Search Results (667)

Background: Anti-programmed death 1 receptor (PD-1) therapy is a promising treatment strategy for patients with unresectable advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer. However, its response rate and survival benefits are still limited; an immunological analysis of the residual tumor after anti-PD-1 therapy would be important. Methods: We evaluated the clinical efficacy of tumor resection (TR) after chemotherapy or anti-PD-1 therapy in patients with unresectable advanced or recurrent G/GEJ cancer and analyzed the immune status of tumor microenvironment (TME) by immunohistochemistry using their surgically resected specimens. Results: Patients treated with TR after anti-PD-1 therapy had significantly longer survival compared to those treated with chemotherapy and anti-PD-1 therapy alone. Expression of human leukocyte antigen (HLA) class I and major histocompatibility complex (MHC) class II on tumor cells was markedly downregulated after anti-PD-1 therapy compared to chemotherapy. Furthermore, the downregulation of HLA class I may be associated with the activation of transforming growth factor-β signaling pathway in the TME. Conclusions: Immune escape from cytotoxic T lymphocytes may be induced in the TME in patients with unresectable advanced or recurrent G/GEJ cancer after anti-PD-1 therapy due to the downregulation of HLA class I and MHC class II expression on tumor cells. TR may be a promising treatment strategy for these patients when TR is feasible after anti-PD-1 therapy. Full article

Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM. Full article

Conventional immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells, has revolutionized cancer therapy over the past decade. Yet, the efficacy of these therapies is limited by tumor resistance, antigen escape mechanisms, poor persistence, and T-cell exhaustion, particularly in the treatment of solid tumors. The emergence of unconventional immunotherapies offers novel opportunities by leveraging diverse immune cell subsets and synthetic biologics. This review explores various immunotherapy platforms, including gamma delta T cells, invariant natural killer T cells, mucosal-associated invariant T cells, engineered regulatory T cells, and universal CAR platforms. Additionally, it expands on biologics, including bispecific and multispecific antibodies, cytokine fusions, agonists, and oncolytic viruses, showcasing their potential for modular engineering and off-the-shelf applicability. Distinct features of unconventional platforms include independence from the major histocompatibility complex (MHC), tissue-homing capabilities, stress ligand sensing, and the ability to bridge adaptive and innate immunity. Their compatibility with engineering approaches highlights their potential as scalable, efficient, and cost-effective therapies. To overcome translational challenges such as functional heterogeneity, immune exhaustion, tumor microenvironment-mediated suppression, and limited persistence, novel strategies will be discussed, including metabolic and epigenetic reprogramming, immune cloaking, gene editing, and the utilization of artificial intelligence for patient stratification. Ultimately, unconventional immunotherapies extend the therapeutic horizon of cancer immunotherapy by breaking barriers in solid tumor treatment and increasing accessibility. Continued investments in research for mechanistic insights and scalable manufacturing are key to unlocking their full clinical potential. Full article

Polyomaviruses are a family of small DNA viruses capable of establishing persistent infections, and they can pose significant pathogenic risks in immunocompromised hosts. While traditionally studied in the context of viral reactivation and immune suppression, recent evidence has highlighted the gut microbiota as a critical regulator of host immunity and viral pathogenesis. This review examines the complex interactions between polyomaviruses, the immune system, and intestinal microbiota, emphasizing the role of short-chain fatty acids (SCFAs) in modulating antiviral responses. We explore how dysbiosis may facilitate viral replication, reactivation, and immune escape and also consider how polyomavirus infection can, in turn, alter microbial composition. Particular attention is given to the Firmicutes/Bacteroidetes ratio as a potential biomarker of infection risk and immune status. Therapeutic strategies targeting the microbiota, including prebiotics, probiotics, and fecal microbiota transplantation (FMT), are discussed as innovative adjuncts to immune-based therapies. Understanding these tri-directional interactions may offer new avenues for mitigating disease severity and improving patient outcomes during viral reactivation. Full article

CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9)-mediated genome editing has emerged as a transformative tool in medicine, offering significant potential for cancer therapy because of its capacity to precisely target and alter the genetic modifications associated with the disease. However, a major challenge for its clinical translation is the safe and efficient in vivo delivery of CRISPR/Cas9 components to target cells. Nanotechnology is a promising solution to this problem. Nanocarriers, owing to their tunable physicochemical properties, can encapsulate and protect CRISPR/Cas9 components, enabling targeted delivery and enhanced cellular uptake. This review provides a comprehensive examination of the synergistic potential of CRISPR/Cas9 and nanotechnology in cancer therapy and explores their integrated therapeutic applications in gene editing and immunotherapy. A critical aspect of in vivo CRISPR/Cas9 application is to achieve effective localization at the tumor site while minimizing off-target effects. Nanocarriers can be engineered to overcome biological barriers, thereby augmenting tumor-specific delivery and facilitating intracellular uptake. Furthermore, their design allows for controlled release of the therapeutic payload, ensuring sustained efficacy and reduced systemic toxicity. The optimization of nanocarrier attributes, including size, shape, surface charge, and composition, is crucial for improving the cellular internalization, endosomal escape, and nuclear localization of CRISPR/Cas9. Moreover, surface functionalization with targeting ligands can enhance the specificity of cancer cells, leading to improved gene-editing accuracy. This review thoroughly discusses the challenges associated with in vivo CRISPR/Cas9 delivery and the innovative nanotechnological strategies employed to overcome them, highlighting their combined potential for advancing cancer treatment for clinical application. Full article

Background: Personalized anti-tumor therapy that activates the immune response has demonstrated clinical benefits in various cancers. However, its efficacy against testicular cancer (TC) remains uncertain. This study aims to identify suitable patients for anti-tumor immunotherapy and to uncover potential therapeutic targets in TC for the development of tailored anti-tumor immunotherapy. Methods: Consensus clustering analysis was conducted to delineate immune subtypes, while weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, and support vector machine (SVM) algorithms were employed to evaluate the potential efficacy of anti-tumor immunotherapy. Candidate immunotherapy targets were systematically identified through multi-gene panel analyses and subsequently validated using molecular biology assays. A prioritized target emerging from cellular screening was further evaluated for its capacity to potentiate anti-tumor immunity. The therapeutic efficacy of this candidate was rigorously confirmed through a comprehensive suite of immunological experiments. Results: Following systematic screening of five candidate genes (WNT11, FAM181B, GRK5, FSCN1, and ECHS1), GRK5 emerged as a promising therapeutic target for immunotherapy based on its distinct functional and molecular associations with immune evasion mechanisms. Cellular functional assays revealed that GRK5 knockdown significantly attenuated the malignant phenotype of testicular cancer cells, as evidenced by reduced proliferative capacity and invasive potential. Complementary immunological validation established that specific targeting of GRK5 with the selective antagonist GRK5-IN-2 disrupts immune evasion pathways in testicular cancer, as quantified by T-cell-mediated cytotoxicity. Conclusions: These findings position GRK5 as a critical modulator of tumor-immune escape, warranting further preclinical exploration of GRK5-IN-2 as a candidate immunotherapeutic agent. Full article

