding of the mechanisms by which EVs facilitate TGF-β-mediated intercellular communication may have practical implications for better controlling oncological disorders and providing new methods for cancer diagnostics and treatment, including approaches targeting EVs.

Circulating tumor cells (CTCs) are cancer cells that are detached from the primary and metastatic tumor site and invade the bloodstream. Most importantly, CTCs are the key players in the development of metastasis. As one of the main components of liquid biopsy, they may significantly contribute to improvements in early cancer diagnosis, monitoring response to therapy, and predicting recurrence of the disease. Although identifying and analyzing CTCs offers the potential for a real-time liquid biopsy, their detection is associated with a number of challenges, which mainly stem from three sources: complexity of the CTCs, complexity of the media (blood), and performance of the detection assays. Particularly, low concentration of the CTCs and the presence of a vast population of hematopoietic cells in the blood make their detection technically complex. The heterogeneity of the target cells and not enough sensitivity of the measuring platforms are also among major technical challenges in CTC detection. Therefore, this review aims to give an update on various methods developed for CTC isolation, including chip-based assays and biosensors. The work will elucidate various challenges associated with the isolation and detection of CTCs and showcase the studies that aimed to tackle them. A number of available commercial platforms for CTC detection and hurdles associated with their widespread applications in clinical settings will also be discussed.

Musculoskeletal sarcomas represent heterogeneous and rare malignant bone and soft tissue tumors, affecting children and adults. Patients exhibiting poor clinical outcomes are often described, being associated with non-response to chemotherapy, amputation needs, or metastatic disease. Potential biomarkers contributing to diagnosis, prognosis, and treatment response could improve this scenario. Despite this, little is known about the genomic aspects of musculoskeletal sarcomas. DNA methylation is the most studied epigenetic mechanism, where changes in methylation profiling are characteristic hallmarks of cancer. Cancer-related methylome profiling has been investigated both in tumor biopsies (genomic DNA) and liquid biopsies (cell-free DNA). Epigenetic therapies by using DNA-demethylating drugs are promising strategies for cancer treatment. This review will discuss translational studies describing how DNA methylation landscape of musculoskeletal sarcomas can be a powerful molecular tool to improve diagnostic accuracy, predict prognosis, and treatment response. Additionally, this review will describe the promising role of epigenetics-targeted drugs as well as the ongoing clinical trials for sarcomas, highlighting the challenges and future directions.

The role of circulating tumor DNA (ctDNA) in urothelial cancers is a rapidly evolving area of research. Urothelial cancer is the most common subtype of bladder cancer, and biomarkers that predict response or prognosticate outcomes have been long sought after. Tumor-informed ctDNA assays have been utilized in several other cancers and increasingly used in both muscle invasive bladder cancer (MIBC) and metastatic urothelial cancer (mUC) to inform treatment decision-making. While a universal consensus on ctDNA testing has not been fully defined and discussed herein, understanding its benefits and limitations is important to help guide the practical application in the clinic.

With the escalating application of immune checkpoint inhibitors (ICIs) in solid tumors, these therapies have demonstrated clinical benefits but remain hampered by relatively low response rates. Reliable biomarkers to predict ICIs responsiveness are essential for selecting appropriate patients and optimizing therapeutic outcomes. Given the pivotal role of tumor-draining lymph nodes (TDLNs) in orchestrating systemic antitumor immunity, their intrinsic features—such as dynamic organization in T cell subsets and functional status of antigen-presenting cells, hold considerable potential as predictive biomarkers for ICIs. Moreover, the complexity of ICIs-induced responses in TDLNs necessitates integrating multiple biomarkers for accurate prediction. Through continuous refinement of predictive strategies, TDLNs are poised to play an indispensable role in enhancing ICIs efficacy and guiding personalized immunotherapy. Here, we provide a review to discuss the possibility of using the intrinsic features of TDLNs as a predictive marker for ICI therapy.

