Search Results (2,090)

Dysregulation of the kynurenine pathway (KYNP) is increasingly recognized as a hallmark of cancer-associated metabolic reprogramming, contributing to immune evasion, oxidative stress, and tumor progression through the activity of enzymes such as indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO2). This systematic review aimed to evaluate the current evidence on the ability of phytochemicals to modulate the KYNP and their potential implications for cancer prevention and therapy. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included English-language articles and book chapters published between 2016 and 2026 that were retrieved from the Scopus and PubMed databases. A keyword co-occurrence network was generated using VOSviewer (v1.6.20) based on the complete Scopus and PubMed exports of the included studies to identify major research themes. The available evidence indicates that phytochemicals restore anticancer immunity by targeting multiple components of the KYNP, including inhibition of IDO1-mediated kynurenine production and suppression of downstream aryl hydrocarbon receptor signalling, thereby enhancing cytotoxic T-cell responses, reducing immunosuppressive cell populations, and improving antitumor immune activity. Collectively, these findings support the KYNP as a promising immunometabolic target and highlight phytochemicals as potential complementary agents for cancer immunotherapy while emphasizing the need for further investigation of the biological and immunological roles of IDO2. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

Background/Objectives: Kidney graft dysfunction remains a major challenge limiting long-term transplant survival despite advances in immunosuppressive therapy. Cytokine signaling pathways have been implicated in the regulation of alloimmune responses and chronic inflammation, but their contribution to long-term graft function and immunosuppressant pharmacokinetics remains incompletely understood. This study investigated associations among selected cytokine gene polymorphisms (IL-2 −330T>G, IL-6 −174G>C, and IL-10 −1082A>G), biochemical and hematological parameters, and calcineurin inhibitor (tacrolimus and cyclosporine) dosing in kidney transplant recipients. Methods: A total of 394 kidney transplant recipients receiving tacrolimus or cyclosporine were enrolled. Genotyping of IL-2 rs2069762, IL-6 rs1800795 and IL-10 rs1800896 was performed using real-time PCR. Clinical, biochemical, and pharmacokinetic data were analyzed using univariate and multivariate statistical models adjusted for relevant demographic and clinical covariates. Results: IL-2 rs2069762 and IL-6 rs1800795 polymorphisms were not associated with clinically relevant differences in biochemical parameters, calcineurin inhibitor dosing, or transplant outcomes. For IL-10 rs1800896, no statistically significant associations were observed with cyclosporine A blood levels, dose, or C/D ratio. Among tacrolimus-treated patients, the regression model for the C/D ratio was borderline significant (F(2,207) = 3.048, p = 0.050, R² = 0.029). However, the genotype-specific association for the heterozygous GA genotype versus AA was not statistically significant in the unadjusted model (B = −0.462, 95% CI: −0.97 to 0.04, p = 0.072) or after adjustment for age, sex, and time since transplantation (B = −0.450, 95% CI: −0.95 to 0.05, p = 0.078). Although univariate analyses identified associations between IL-10 rs1800896 and selected biochemical parameters, these findings were not confirmed in multivariable models. No significant associations were observed between the analyzed cytokine polymorphisms and graft rejection, graft survival, patient survival, or clinically relevant markers of kidney graft function. Conclusions: The results suggest a possible, although not statistically significant, association between IL-10 rs1800896 and tacrolimus exposure, as assessed by the C/D ratio. This observation should be considered preliminary and interpreted with caution. The lack of CYP3A5 genotyping and functional assessment of IL-10 activity, inflammation, and CYP3A-dependent metabolism further limits the interpretation of this potential association. Larger prospective studies with comprehensive pharmacogenetic and functional characterization are needed to determine whether IL-10 rs1800896 contributes to interindividual variability in tacrolimus exposure and whether it may have potential applications in individualized immunosuppressive therapy. Full article

