Search Results (1,742)

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

Heat shock proteins (HSPs) play a key role in enhancing insect resilience to abiotic and biotic stresses by preserving cellular integrity and modulating immune responses. This review summarizes the main functions of HSPs in insects, including protein stabilization, interaction with antioxidant systems, and involvement in the innate immune response. The expression of HSPs under environmental conditions reflects their evolutionary adaptation to various stressors, including thermal changes, chemical exposure, and pathogens. Future research should focus on the interaction between HSPs and other stress response systems to improve our understanding of insect adaptation. Furthermore, in the context of global climate change, HSPs emerge as a crucial resilience factor and potential biomarkers for environmental monitoring. Full article

Heart failure (HF), a prevalent global health issue characterized by the heart’s impaired ability to pump or fill blood, affects millions worldwide and continues to pose significant challenges despite advancements in treatment. This review delves into the critical and increasingly recognized role of inflammation in the development and progression of this complex syndrome. While the incidence of HF has seen a decline in some regions due to improved cardiac care, its overall prevalence is rising, particularly among younger adults and those with heart failure with a preserved ejection fraction (HFpEF). Given the persistently high rates of hospitalization and mortality associated with HF, understanding the underlying mechanisms, including the contribution of inflammation, is crucial for identifying novel therapeutic strategies. Inflammation in heart failure is a multifaceted process involving the activation of the immune system, both innate and adaptive, and encompasses various mechanisms such as the release of pro-inflammatory mediators, endothelial dysfunction, and neurohormonal activation. Myocardial damage triggers the innate immune response, while humoral immunity and chronic systemic inflammation, often linked to cardiovascular risk factors and autoimmune diseases, also play significant roles. Notably, heart failure and inflammation have a reciprocal relationship, with HF itself contributing to inflammatory processes within the cardiac tissue and systemically. Understanding these intricate pathways, including the involvement of specific immune cells and molecular mediators, is essential for comprehending the pathogenesis of heart failure and exploring potential therapeutic interventions. The review further examines various inflammatory biomarkers that have been implicated in heart failure, such as cytokines (including TNF-α and IL-1) and C-reactive protein (CRP). While these markers often correlate with the severity and prognosis of HF, clinical trials targeting specific inflammatory mediators have largely yielded disappointing results, highlighting the complexity of the inflammatory response in this context. The exploration of these biomarkers and the challenges encountered in translating anti-inflammatory strategies into effective treatments underscore the need for continued research to unravel the precise role of inflammation across different HF subtypes and to develop more targeted and effective anti-inflammatory therapies. Full article

Adoptive cell therapies have transformed the treatment landscape for hematologic malignancies. Yet, translation to solid tumors remains constrained by antigen heterogeneity, an immunosuppressive tumor microenvironment (TME), and poor persistence of conventional CAR-T cells. In response, innate immune cell platforms, particularly chimeric antigen receptor–engineered natural killer (CAR-NK) cells and chimeric antigen receptor–macrophages (CAR-MΦ), have emerged as promising alternatives. This review summarizes recent advances in the design and application of CAR-NK and CAR-MΦ therapies for solid tumors. We highlight key innovations, including the use of lineage-specific intracellular signaling domains (e.g., DAP12, 2B4, FcRγ), novel effector constructs (e.g., NKG7-overexpressing CARs, TME-responsive CARs), and scalable induced pluripotent stem cell (iPSC)-derived platforms. Preclinical data support enhanced antitumor activity through mechanisms such as major histocompatibility complex (MHC)-unrestricted cytotoxicity, phagocytosis, trogocytosis, cytokine secretion, and cross-talk with adaptive immunity. Early-phase clinical studies (e.g., CT-0508) demonstrate feasibility and TME remodeling with CAR-MΦ. However, persistent challenges remain, including transient in vivo survival, manufacturing complexity, and risks of off-target inflammation. Emerging combinatorial strategies, such as dual-effector regimens (CAR-NK⁺ CAR-MΦ), cytokine-modulated cross-support, and bispecific or logic-gated CARs, may overcome these barriers and provide more durable, tumor-selective responses. Taken together, CAR-NK and CAR-MΦ platforms are poised to expand the reach of engineered cell therapy into the solid tumor domain. Full article

