Search Results (421)

Extracellular vesicles (EVs), particularly small EVs or exosomes, are promising cell-free therapeutics with superior biocompatibility and intrinsic targeting for synthetic nanoparticles. However, conventional bulk preparation methods suffer from low yield, poor reproducibility, and structural instability. Microfluidic technologies resolve these issues by enabling precise, automated, and low-shear fluidic manipulation. This mini-review highlights recent advances in microfluidic-engineered exosomes for cancer immunotherapy and infectious diseases. We evaluate critical microfluidic strategies for isolation, surface engineering, and cargo loading, contrasting platforms like ExoArc, acoustofluidics, cellular nanoporation, and electroporation. Particular emphasis is placed on complex modalities, including immune cell-derived exosomes (IEX), neo-antigen presentation, chimeric antigen receptor (CAR)-derived exosomes, and targeted siRNA delivery networks. Crucially, we analyze the technological disconnect between analytical microfluidic scales and massive therapeutic manufacturing volumes, addressing how physical forces risk damaging conformationally sensitive surface proteins (e.g., CAR scFv). Finally, we outline future perspectives, including high-throughput 3D-multiplexed networks, stimulus-responsive scarless elution, and integrated “sample-to-therapy” circuits. Guided by the MISEV2023 guidelines, this review frames the path toward standardized, clinical-scale engineering of multi-functional, cell-free immunotherapies. Full article

A single vaccine cannot prevent or treat all cancers; however, recurrent tumor-specific epitopes may facilitate the development of pre-manufactured, HLA-matched mRNA vaccines tailored for specific molecular subgroups. We define the shared tumor-specific epitope as a recurring peptide derived from a viral oncoprotein, a driver mutation, a frameshift, an altered protein C-terminus, or a fusion junction, and we employ a rigorous cancer-cell-only criterion: a target must be recurrent within a defined subgroup, absent from essential normal tissues at the peptide–HLA level, naturally presented on tumor cells, and sufficiently clonal to minimize immune escape. Under this criterion, we present fifteen sequence-anchored reference designs alongside one conceptual placeholder across thirteen candidates divided into four superclasses: viral oncoproteins (such as HPV16/18 E6 and E7 as attenuated antigenic reference designs; Merkel cell polyomavirus serving as a design-specific placeholder), recurrent driver neoepitopes (including KRAS G12/G13, IDH1 R132H, and H3 K27M), hematologic neoantigens (such as NPM1 Type A C-terminus; and a single CALR exon 9 construct encoding the shared novel C-terminus of types 1 and 2 mutations), and fusion junctions (notably EWS-FLI1 and BCR-ABL). Each open reading frame is anchored to a canonical accession with its documented event; representative ORFs are provided as reference designs, with the intended residue-level verification records. These sequence designs are intended as reference constructs and are not suitable as clinical-grade or manufacturing-ready products; they require independent residue-level validation and comprehensive safety assessments prior to laboratory or clinical application. The historical record of non-personalized vaccination—including HPV and hepatitis B prophylaxis, intravesical BCG, and unsuccessful tumor-associated antigen trials—frames both the potential and limitations of such approaches. The practical product is not a universal vaccine but rather a governed library aligned with specific genotype, viral etiology, HLA context, and clinical setting. Currently, none of these designs have established proof-of-benefit-tier evidence. Full article