Although papillary thyroid carcinoma (PTC) is widely considered an immunologically cold tumor, detectable T-cell infiltration can influence disease progression in selected patients. Previous bulk analyses have linked cAMP-responsive element modulator (CREM) expression to a favorable progression-free interval and an inverse correlation with regulatory T-cell infiltration but have not resolved the cellular origin or functional state. In this study, we integrate single-cell RNA-sequencing data from a 23-sample PTC atlas with bulk Cancer Genome Atlas Thyroid Carcinoma (TCGA–THCA) validation. We show that CREM marks a T-cell receptor (TCR)-driven immediate early gene activation state in tumor-infiltrating T cells rather than a cAMP program; this state is consistently and modestly enriched within the FOXP3⁺ regulatory T-cell compartment, challenging the interpretation that bulk inverse Treg–CREM correlations reflect Treg-intrinsic repression. CREM-high T cells upregulate ANXA1, and permutation-controlled analysis identifies a candidate paracrine axis from CD4/CD8 T cells to the epithelial epidermal growth factor receptor (EGFR). At the bulk level, CREM expression correlates with reduced proliferation programs and is associated with a prolonged progression-free interval (multivariate HR 0.56, 95% CI 0.31–1.00, p = 0.050), with the effect direction preserved after immune and sex adjustment. Genome-wide differential expression and gene-set enrichment in an independent cohort (GSE193581) confirm that CREM-detected T cells are enriched for a TCR-driven immediate early transcriptional program, supporting the reinterpretation of CREM as a marker of TCR-driven IEG activation. Full article

In 1909, Paul Ehrlich first suggested that the immune system is critical for suppressing carcinogenesis and cancer growth, which led to the introduction of cancer immunosurveillance by Sir MacFarlane Burnet in 1960. Burnet’s cancer immunosurveillance was further supported and elaborated by Thomas Lewis in 1982, who noted, for example, the limitations of investigating cancer immunosurveillance in available experimental models, except for virus-induced cancers. The concept of cancer immunosurveillance in 2001 was revised to cancer immunoediting (the immunoediting term was introduced by Dr. Rober Schreiber), based on findings that the immune system not only controls tumorigenesis and tumor growth but also tumor quality/grade or immunogenicity. Advances in immunology, including the identification of target organs and the local immune system, and the identification of novel innate immune cells regulating the adaptive immune response, have further advanced the understanding of cancer immunosurveillance and immunoediting. The current article discusses the evolution of the cancer immunosurveillance hypothesis into cancer immunoediting. At the time of the introduction of cancer immunoediting, the direct role of dendritic cells (DCs) in tumor immunity and immunoediting was not much explored. Similarly, the concept of tumor-associated macrophages (TAMs) and their role in cancer immunosurveillance and immunoediting was not much studied. The current article discusses the evolution of DCs and TAMs in the context of tumor immunity, cancer immunoediting, and immunotherapies specifically targeting these innate immune cells. Full article

Immune cells possess an intrinsic covalent signalling system in which endogenous electrophilic species function as molecular regulators of cellular state that integrate metabolic activity, oxidative stress, and inflammatory signals. Lipid peroxidation-derived electrophiles, enzymatically generated electrophilic lipid mediators, nitro-fatty acids, and metabolite-derived electrophiles selectively modify reactive amino acid residues within signalling proteins to regulate immune cell differentiation, metabolic adaptation, stress responses, and tissue responses. This perspective highlights that endogenous electrophilic signalling provides a biological blueprint for the development of next-generation precision covalent immunotherapeutics. Beyond exploiting electrophilic chemistry as a reactive pharmacological strategy, emerging insights reveal that immune cells naturally employ regulated covalent modifications to achieve stimulus-dependent control of signalling networks. Advances in chemoproteomics, structural biology, systems immunology, computational chemistry, and targeted delivery technologies are enabling the identification of electrophile-sensitive regulatory targets and the rational design of selective covalent modulators. The discussion includes how the principles derived from endogenous electrophilic signalling can guide therapeutic innovation across major immunotherapeutic areas, including chronic inflammatory diseases, cancer immunology, inflammasome-driven disorders, fibrotic disease, neuroinflammation, and vascular immunometabolic disorders. By translating endogenous covalent regulatory mechanisms into precision drug design strategies, electrophile-guided pharmacology offers an emerging strategy for developing therapies that reprogramme immune cell states, restore immune homeostasis, and achieve stimulus-dependent modulation of disease-associated immune responses. Full article