B-cell maturation antigen (BCMA)-targeted therapies including both chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), have revolutionized the treatment landscape for relapsed/refractory multiple myeloma (MM), offering both deep and durable responses, even in heavily pretreated patients. Despite these advances, most patients ultimately experience relapse. This is likely related to the development of resistance mechanisms that limit the long-term efficacy and durability of BCMA-targeted approaches. In this review, we examine the current landscape of BCMA-directed therapies, including Idecabtagene Vileucel, Ciltacabtagene Autoleucel, Teclistamab, and Elranatamab and explore the multifactorial mechanisms driving resistance. These mechanisms include tumor-intrinsic factors, host-related and tumor-extrinsic factors, and factors related to the tumor-microenvironment itself. We outline emerging strategies to overcome resistance, such as dual-targeting therapies, γ-secretase inhibitors, immune-checkpoint blockade, armored CAR T constructs, and novel combination regimens. Additionally, we discuss the role of therapy sequencing, emphasizing how prior exposure to BsAbs or CAR T-cell therapies may influence the efficacy of subsequent treatments. A deeper understanding of resistance biology, supported by integrated immune and genomic profiling, is essential to optimizing therapeutic durability and ultimately improve patient outcomes for patients with MM. Full article

Background/Objectives: Cardiac aging involves the progressive structural and functional decline of the myocardium. Endurance training is a well-recognized non-pharmacological intervention that counteracts this decline, yet the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated. This study aimed to identify key effector genes and regulatory pathways by integrating human cardiac aging transcriptomic data with multi-omic exercise response datasets. Methods: A systems biology framework was developed to integrate age-downregulated genes (n = 243) from the GTEx human heart dataset and endurance-exercise-responsive genes (n = 634) from the MoTrPAC mouse dataset. Thirty-seven overlapping genes were identified and subjected to Enrichr for pathway enrichment, KEA3 for kinase analysis, and ChEA3 for transcription factor prediction. Candidate effector genes were ranked using ToppGene and ToppNet, with integrated prioritization via the FLAMES linear scoring algorithm. Results: Pathway enrichment revealed complementary patterns: aging-associated genes were enriched in mitochondrial dysfunction and sarcomere disassembly, while exercise-responsive genes were linked to protein synthesis and lipid metabolism. TTN, PDK family kinases, and EGFR emerged as major upstream regulators. NKX2-5, MYOG, and YBX3 were identified as shared transcription factors. SMPX ranked highest in integrated scoring, showing both functional relevance and network centrality, implying a pivotal role in mechano-metabolic coupling and cardiac stress adaptation. Conclusions: By integrating cardiac aging and exercise-responsive transcriptomes, 37 effector genes were identified as molecular bridges between aging decline and exercise-induced rejuvenation. Aging involved mitochondrial and sarcomeric deterioration, while exercise promoted metabolic and structural remodeling. SMPX ranked highest for its roles in mechano-metabolic coupling and redox balance, with X-inactivation escape suggesting sex-specific relevance. Other top genes (e.g., KLHL31, MYPN, RYR2) form a regulatory network supporting exercise-mediated cardiac protection, offering targets for future validation and therapy. Full article

This manuscript assesses the critical role of exosomal PD-L1 (ExoPD-L1) in immune suppression, tumor progression, and resistance to therapy. ExoPD-L1 has been identified as a key mediator of tumor immune evasion, contributing to systemic immunosuppression beyond the tumor microenvironment (TME) due to its capacity to travel to distant anatomical sites. In this context, the review aims to elaborate on the mechanisms by which exosomal PD-L1 interacts with T cell receptors and modulates both the tumor microenvironment and immune responses, impacting patient outcomes. We further explore emerging therapeutic strategies that target ExoPD-L1 to enhance the effectiveness of immunotherapy. Blocking ExoPD-L1 offers a novel approach to counteracting immune escape in cancer. Promising strategies include inhibiting exosome biogenesis with GW4869 or Rab inhibitors, neutralizing ExoPD-L1 with targeted antibodies, and silencing PD-L1 expression through RNA interference (RNAi) or CRISPR-based methods. While each approach presents certain limitations, their integration into combination therapies holds significant potential to improve the efficacy of immune checkpoint inhibitors. Future research should focus on optimizing these strategies for clinical application, with particular attention to improving delivery specificity and minimizing off-target effects. Full article