Mismatch repair–deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers exhibit high mutational burden and abundant neoantigen formation, generating a highly immunogenic tumour microenvironment characterised by dense lymphocytic infiltration and strong sensitivity to immune checkpoint inhibition. In metastatic colorectal cancer, PD-1 blockade produces durable responses almost exclusively in dMMR tumours, establishing mismatch repair status as a predictive biomarker for immunotherapy responsiveness. Recent studies extending immune checkpoint inhibitors (ICIs) into the neoadjuvant setting for localised dMMR colorectal cancer have produced major pathological response rates exceeding 90%, with pathological complete response (pCR) rates frequently surpassing 60%, challenging traditional oncologic staging frameworks, particularly with respect to lymph node assessment. Baseline clinical nodal staging in dMMR tumours is complicated by immune-mediated lymphadenopathy. Reactive lymphoid hyperplasia driven by tumour antigen exposure frequently produces enlarged lymph nodes that mimic metastatic disease on cross-sectional imaging. Following neoadjuvant immunotherapy, treatment-related immune activation may further increase nodal size or metabolic activity, while pathological examination often reveals sterilised nodes or immune infiltration without viable tumour. Consequently, conventional radiologic criteria for nodal metastasis demonstrate limited specificity in this context. The discordance between imaging findings and pathological outcomes raises important implications for staging accuracy, response assessment, and treatment planning. This review examines the biological basis of lymphatic involvement in dMMR colorectal cancer, evaluates the performance of current imaging modalities for nodal staging, and summarises emerging evidence from neoadjuvant immunotherapy trials. Particular emphasis is placed on the interpretation of lymph node findings in the era of immune checkpoint blockade and the implications for surgical decision-making, organ preservation, and future staging paradigms. Full article

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Colorectal cancer (CRC) is a leading cause of cancer death worldwide, mainly due to metastasis. Circulating tumor cells (CTCs) act as the biological “seeds” of dissemination, traveling through the bloodstream to colonize distant organs. However, the blood is a hostile environment where CTCs must constantly face immune pressure. This review explores the bidirectional interactions between CTCs and immune cells in CRC, asking whether CTCs are merely vulnerable targets of immunosurveillance or can exploit the immune system for survival and metastasis. We dissect intrinsic and extrinsic immune evasion mechanisms, including MHC-I modulation, immune checkpoint expression (PD-L1, CD47, FasL), platelet cloaking, and neutrophil extracellular traps (NETs). Furthermore, we examine how CTCs form heterotypic clusters with monocytes, neutrophils, and lymphocytes, creating pro-metastatic niches and promoting phenotypic plasticity. The impact of CTCs on systemic immunity, including reprogramming of NK cells, T lymphocytes, and myeloid-derived suppressor cells (MDSCs), is discussed. Importantly, we highlight the emerging role of CTCs as dynamic biomarkers for immunotherapy, focusing on the predictive value of PD-L1+ CTCs and the potential of CTC-derived neoantigens for personalized vaccination. Despite progress, challenges remain in standardization, detection sensitivity, and clinical validation. Understanding the equilibrium between immune elimination and evasion by CTCs is crucial to develop novel interventions that interrupt the metastatic dialog and improve outcomes for CRC patients. Full article

Despite significant improvement in long-term survival with the advent of immunotherapy, a substantial proportion of lung cancer patients develop primary and acquired resistance. Among emerging strategies to overcome this challenge, cancer vaccines represent a promising approach, especially for non-small-cell lung cancer (NSCLC). A variety of vaccine platforms have been investigated, including nucleic acid-based vaccines, peptide vaccines, dendritic cell vaccines, and viral vector-based approaches. To date, cancer vaccines have not demonstrated consistent survival benefit in large randomized trials, and their clinical application remains limited. Challenges include high production costs, complexity in manufacturing, and issues related to drug stability and scalability. However, several ongoing early-phase trials show promising signals for several platforms, as new tools and technology become available to optimize neoantigen selection, vaccine production, efficacy, and safety. In this review, we summarize the current evidence of vaccines in NSCLC treatment across different stages and therapeutic settings. Full article

Post-translational modification (PTM) neoantigens have emerged as key drivers of autoimmune inflammation. However, standardized protocols for MHC Class II tetramer preparation for the detection of such antigen-specific T cells remain limited, hindering the broader application of this important discovery. This study systematically engineered an HLA-DR4 (HLA-DRB1*04:02 and HLA-DRA*01:01) tetramer platform based on carboxyethyl-modified neoantigen ITGA2B peptide (ITG-CE), a PTM associated with autoimmune diseases (AUIDs) such as Ankylosing Spondylitis (AS). The platform provides a major histocompatibility complex (MHC) Class II tetramer associated with the PTM neoantigen and integrates modular protein construct, a controllable PTM peptide exchange strategy, and a specific T cell receptor (TCR) validation model. It can be employed to investigate PTM neoantigen presentation and CD4⁺ T cell auto-reactivity, providing extensive application value for future research into the mechanisms of PTM-induced AUIDs and immune monitoring. Full article