Background and Objectives: Endometriosis is associated with chronic inflammation, immune dysregulation, oestrogen-dependent growth, oxidative stress, altered steroid hormone metabolism, compromised epithelial barrier integrity, and the production of bioactive microbial metabolites. These interconnected alterations have been proposed to create, in principle, a permissive local microenvironment for malignant transformation. This narrative review examines whether endometriosis-associated dysregulation of the gut and reproductive tract microbiota may act as a hypothetical biological modulator linking these multi-axis changes to endometrial carcinogenesis, with attention to immunological, endocrine, metabolic, microbial–metabolite, oxidative, and barrier-related pathways. Material and Methods: We narratively integrated current evidence on gut and reproductive tract microbiota alterations relevant to endometrial homeostasis, with emphasis on the estrobolome, low-biomass uterine microbial communities, inflammatory and immune signaling, microbial metabolites, and pathways implicated in carcinogenesis. Results: Available data suggest that dysbiosis may influence endometrial carcinogenesis through interconnected endocrine, inflammatory, metabolic, and immune mechanisms. Attention has been given to loss of Lactobacillus dominance, enrichment of anaerobic and pro-inflammatory taxa, altered estrogen recirculation, progesterone resistance, Toll-like receptor activation, NF-κB/STAT3 signaling, COX-2/PGE2 activity, PI3K/AKT/mTOR pathway activation, oxidative stress, macrophage polarization, and impaired natural killer cell surveillance. These alterations may contribute to a permissive microenvironment characterized by persistent inflammation, defective immune control, and disrupted endometrial homeostasis. However, the current literature remains limited by small and heterogeneous cohorts, predominantly cross-sectional designs, contamination risk, and marked methodological variability, particularly in low-biomass uterine samples. Conclusions: Current evidence supports the view that microbiome dysregulation is a context-dependent biological modulator that intersects with endocrine, inflammatory, metabolic, immune, oxidative, and barrier-related pathways relevant to endometrial carcinogenesis. Microbiome dysbiosis should be regarded as a hypothetical contributory factor rather than as an established causal driver. Its near-term translational relevance appears greater for biomarker development and risk stratification than for immediate microbiome-directed therapy. Longitudinal, standardized, and functionally integrated studies are needed to clarify whether microbiome-associated signatures can be translated into clinically meaningful prevention and management strategies in endometrial cancer. Full article