Inflammation is a self-defense mechanism that controls the homeostasis of an organism, and its alteration by persistent noxious stimuli could lead to an imbalance in the regulation of inflammatory responses mediated by innate and adaptive immunity. During chronic inflammation, sustained exposure of myeloid cells to the various inflammatory signals derived from inflamed tissue could lead to the generation of myeloid cells with an immunosuppressive state, called myeloid-derived suppressor cells (MDSCs), which can exert protective or deleterious functions depending on the nature of signals and the specific inflammatory conditions created by different pathophysiological contexts. Initially identified in various tumor models and cancer patient samples, these cells have long been recognized as negative regulators of anti-tumor immunity. Consequently, researchers have focused on elucidating the molecular mechanisms underlying their potent immunosuppressive activity. As a key component of the signal transducing processes, protein kinases play a central role in regulating the signal transduction mechanisms of many cellular activities, including differentiation and immunosuppression. Over the past decade, at least a dozen kinases, including mechanistic target of rapamycin (mTOR), phosphoinositide 3-kinases (PI3Ks), TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (TAM RTKs), mitogen-activated protein kinases (MAPKs), and others, have emerged as key contributors to the generation and differentiation of MDSCs. Here, we discuss the recent findings on these kinases that directly contribute to the immunosuppressive functions of MDSCs. Full article

Circular RNA (CircRNA) is a single-stranded RNA arising from back splicing. CircRNAs interact with mRNA, miRNA, and proteins. These interactions regulate various life processes, including transcription, translation, cancer progression, anticancer drug resistance, and metabolism. Due to a lack of cap and poly(A) tails, circRNAs show exceptional stability and resistance to RNase degradation. CircRNAs exhibit dysregulated expression patterns in various cancers and influence cancer progression. Stability and regulatory roles in cancer progression make circRNAs reliable biomarkers and targets for the development of anticancer therapeutics. The dysregulated expression of circRNAs is associated with resistance to anticancer drugs. Enhanced glycolysis by circRNAs leads to resistance to anticancer drugs. CircRNAs have been known to regulate the response to chemotherapy drugs and immune checkpoint inhibitors. Exogenous circRNAs can encode antigens that can induce both innate and adaptive immunity. CircRNA vaccines on lipid nanoparticles have been shown to enhance the sensitivity of cancer patients to immune checkpoint inhibitors. In this review, we summarize the roles and mechanisms of circRNAs in anticancer drug resistance and glycolysis. This review discusses clinical applications of circRNA vaccines to overcome anticancer drug resistance and enhance the efficacy of immune checkpoint inhibitors. The advantages and disadvantages of circRNA vaccines are also discussed. Overall, this review stresses the potential value of circRNAs as new therapeutic targets and diagnostic/prognostic biomarkers for cancer Full article

Background: Dendritic cells (DCs) play an important role as a bridge between innate and adaptive immunity, and changes in gene expression of DCs during the immune response to Mycobacterium tuberculosis (M.tb) may affect the development of tuberculosis. Methods: Using systems biology methods, mRNA and miRNA expression profile data of DCs infected with M.tb were obtained. A total of 1398 differentially expressed mRNAs and 79 differentially expressed miRNAs were identified, and a corresponding miRNA–mRNA regulatory network was constructed using Cytoscape 3.9.1 software. The functional annotations and pathway classifications of the miRNA–mRNA network were identified using the DAVID tool. Then, the key pathway modules in the miRNA–mRNA network were screened and subjected to PPI network analysis to identify hub nodes. Subsequently the miRNA/mRNA axis was determined, validated by qRT-PCR, and evaluated through ROC curve analysis. Results: The TNF signaling pathway and the Tuberculosis pathway were key pathway modules, with miR-34a-3p/TNF and miR-190a-3p/IL1B being the greatest correlations with the two pathway modules. qRT-PCR results showed that IL1B and miR-190a-3p exhibited significant differences in both the H37Ra and BCG infection groups. The AUC of two factors (IL1B and miR-190a-3p) was 0.9561 and 0.9625, respectively, showing high sensitivity and specificity. Conclusions: Consequently, miR-190a-3p/IL1B might be a good candidate marker to characterize the immune response of DCs to M.tb and a transition signal from innate to adaptive immunity. Full article

Previous studies have shown that patients with a history of endometriosis have an increased susceptibility for developing a big number of comorbidities, including various autoimmune diseases. Endometriosis is a complex, inflammatory, estrogen-dependent, heterogeneous gynecological disorder with an incidence of up to 10% in women of reproductive age. It is characterized by the implantation and growth of endometrial tissue outside the uterus and is associated with dysmenorrhea, deep dyspareunia, pelvic pain and infertility. Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disorder of the connective tissue, characterized by impaired innate and adaptive immune responses and the production of pathogenic autoantibodies that drive inflammation and damage in multiple organs. Its etiology is elusive yet associated with high heritability. Importantly, it has been found that endometriosis and SLE share some underlying molecular and cellular pathways. In the present study, we sought to delineate the co-occurrence of endometriosis with SLE from the biological and genetic viewpoint, aiming to identify the putative shared genetic components and clarify the underlying pathogenetic mechanisms. This information may contribute further to the design of new therapeutic protocols for both disorders under study. Full article