The therapeutic armamentarium for colorectal cancer (CRC) has been significantly expanded with the introduction of immunotherapy, particularly immune checkpoint inhibitors (ICIs). However, the response to immunotherapy is strongly dependent on microsatellite instability (MSI) status. Tumors with high MSI (MSI-H) and/or mismatch repair deficiency (dMMR) exhibit high tumor mutational burden (TMB), increased neoantigen load, and enhanced immunogenicity, leading to improved responses to ICIs compared with microsatellite-stable (MSS) and/or mismatch repair-proficient (pMMR) tumors. This has changed the treatment landscape of this small subgroup of metastatic CRC (mCRC), including the approval of pembrolizumab as a first-line option. In contrast, most mCRC cases are MSS/pMMR and are resistant or poorly responsive to ICIs, with no established standard immunotherapy strategy. Therefore, current approaches aim to convert these “cold” tumors into “hot,” immunologically active tumors. This review summarizes the distinct molecular basis of MSI phenotypes and their interaction with the tumor microenvironment, and provides relevant insights into current clinical evidence for prognostic and predictive biomarkers beyond MSI status, as well as novel therapeutic strategies to overcome resistance in MSS disease. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is challenging to treat with chemotherapy. Immunotherapy has shown moderate responses in inflammatory and immunosuppressive tumor environments. Hepatic cytochrome P450 monooxygenases (CYPs) play a crucial role in xenobiotic and drug metabolism, as well as lipid and steroid metabolism. We aimed to investigate whether CYP expression and various parameters of the innate and adaptive immune system are prognostic factors for the survival of HCC patients. Methods: HCC biopsies (n = 370) from The Cancer Genome Atlas (TCGA) database were analyzed using Kaplan–Meier statistics and the KMPlotter algorithm. Parameters such as immune cell infiltration, DNA mutation rates, and neoantigen load were selected for survival analysis and subjected to hierarchical cluster analysis. The expression of candidate CYP genes in tumors was compared to that in normal liver tissues. Furthermore, tumor infiltration of innate immune cells (basophilic and eosinophilic granulocytes, natural killer cells), adaptive immune cells (CD4+ memory and CD8+ cytotoxic T cells, regulatory T cells, type 1 and type 2 helper T cells), and mesenchymal stem cells was examined. Results: High expression of CYP19A1 and CYP26B1 was associated with shorter survival, whereas high expression of CYP3A5, CYP3A43, CYP7A1, and CYP27A1 was linked to longer survival. Mutation rates combined with CYP expression showed a correlation with five out of six CYP genes, while a high neoantigen load produced less definitive results. A specific cluster exhibiting high CYP expression and immune cell counts or mutation/neoantigen rates was associated with shorter survival, while another cluster was linked to longer survival. Conclusions: CYPs involved in the metabolic regulation of HCC, including CYP3A5, CYP3A43, CYP7A1, CYP19A1, CYP26B1, and CYP27A1, were found to have prognostic value for patient survival. Combined signatures that include CYP expression, mutational rates, and immune cell infiltration into tumors further enhanced the prognostic value for patient survival. This suggests that CYPs may influence the creation of a tumor-specific metabolic microenvironment that impacts immune functions. These combined signatures could be utilized for patient stratification to personalize tumor treatment and develop novel combination therapies aimed at optimizing treatment outcomes, such as combining transarterial chemoembolization (TACE) with immune checkpoint inhibitors. Full article