Background: The relationship between Graves’ disease (GD) and thyroid carcinoma (TC) remains controversial, particularly regarding the predictive value of metabolic, hormonal, immunological, and ultrasound biomarkers. We performed a systematic review and meta-analysis to evaluate the prevalence of TC in patients with GD and to identify biomarkers associated with an increased risk of malignancy. Methods: A systematic literature search of PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library was conducted in accordance with PRISMA 2020. Primary studies providing direct evidence in patients with Graves’ disease or indirect evidence concerning thyroid carcinoma-associated biomarkers were considered. Owing to substantial differences in study populations, designs, exposures, and outcomes, quantitative pooling was restricted to sufficiently comparable estimates, while the remaining evidence was synthesized descriptively. Results: Six primary studies were included. Two retrospective cohorts directly evaluated thyroid carcinoma in patients with Graves’ disease and included 1051 patients, of whom 317 had thyroid carcinoma. The remaining studies provided indirect evidence from patients with hyperthyroidism, population-based thyroid cancer cohorts, or genetic datasets. Because of substantial clinical and methodological heterogeneity, a single pooled estimate was not considered appropriate. Thyroid nodules and larger nodule size were associated with malignancy in Graves’ disease, while elevated triglycerides, reduced HDL cholesterol, and higher body mass index were associated with thyroid carcinoma in a surgically selected Graves’ disease cohort. Evidence concerning hormonal, immunological, inflammatory, and genetically determined metabolic markers was heterogeneous and largely indirect. Conclusions: Thyroid carcinoma risk in Graves’ disease is heterogeneous and appears to be concentrated in patients presenting with suspicious ultrasound findings and adverse metabolic profiles. Ultrasound biomarkers remain the most robust predictors of malignancy, while metabolic biomarkers represent promising complementary tools for individualized risk stratification. Current evidence does not support the routine use of hormonal or immunological biomarkers as independent predictors of thyroid carcinoma. Large prospective multicenter studies using standardized biomarker assessment are required to validate these findings and optimize personalized surveillance strategies. Full article

Therapeutic antibodies have transformed the management of infectious diseases, autoimmune disorders, and cancer, yet most approved agents continue to rely on a limited range of IgG-based Fc scaffolds. Consequently, the broader therapeutic potential of antibody isotypes, subclasses, allotypes, and host Fc receptor (FcR) genetics remains incompletely integrated into antibody design and clinical development. Emerging evidence indicates that these determinants profoundly influence effector function, pharmacokinetics, tissue distribution, immunogenicity, and therapeutic efficacy. This review provides a comprehensive, translational perspective on how antibody isotype selection, IgG subclass biology, allotypic variation, Fcγ receptor (FcγR) and neonatal Fc receptor (FcRn) genetics, and Fc engineering collectively shape therapeutic outcomes. Distinct from previous reviews that examine these factors individually, we integrate their roles across infectious diseases, autoimmunity, and cancer to identify common principles governing Fc-dependent immunity and therapeutic response. We further describe the clinical implications of Fc-mediated mechanisms, Fc glycoengineering, FcRn-targeted therapies, systems serology, and emerging non-IgG antibody platforms, highlighting both established applications and unresolved challenges. By unifying structural immunology, Fc pharmacology, host genetics, and disease biology, this review advances the concept of precision Fc pharmacology, in which antibody scaffold selection and Fc optimization are tailored to specific disease contexts and patient immune profiles. This framework provides a roadmap for the rational development of next-generation antibody therapeutics with improved efficacy, safety, and clinical precision. Full article

Background/Objectives: Because human prostate cancer (PCa) typically exhibits slow tumor growth, establishing reliable PCa tumor models is often time-consuming and unpredictable, thereby limiting the efficiency of preclinical theranostic research. To overcome this limitation, this study employed a non-viral PiggyBac transposon system to introduce triple-reporter genes into PSMA-expressing C4-2 cells, generating orthotopic and subcutaneous xenograft models that allow noninvasive, real-time monitoring of PCa progression and treatment response. Methods: Reporter-engineered C4-2 3R cells were generated by co-transfecting constructs encoding the reporter cassette and PB transposase, followed by enrichment through fluorescence microscopy and fluorescence-activated cell sorting (FACS) and implantation orthotopically or subcutaneously into mice. Tumor growth and treatment response to a single 2 Gy X-ray dose followed by 14.8 MBq of ¹⁷⁷Lu-PSMA-617, or to each monotherapy, were monitored weekly using an IVIS imaging system. Imaging findings were validated by tumor dissection and hematoxylin and eosin (H&E) staining, while PSMA expression was assessed by Western blotting and ¹⁸F-PSMA-1007 PET/CT. Results: C4-2 3R cells stably expressed the triple reporter genes (mRFP, luc2, and HSV1-tk), generating detectable orthotopic bioluminescence within one week and persisting for at least five weeks. In contrast, subcutaneous implantation generated only transient luc2 signals with no tumor formation. X-ray exposure did not increase total PSMA levels but induced the redistribution of PSMA to the cell membrane. Combined external beam radiotherapy (EBRT) and ¹⁷⁷Lu-PSMA-617 treatment produced higher ¹⁸F-PSMA-1007 uptake and stronger tumor suppression, with minimal residual tumor mass, as compared to single-treatment or control groups. Conclusions: This preliminary investigation suggests that the C4-2 3R model provides a practical and trackable tool for investigating slow-growing PCa tumors and evaluating PSMA-targeted therapies, either alone or in combination with EBRT. Full article