Endothelial-to-mesenchymal transition (EndMT) is a dynamic cellular process characterized by a phenotypic-functional switch of cells from endothelial-to-mesenchymal traits. Many studies have identified EndMT as a key driver of tumor growth and progression. EndMT supports tumor cell proliferation by creating a tumor microenvironment that facilitates cancer cell survival. Notably, EndMT is an important source of cancer-associated fibroblasts, leads to immune dysregulation and immune escape, and supports metastasis and resistance to therapy. Hence, understanding the intricate relationship between EndMT and cancer progression offers exciting new avenues for therapeutic intervention. This review aims to describe the central role of EndMT in tumor progression, highlighting the molecular mechanisms underlying this endothelial alteration and its significant involvement at all stages of tumor progression. Full article

RNA interference (RNAi) was originally regarded as a mechanism of eukaryotic post-transcriptional gene regulation mediated by small interfering RNA (siRNA)-induced sequence-specific RNA degradation. It is well known to exert as an important antiviral defense mechanism in a wide range of organisms, from plants to invertebrates. The specificity, ease of design, and ability to target conserved gene regions make siRNA technology a promising approach to combat viral pathogenesis, allowing the targeting of multiple virus strains. The mechanism of sequence complementarity utilized by siRNAs against their targets presents a novel strategy to combat viral infections, as they can specifically target and degrade viral RNA. Consequently, siRNA-based therapeutics have been applied to various viral diseases. This is largely due to the design flexibility and rapid response potential of RNAi technologies, which provide advantages over traditional antiviral agents. However, the emergence of viral escape mutants poses a major barrier to the sustained antiviral activity of siRNA-based therapy. Therefore, devising strategies to overcome the emergence of escape mutants to antiviral siRNAs could enhance the efficacy of siRNA-based therapeutics in providing a rapid response to emerging viral infectious diseases. This review aims to comprehensively summarize the current knowledge on siRNA-based therapeutic approaches against viral infections and elucidate the challenges associated with implementing siRNA treatment, with a specific emphasis on antiviral resistance. Full article

Human induced pluripotent stem cells (iPSCs) offer immense potential as a source for cell therapy in spinal cord injury (SCI) and other diseases. The development of hypoimmunogenic, universal cells that could be transplanted to any recipient without requiring a matching donor could significantly enhance their therapeutic potential and accelerate clinical translation. To create off-the-shelf hypoimmunogenic cells, we used CRISPR-Cas9 to delete B2M (HLA class I) and CIITA (master regulator of HLA class II). Double-knockout (DKO) iPSC-derived neural progenitor cells (NPCs) evaded T-cell-mediated immune rejection in vitro and after grafting into the injured spinal cord of athymic rats and humanized mice. However, loss of HLA class I heightened susceptibility to host natural killer (NK) cell attack, limiting graft survival. To counter this negative effect, we engineered DKO NPCs to overexpress macrophage migration inhibitory factor (MIF), an NK cell checkpoint ligand. MIF expression markedly reduced NK cell-mediated cytotoxicity and improved long-term engraftment and integration of NPCs in the animal models for spinal cord injury. These findings demonstrate that MIF overexpression, combined with concurrent B2M and CIITA deletion, generates hiPSC neural derivatives that escape both T- and NK-cell surveillance. This strategy provides a scalable route to universal donor cells for regenerative therapies in SCI and potentially other disorders. Full article

MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, a phenomenon referred to as oncogene addiction. However, in vitro studies reveal that the knockout or knockdown of MYC in numerous tumor cell lines does not necessarily result in cell death, despite these tumors exhibiting MYC addiction in vivo. This discrepancy suggests that the unique tumor microenvironment in vivo may play a critical role in facilitating MYC addiction in cancer cells. MYC is also widely acknowledged for its role in mediating the immune evasion of tumor cells. Nevertheless, due to the extensive regulation of cellular gene expression by MYC and the incomplete understanding of the mechanisms underlying tumor immune escape, the precise pathways through which MYC influences tumor immune evasion remain inadequately elucidated. Recent years have seen the identification of novel tumor immune escape mechanisms, some of which have been demonstrated to be directly or indirectly regulated by MYC. For instance, MYC may contribute to immune evasion by modulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine biosynthesis. Herein, in this study, we explore some novel potential mechanisms through which MYC facilitates the immune evasion of tumor cells, alongside a combined therapeutic approach targeting MYC and employing immunotherapy based on this mechanism. Furthermore, we suggest that targeting proteins interacting with MYC to modulate its expression and function may serve as an alternative strategy to direct MYC targeting, thereby expediting the clinical translation of combination therapies. Full article