TP53 is the most frequently altered tumor-suppressor gene in human cancer, yet efforts to therapeutically target p53 have yielded limited and inconsistent clinical success. We argue that this gap reflects not a lack of druggable biology, but an oversimplified conceptual framework that treats p53 as a binary wild-type versus mutant entity. Here, we synthesize emerging evidence supporting a model in which p53 operates across a spectrum of functional states defined by mutation class, allelic burden, isoform composition, aggregation propensity, post-translational regulation, and cellular context. These states shape distinct biological outputs, including transcriptional activity, dominant-negative and gain-of-function effects, immune modulation, and checkpoint dependency, which collectively determine therapeutic vulnerability. We review current strategies targeting the p53 pathway, including mutant p53 reactivation, targeted degradation, anti-aggregation approaches, immune-directed therapies, restoration of wild-type pathway activity, gene replacement, and synthetic lethal targeting of DNA damage response dependencies. Clinical and preclinical evidence highlights key limitations of each approach, including stoichiometric constraints, mutation specificity, context-dependent efficacy, and adaptive resistance. Notably, emerging evidence from preclinical and correlative clinical studies suggests that therapeutic outcomes may be more closely associated with p53 functional state than with TP53 mutation status alone. We further emphasize the emerging roles of p53 isoforms and the tumor immune microenvironment as critical modifiers of p53 activity and determinants of treatment response. Collectively, these insights support a paradigm shift toward mechanism-matched, biomarker-stratified strategies that align therapeutic modality with the operative p53 network. Future progress will depend on integrating multi-parameter diagnostics with rational combination therapies to fully exploit p53 as a central vulnerability in cancer. Full article

Therapeutic cancer vaccines are a promising immunotherapy approach in genitourinary (GU) cancers, designed to stimulate antitumor immune responses through antigen-specific T-cell activation. Although agents such as bacillus Calmette–Guérin in bladder cancer and sipuleucel-T in prostate cancer have shown success, vaccine monotherapy has generally produced limited clinical benefit due to tumor heterogeneity, poor immune infiltration, and immunosuppressive tumor microenvironments. Multiple vaccine platforms have demonstrated safety and immunogenicity in prostate, renal cell, and urothelial cancers, but efficacy remains modest. Current strategies focus on multi-antigen targeting, improved antigen presentation, and combination therapies with immune checkpoint inhibitors, radiotherapy, and targeted agents to enhance antitumor activity. Advances in personalized vaccine design and delivery systems are driving progress, though challenges such as manufacturing complexity, cost, and biomarker development remain. Ongoing translational and clinical research will be critical to improving the effectiveness of vaccine-based immunotherapy in GU malignancies. Full article

Therapeutic cancer vaccines represent a rational immunotherapeutic strategy aimed at inducing tumor-specific adaptive immune responses in patients with established malignancies. In contrast to prophylactic vaccines, these approaches must function within immunosuppressive tumor microenvironments characterized by antigenic heterogeneity, immune dysfunction, and dynamic tumor evolution. Effective vaccine design requires the integration of three essential components: the selection of appropriate tumor-associated or tumor-specific antigens, efficient delivery platforms that enable antigen presentation, and adjuvant systems that promote robust T-cell priming and expansion. Initial clinical investigations in B-cell malignancies and multiple myeloma demonstrated that idiotype-based vaccines can elicit tumor-specific immune responses. However, durable clinical benefit has been inconsistent, reflecting limitations in antigen selection, suboptimal immunogenicity, and tumor-mediated immune evasion. Over the past decade, advances in tumor genomics, next-generation sequencing, and immune monitoring have enabled the development of next-generation vaccine platforms, including dendritic cell-based approaches, personalized neoantigen vaccines, and mRNA-based technologies. Emerging evidence suggests that vaccine efficacy is highly dependent on disease context. Biologically favorable settings such as minimal residual disease (MRD) and post-transplant immune reconstitution provide reduced tumor burden and improved immune competence, thereby enhancing the likelihood of effective immune priming. In parallel, combination strategies incorporating immune checkpoint inhibitors, immunomodulatory agents, and cellular therapies are increasingly being explored to overcome tumor-induced immunosuppression. This review synthesizes current knowledge of therapeutic cancer vaccines in B-cell malignancies and multiple myeloma, with emphasis on immunologic mechanisms, antigen selection, vaccine platforms, and clinical evidence. We further propose a conceptual framework integrating tumor biology, immune context, and combination strategies to guide the rational development of next-generation vaccine therapies. Full article