Human secreted phospholipase A₂ group IIA (hGIIA) is a Ca²⁺-dependent extracellular enzyme that supports host defense and amplifies inflammation through lipid mediator generation and receptor-linked signaling. In prostate cancer (PCa), hGIIA is commonly elevated compared with benign tissue and can persist after androgen deprivation, implicating it in tumor progression. PCa is typically an immunologically “cold” disease sustained by an immunosuppressive tumor microenvironment enriched in regulatory T cells ( T_reg), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and pro-tumor stromal cells, alongside hypoxia and metabolic rewiring. Because hGIIA is released by innate immune cells and is inducible in macrophages, it is well positioned to strengthen inflammatory lipid networks and promote immune dysfunction within the prostate tumor microenvironment. Here, we review the PCa microenvironment and evaluate evidence linking hGIIA to tumor–stroma crosstalk, angiogenic programming, and therapy resistance, highlighting major knowledge gaps in prostate-focused immune studies. Full article

Inflammation can either encourage or suppress tumor growth, thus having a two-sided effect on cancer development. This depends on the balance between pro-tumor and anti-tumor immune responses within the tumor microenvironment (TME). Pro-tumor inflammation, driven by specific immune cells, enhances blood flow and nutrient supply to tumors, promoting the activation of dormant cancer cells (DCCs). Conversely, antitumor inflammation hinders blood flow and can force active cancer cells into a state of dormancy. Tumors actively shift this balance towards pro-tumor inflammation to create a favorable environment for growth. Therefore, anti-inflammatory therapy may be an integral part of comprehensive cancer immunotherapy. This review explores how different anti-inflammatory medications, such as glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, anti-leukotrienes, statins, drugs that block pro-inflammatory cytokines, agents that inhibit oxidative phosphorylation, antioxidant vitamins, anti-angiogenic drugs, and low-dose chemotherapy, can be used to combat cancer. Granulocyte counts and erythrocyte sedimentation rate (ESR) can be used to assess inflammation levels and the effectiveness of anti-inflammatory treatments. We advocate for a paradigm shift in cancer treatment, moving away from aggressive tumor destruction, which triggers uncontrolled tumor regeneration, toward long-term immunological control of tumor growth while preserving the patient’s overall health. Full article