MicroRNAs (miRNAs) are pivotal modulators of tumor progression and immune function. Given the central role of the immune system in recognizing and eliminating malignant cells, understanding how miRNAs influence immune responses has become essential for advancing cancer therapy. This review explores the emerging roles of miRNAs in orchestrating cancer immunology, emphasizing their regulation of tumor immune surveillance, immune equilibrium, immune evasion, and immunometabolism. We further illustrate how specific miRNAs modulate the tumor microenvironment by shaping immune cell phenotypes, cytokine networks, and antigen presentation. Some miRNAs enhance cytotoxic T lymphocyte activity, while others promote immune escape by expanding regulatory T cells and myeloid-derived suppressor cells. miRNAs also regulate immune checkpoints (e.g., PD-L1 and CTLA-4), metabolic reprogramming, and stress responses that collectively influence tumor immunogenicity. Additionally, miRNAs are gaining traction as biomarkers for immune activity and predictors of immunotherapy response. Therapeutically, miRNA mimics and inhibitors can enhance anti-tumor immunity, particularly when combined with advanced delivery platforms or immune checkpoint inhibitors. However, challenges such as delivery specificity, off-target effects, and the context-dependent nature of miRNA activity remain significant barriers to clinical translation. Despite shortcomings, miRNAs represent a class of immune regulators with substantial therapeutic potential. Accelerated progress in miRNA-guided therapies is anticipated through deepening insights into miRNA regulatory networks, coupled with integrative multi-omics and AI-driven analytical frameworks. Altogether, miRNAs are a promising frontier in next-generation cancer immunotherapy and precision oncology. Full article

Background: Head and neck cancer (HNC) remains a global health challenge with a poor 5-year survival rate among patients with relapsed or advanced-stage disease. Immune checkpoint blockade therapies have emerged as a promising approach to improve outcomes; however, their effectiveness is limited, with response rates of only 15–20% because of immune evasion mechanisms. MicroRNA (miRNA) dysregulation plays a key role in facilitating such immune evasion. In this study, we aim to identify specific miRNAs whose altered expression contributes to immune escape in HNC. Methods: We employed an integrated bioinformatics approach, incorporating differential expression analysis, survival analysis, target prediction, KEGG immune pathway analysis, a protein–protein interaction network, and the identification of hub genes using in silico tools. Results: Our analysis revealed that a high expression of miR-18a and miR-2355 was associated with reduced survival, with the median survival decreasing from 42.9 to 27.8 months, respectively, in advanced-stage patients. Conversely, a low expression of let-7c and miR-6510 was linked to poor prognosis, with survival decreasing from 40.1 to 19.2 months and from 50.1 to 26.8 months, respectively, across disease progression. Further pathway analysis revealed that these miRNAs are significantly involved in the regulation of key immune evasion signaling pathways, including T cell receptor, PD-L1/PD-1 checkpoint, JAK-STAT, TGF-beta, NF-kappa B, and TNF signaling pathways. Hub gene analysis identified AKT1, STAT3, NFKB1, CD4, IL2RB, TLR4, and CTLA-4 as potential dysregulated miRNA targets, with enrichment in immune-related signaling pathways. Conclusions: Taken together, these findings suggest that targeting these miRNAs could modulate immune evasion mechanisms and potentially enhance the efficacy of ICB therapies in HNC. Full article