Despite major improvements in cancer treatment, detection, and health promotion, the mortality rates of late-stage cancer remain high. This is a critical issue because a large proportion of cancer mortality is experienced by patients who have late-stage disease at diagnosis. As survival is substantially higher for almost all cancers when diagnosed at an early stage, effective early cancer detection strategies could drastically reduce overall cancer mortality. Advances in various technologies have culminated in the development of liquid biopsies. The tumour biomarkers applied for non- or minimally-invasive cancer detection include tumour cells and their components in bodily fluids, especially peripheral blood for circulating tumour biomarkers. The most well-studied circulating tumour biomarkers in recent years for the early detection of cancer are circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), with research into other classes rapidly expanding. CTCs and ctDNA have been detected at an early stage in several types of cancer with high specificity, aiding risk stratification and, in some cases, identifying clinically actionable molecular features. Therefore, these circulating biomarkers offer several advantages over the traditional cancer detection methods. Although their limitations are considerable, the evolving evidence suggests they have tremendous potential as tools for early cancer detection. In this review, we evaluate the development and applications of circulating biomarkers for early cancer detection, with a focus on CTCs and ctDNA. We also briefly explore the emerging evidence on extracellular vesicles, circulating proteins and synthetic biomarkers, discuss the limitations of current approaches and provide suggestions to achieve further progress in this setting.

Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.

Emerging cancer immunotherapy methods, notably cytokine-based ones that modify immune systems’ inflammatory reactions to tumor cells, may help slow gastric cancer progression. Cytokines, tiny signaling proteins that communicate between immune cells, may help or hinder cancer growth. Pro-inflammatory cytokines encourage tumor development, whereas antitumor ones help the host reject cancer cells. This study considers cytokine-targeted methods for gastric cancer pro-inflammatory and antitumor immune responses. Researchers want to renew immune cells like cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells by delivering cytokines like interleukin-2 (IL-2), interferons (IFNs), and tumor necrosis factor-alpha (TNF-α) to activate inflammatory pathways and combat tumors. Since cytokines have significant pleiotropic effects, their therapeutic use is difficult and may cause excessive systemic inflammation or immunological suppression. This review covers current advancements in synthetic cytokines, cytokine-conjugates, and local administration of these aimed to enhance the therapeutic index: increase the potential to kill cancer cells while minimizing off-target damage. The study examines the relationship between cytokines and tumor microenvironment (TME), revealing the role of immunosuppressive cytokines like IL-10 and transforming growth factor-beta (TGF-β) in promoting an immune-evasive phenotype. These results suggest that inhibitory pathway targeting, and cytokine-based therapy may overcome resistance mechanisms. Cytokine-based immunotherapies combined with immune checkpoint inhibitors are predicted to change gastric cancer therapy and rebuild tumor-immune microenvironment dynamics, restoring antitumor immunity. Comprehensive data from current clinical studies will assist in establishing the position of these treatments in gastric cancer.

This review explores the intricate relationship between viral infections and Bacillus Calmette-Guerin (BCG) efficacy, emphasizing immune modulation mechanisms that may influence treatment outcomes. Since its introduction in 1976, intravesical BCG has been a cornerstone in managing non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumors (TURBT). Despite its success, variability in response rates suggests that host immune status, influenced by persistent infections, immunosenescence, and antigenic overload, may play a crucial role in therapeutic effectiveness. Chronic viral infections can modulate T cell responses, leading to immune exhaustion and impaired antitumor immunity. This review discusses the interplay between viral antigenic load, immune dysfunction, and tumor microenvironment remodeling, highlighting their potential impact on immunotherapies. By integrating insights from virome analysis, immune profiling, and tumor characterization, this review proposes personalized strategies to enhance immunotherapy efficacy. A deeper understanding of viral-induced immune dysregulation may improve prognostic assessment, optimize treatment protocols, and reduce healthcare costs associated with bladder cancer. Future research should focus on targeted interventions to mitigate the immunosuppressive effects of chronic infections, ultimately improving patient outcomes in NMIBC management.

Exportin-1 (XPO1) is a nuclear export protein that, when overexpressed, can facilitate cancer cell proliferation and survival and is frequently overexpressed or mutated in cancer patients. As such, selective inhibitors of XPO1 (XPO1i) function have been developed to inhibit cancer cell proliferation and induce apoptosis. This review outlines the evidence for the immunomodulatory properties of XPO1 inhibition and discusses the potential for combining and sequencing XPO1i with immunotherapy to improve the treatment of patients with cancer. Selinexor is a first-in-class XPO1i that is FDA-approved for the treatment of patients with relapsed and refractory (RR) multiple myeloma and RR diffuse large B cell lymphoma. In addition to the cancer cell intrinsic pro-apoptotic activity, increasing evidence suggests that XPO1 inhibition has immunomodulatory properties. In this review, we describe how XPO1i can lead to a skewing of macrophage polarisation, inhibition of neutrophil extracellular traps, modulation of immune checkpoint expression, blockade of myeloid-derived suppressor cells (MDSCs) and sensitisation of cancer cells to T cell and NK (natural killer) cell immunosurveillance. As such, there is an opportunity for selinexor to enhance immunotherapy efficacy and thus a need for clinical trials assessing selinexor in combination with immunotherapies such as immune checkpoint inhibitors, direct targeting monoclonal antibodies, chimeric antigen receptor (CAR)-T cells and cereblon E3 ligase modulators (CELMoDs).