Non-communicable diseases (NCDs), including cancer, cardiovascular, neurodegenerative, autoimmune, and allergic diseases, account for a significant amount of global morbidity and mortality. Chronic viral infections have not been recognized as NCDs, despite the availability of several therapeutic vaccination strategies against oncogenic viruses, such as the hepatitis B virus (HBV) and the human papillomavirus (HPV). Indeed, chronic viral infection leads to the development and progression of malignancies directly linked to the viruses. These considerations support a connection between NCDs, infectious diseases, and therapeutic vaccination. Recent advances in technology have paved the way to the use of vaccines beyond the prevention of infectious diseases, heralding innovative therapeutic and preventative strategies for a variety of chronic NCDs. Here we will review the state of the art of personalized vaccine strategies for NCDs, with an emphasis on the diverse technological platforms used to develop them, including mRNA and DNA vaccines, viral vectors, dendritic cell-based vaccines, nanoparticle delivery systems, and next-generation adjuvants. The review intends to make the case for personalized and antigen-specific vaccination strategies as a compelling option for precision immunotherapy primarily in oncology, where neoantigen-based vaccines are being developed. In addition, we will also review tolerogenic vaccination strategies, vaccination strategies targeting pathological proteins and pathways in neurodegenerative and cardiovascular diseases, and vaccine-based treatment of chronic viral infections. Current evidence about vaccines suggests that several ways are available to induce an immune response or create tolerance to a disease, and possibly altering its course instead of simply controlling the symptoms. However, many challenges are still to be overcome, including disease variability, how to identify appropriate target antigens, the complexity of manufacturing process, long-term safety, and integration with already established treatments. By virtue of the convergence of multiple fields—immunology, genomics, bioinformatics, and new delivery systems—precision vaccinology is gaining momentum. Thus, it is envisaged that personalized vaccines will be an increasingly essential component of future preventive and therapeutic approaches for non-communicable diseases. Full article

Traditional inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have long been characterized as classical antiproliferative agents that induce G1 cell cycle arrest by blocking the phosphorylation of the retinoblastoma protein (Rb). However, recent studies in lung cancer have expanded this paradigm, revealing a functional transition from exclusive tumor suppression to the profound remodeling of the tumor microenvironment (TME) to enhance antitumor immunity. This review systematically outlines the genomic aberrations of the CDK4/6-Rb axis across lung cancer subtypes and dissects its immunomodulatory networks. These encompass the activation of effector T cells, the alleviation of immunosuppression mediated by regulatory T cells (Tregs), and the enhancement of antigen presentation via the Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Furthermore, we analyze acquired resistance mechanisms, primarily focusing on p21-CDK2 bypass activation mediated by Cyclin E1 gene (CCNE1) amplification and tumor protein 53 gene (TP53) mutations. We also review clinical investigations combining CDK4/6 inhibitors with targeted therapies against driver genes, as well as immune checkpoint inhibitors in lung cancer. Notably, in the context of lung cancer, these combinatorial strategies have been primarily investigated in the second-line or subsequent settings following progression on standard platinum-based chemotherapy or immunotherapy. Finally, we propose individualized, stratified treatment strategies based on genomic and immunological biomarkers, providing a translational framework for overcoming multidrug resistance and optimizing next-generation combinatorial regimens in lung cancer. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) and other systemic therapies can extend the survival of many patients with advanced melanoma, renewing interest in complementary strategies for unresectable or metastatic disease. Therapeutic cancer vaccines represent a possible approach. Recent evidence suggests commercially available mRNA vaccines can sensitize tumors to ICIs, challenging prior assumptions about neoantigen presentation. Despite renewed public interest in personalized cancer vaccine development, the proliferation of narrative and scoping reviews has not been matched by systematic mechanistic synthesis—platforms investigated across the 2010s and 2020s have not been rigorously compared within a single article. Accordingly, this review focuses on major vaccine platforms and proposes a comparative framework for understanding therapeutic melanoma vaccine development and immunologic rationale. Methods: Melanoma vaccine clinical trials listed on ClinicalTrials.gov were identified from 2010 to 2025. Eligible studies were screened and included in a qualitative review evaluating trial characteristics, vaccine platforms, study design, and reported outcomes. Results: There is one active Phase III clinical trial for melanoma vaccines in the US. Key principles of melanoma vaccinology include adjuvant, antigen, and delivery platform selection. From 2010 to 2025, four vaccine candidates advanced to Phase III trials, two provided Phase III results for peer review, one trial is ongoing, and no vaccines have been FDA-approved. Inconsistent reporting of outcomes and a lack of published results limited comparability across studies, precluding formal meta-analysis. Conclusions: Therapeutic melanoma vaccine options remain limited by translational challenges in study design and reporting gaps. This review synthesizes contemporary clinical trial activity and immunologic principles to inform future research. Full article