mRNA vaccines are a relevant approach in cancer immunotherapy, using messenger RNA to induce immune responses against tumor-associated antigens. In this review, BNT111 and BNT122 are compared as representative off-the-shelf and personalized models. BNT111 is a fixed mRNA vaccine that has demonstrated significant antitumor efficacy against shared melanoma antigens, particularly when combined with immune checkpoint inhibitors. It allows a standardized production via in vitro transcription (IVT) in a cell-free system. Conversely, BNT122 is a personalized vaccine designed to match an individual’s tumor mutations by targeting patient-specific neoantigens to elicit more robust immune responses. It has significant suitability in the adjuvant setting to target minimal residual disease. Despite favorable safety and immunogenicity, the effectiveness of these vaccines is influenced by various factors, including tumor heterogeneity, differences in antigen expression, off-target effects on mRNA-LNP distribution, molecular instability, and complex manufacturing constraints. Neither approach can be directly considered as the definitive optimal vaccine. A comprehensive analysis of their strengths and limitations is vital for a balanced and objective future research direction. Collectively, this emphasizes the need for further improvements in vaccine design and strategies, prioritizing high-quality, safe, and accessible treatments for every cancer-based patient and ensuring their successful integration into healthcare. Full article

Melanoma adjuvant therapy has substantially improved recurrence-free and distant metastasis-free survival in patients with resected high-risk disease, and more recently, these advances have extended to earlier stages. However, important unmet needs remain, including the management of stage IIIA disease, the optimal treatment strategy after relapse on adjuvant therapy, and the identification of biomarkers capable of refining patient selection. This review summarizes recent advances and unresolved questions in the adjuvant and neoadjuvant treatment of melanoma. We discuss novel systemic strategies, including immune checkpoint inhibitor combinations and personalized neoantigen mRNA vaccines, together with the expanding role of neoadjuvant approaches. We also examine prognostic and predictive tools—such as clinicopathologic models, circulating tumor DNA, serum biomarkers, tumor microenvironment features, and gene expression profiling—that may help better define recurrence risk and therapeutic benefit. Current evidence suggests that although modern therapies have changed the natural history of resected melanoma, a substantial proportion of patients are still overtreated or undertreated when treatment decisions are based on stage alone. Future progress will depend on integrating biological risk stratification with clinical staging and optimizing treatment sequencing across adjuvant and neoadjuvant settings. Full article

Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and eliminate malignant cells. However, many cancers exhibit limited or variable responses to this class of treatment due to insufficient antigen presentation and impaired interferon (IFN) signaling, creating an immunologically “cold” tumor microenvironment (TME) characterized by poor immune cell infiltration and treatment resistance. Viral mimicry has emerged as a therapeutic strategy to overcome these limitations by reactivating innate antiviral pathways within tumor cells. Viral mimicry occurs through the reactivation of endogenous retroviruses (ERVs) and other retrotransposons (e.g., LINE-1), which subsequently stimulate downstream nucleic acid sensing pathways. The resulting type I/III IFN responses restore antigen presentation and attract cytotoxic immune cells, sensitizing resistant tumors to immunotherapy. However, systemic stimulation of these pathways can trigger context-dependent inflammation and adaptive resistance, highlighting the need for temporal and spatial control. In this review, we examine the mechanistic foundation and clinical trajectory of viral mimicry, with an emphasis on its potential integration with established treatments and engineered immune cell platforms. By identifying the molecular and clinical gaps, viral mimicry can be harnessed to enhance tumor-specific immune activation and overcome treatment resistance in cancer immunotherapy. Full article