The ultrastructural morphology of eosinophil cytolysis and extracellular trap cell death (ETosis) has predominantly been examined in non-neoplastic eosinophil-associated diseases, with a limited investigation in neoplasms. This current electron microscopy study examined the ultrastructural characteristics of eosinophil cytolysis and ETosis across four distinct gastric cancer cases: three cases (cases 1–3) exhibited non-ETotic cytolysis, while one case (case 4) presented eosinophils at various stages of ETosis. In cases 1–3, eosinophil non-ETotic cytolysis was characterized by localized plasma membrane disruption, the presence of free extracellular granules (FEGs), and the maintenance of a round or oval nuclear lobe profile. In case 4, eosinophils were observed in progressive stages of ETosis, arbitrarily subdivided into early, intermediate, and advanced. Although early ETosis and non-ETotic cytolysis exhibited overlapping ultrastructural features, chromatin decondensation and nuclear envelope enlargement were more pronounced in early ETosis. Nuclear envelope disruption, loss of the round or oval nuclear lobe profile (intermediate stage), extracellular DNA trap deposition, and the appearance of Charcot-Leyden crystals (advanced stage) were all distinctive features of ETosis. The findings of this case report confirm previous observations of eosinophil cytolysis with or without ETosis in non-neoplastic diseases and extend them to advanced gastric carcinoma. Since Charcot-Leyden crystals were only seen in case 4, their correlation with ETosis was further supported. In gastric cancer, the release of FEGs during non-ETotic cytolysis and the release of both FEGs and DNA traps during ETotic cytolysis may contribute to the formation of an antitumor microenvironment.

Immunotherapy has gathered significant attention and is now a widely used cancer treatment that uses the body’s immune system to fight cancer. Despite initial successes, its broader clinical application is hindered by limitations such as heterogeneity in patient response and challenges associated with the tumor immune microenvironment. Recent advancements in nanotechnology have offered innovative solutions to these barriers, providing significant enhancements to cancer immunotherapy. Nanotechnology-based approaches exhibit multifaceted mechanisms, including effective anti-tumor immune responses during tumorigenesis and overcoming immune suppression mechanisms to improve immune defense capacity. Nanomedicines, including nanoparticle-based vaccines, liposomes, immune modulators, and gene delivery systems, have demonstrated the ability to activate immune responses, modulate tumor microenvironments, and target specific immune cells. Success metrics in preclinical and early clinical studies, such as improved survival rates, enhanced tumor regression, and elevated immune activation indices, highlight the promise of these technologies. Despite these achievements, several challenges remain, including scaling up manufacturing, addressing off-target effects, and navigating regulatory complexities. The review emphasizes the need for interdisciplinary approaches to address these barriers, ensuring broader clinical adoption. It also provides insights into interdisciplinary approaches, advancements, and the transformative potential of nano-immunotherapy and promising results in checkpoint inhibitor delivery, nanoparticle-mediated photothermal therapy, immunomodulation as well as inhibition by nanoparticles and cancer vaccines.

The combination of enfortumab vedotin and pembrolizumab (EVP) has been recently approved for patients with locally advanced and metastatic urothelial carcinoma. This combination showed a higher objective response rate and superior progression-free survival and overall survival over traditional platinum-based chemotherapy in the frontline setting in the pivotal EV-302 trial. Despite the success, a subset of patients has primary refractory disease, and another subset will develop secondary resistance over time. Resistance to enfortumab vedotin may include the downregulation of nectin-4 expression to minimize antibody binding, upregulation of efflux pumps against the toxin, or direct resistance by the tubulin against the toxin. Resistance to pembrolizumab includes several methods to downregulate the immune system. Additionally, the type of histology of the urothelial carcinoma likely plays an important role in resisting EVP. This review summarizes these possible mechanisms of primary and secondary resistance, potential biomarkers predictive of response and resistance, and methods to overcome the resistance to EVP.

The purpose of this review was to provide a comprehensive review of the latest insights on the pathogenesis of uveal melanoma (UM) and its intracellular pathways. This article covers the epidemiology of UM, racial predispositions, cytogenetic and chromosomal alterations, gene mutations, key defective pathways, and their underlying mechanisms, as well as the application of hallmarks of cancer to UM. A key knowledge gap remains in identifying the most effective targeted therapy and determining the central pathway linking multiple signaling networks. UM is a malignant tumor arising from uveal melanocytes, predominantly affecting the choroid, with both genetic and epigenetic contributors. Key cytogenetic alterations include monosomy 3, chromosome 6p gain, chromosome 1p loss, and chromosome 8q gain. The most important UM-related signaling pathways are RAS/MAPK, PI3K/Akt/mTOR, Hippo-YAP, retinoblastoma (Rb), and p53 pathways. In the RAS/MAPK pathway, GNAQ/GNA11 mutations occur which account for more than 80% of UM cases. The PI3K/Akt/mTOR pathway promotes cyclin D1 overexpression and MDM2 upregulation, leading to p53 pathway inhibition. GNAQ/GNA11 mutations activate YAP via the Trio-RhoGTPase/RhoA/Rac1 signaling circuit in the Hippo-YAP pathway. Rb pathway dysregulation results from cyclin D1 overexpression or cyclin-dependent kinase inhibitor (CDKI) inactivation. In the p53 pathway, UM is characterized by p53 mutations, MDM2 overexpression, and Bcl-2 deregulation. Eventually, the ARF-MDM2 axis serves as a critical link between the RAS and p53 pathways. Hallmarks of cancer, such as evasion of growth suppression and self-sufficiency in growth signals, are also evident in UM. Genetic and epigenetic alterations, including NSB1, MDM2 and CCND1 amplification, and BAP1 mutations, play pivotal roles in UM pathobiology. Thus, UM exhibits a multifactorial pathology. By consolidating key mechanisms underlying UM pathogenesis, this review provides a comprehensive perspective on the involved pathways, offering insights that may facilitate the development of effective therapeutic strategies.

The combination of lenvatinib and pembrolizumab (Len + Pembro) demonstrated significant efficacy in the phase 3 CLEAR study for metastatic renal cell carcinoma (RCC). However, poor-risk patients represented only a small proportion of the trial population. This multicenter retrospective cohort study assessed the real-world efficacy and safety of Len + Pembro in patients with clear-cell metastatic RCC and intermediate or poor International Metastatic RCC Database Consortium risk. Outcomes included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Sixty patients were analyzed, with a median age of 56 years. Poor risk was identified in 53% of patients, and 90% had metastases to ≥ 2 organs. ORR was 48.33%, disease control rate was 86.7%, and median PFS was 19.0 months. Grade ≥ 3 adverse events occurred in 25% of patients, with 33.3% requiring lenvatinib dose reductions. Lenvatinib plus pembrolizumab demonstrated robust efficacy and a manageable safety profile in a real-world population with advanced disease and poor-risk features, consistent with outcomes reported in clinical trials.

Bladder cancer (BC) is a heterogeneous disease associated with high mortality if not diagnosed early. BC is classified into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC), with MIBC linked to poor systemic therapy response and high recurrence rates. Current treatments include transurethral resection with Bacillus Calmette-Guérin (BCG) therapy for NMIBC and radical cystectomy with chemotherapy and/or immunotherapy for MIBC. The tumor microenvironment (TME) plays a critical role in cancer progression, metastasis, and therapeutic efficacy. A comprehensive understanding of the TME’s complex interactions holds substantial translational significance for developing innovative treatments. The TME can contribute to therapeutic resistance, particularly in immune checkpoint inhibitor (ICI) therapies, where resistance arises from tumor-intrinsic changes or extrinsic TME factors. Recent advancements in immunotherapy highlight the importance of translational research to address these challenges. Strategies to overcome resistance focus on remodeling the TME to transform immunologically “cold” tumors, which lack immune cell infiltration, into “hot” tumors that respond better to immunotherapy. These strategies involve disrupting cancer-microenvironment interactions, inhibiting angiogenesis, and modulating immune components to enhance anti-tumor responses. Key mechanisms include cytokine involvement [e.g., interleukin-6 (IL-6)], phenotypic alterations in macrophages and natural killer (NK) cells, and the plasticity of cancer-associated fibroblasts (CAFs). Identifying potential therapeutic targets within the TME can improve outcomes for MIBC patients. This review emphasizes the TME’s complexity and its impact on guiding novel therapeutic approaches, offering hope for better survival in MIBC.