Silver nanoparticles (AgNPs), lauded for their unique antibacterial and physicochemical attributes, are proliferating across industrial sectors, raising concerns about their environmental fate, in aquatic systems. While “green” synthesis offers a sustainable production route with reduced chemical byproducts, the safety of these AgNPs for aquatic fauna remains uncertain due to nanoparticle-specific effects. Conversely, mast cells play crucial roles in fish immunity, orchestrating innate and adaptive immune responses by releasing diverse mediators and recognizing danger signals. Goblet cells are vital for mucosal immunity and engaging in immune surveillance, regulation, and microbiota interactions. The interplay between these two cell types is critical for maintaining mucosal homeostasis, is central to defending against fish diseases and is highly responsive to environmental cues. This study investigates the acute dermatotoxicity of environmentally relevant AgNP concentrations (0, 0.031, 0.250, and 5.000 μg/L) on zebrafish epidermis. A 96 h assay revealed a biphasic response: initial mucin hypersecretion at lower AgNP levels, suggesting an early stress response, followed by a concentration-dependent collapse of mucosal integrity at higher exposures, with mucus degradation and alarm cell depletion. A rapid and generalized increase in epidermal mucus production was observed across all AgNP exposure groups within two hours of exposure. Further mechanistic insights into AgNP-induced toxicity were revealed by concentration-dependent alterations in goblet cell dynamics. Lower AgNP concentrations initially led to an increase in both goblet cell number and size. However, at the highest concentration, this trend reversed, with a significant decrease in goblet cell numbers and size evident between 48 and 96 h post-exposure. The simultaneous presence of neutral and acidic mucins indicates a dynamic epidermal response suggesting a primary physical barrier function, with acidic mucins specifically upregulated early on to enhance mucus viscosity, trap AgNPs, and inhibit pathogen invasion, a clear defense mechanism. The subsequent reduction in mucin-producing cells at higher concentrations signifies a critical breakdown of this protective strategy, leaving the epidermis highly vulnerable to damage and secondary infections. These findings highlight the vulnerability of fish epidermal defenses to AgNP contamination, which can potentially compromise osmoregulation and increase susceptibility to threats. Further mechanistic research is crucial to understand AgNP-induced epithelial damage to guide sustainable nanotechnology. Full article

Cutibacterium acnes (C. acnes) is a commensal bacterium of the skin microbiota that can transform itself into a pathogen depending on the peculiar susceptibility of the host: it is the sole microorganism so far to be found in the specific organ lesions of sarcoidosis, and C. acnes-induced activation of T-helper-type-1 cell responses is generally higher in patients with sarcoidosis than in healthy subjects. This bacterium acts as an opportunistic agent in several inflammatory conditions other than sarcoidosis, such as prostate cancer and prosthetic joint infections. Both innate and adaptive immunity systems are involved in the pathogenesis of C. acnes-mediated sarcoid lesions, and a seminal role is played by host toll-like receptor (TLR)-2, TLR-4, TLR-6, NOD-like receptors, and mononuclear cell cytoplasmic receptors. This review summarizes current knowledge on the potential cause–effect relationship existing between C. acnes and sarcoidosis, addressing issues of future research directions and novel therapeutic strategies in the management of a complex disease such as sarcoidosis. Full article

Despite remarkable progress in cancer immunotherapy, many agents that show efficacy in murine or in vitro models fail to translate clinically. Zebrafish (Danio rerio) have emerged as a powerful complementary model that addresses several limitations of traditional systems. Their optical transparency, genetic tractability, and conserved immune and oncogenic signaling pathways enable high-resolution, real-time imaging of tumor–immune interactions in vivo. Importantly, zebrafish offer a unique opportunity to study the core mechanisms of health and sickness, complementing other models and expanding our understanding of fundamental processes in vivo. This review provides an overview of zebrafish immune system development, highlighting tools for tracking innate and adaptive responses. We discuss their application in modeling immune evasion, checkpoint molecule expression, and tumor microenvironment dynamics using transgenic and xenograft approaches. Platforms for high-throughput drug screening and personalized therapy assessment using patient-derived xenografts (“zAvatars”) are evaluated, alongside limitations, such as temperature sensitivity, immature adaptive immunity in larvae, and interspecies differences in immune responses, tumor complexity, and pharmacokinetics. Emerging frontiers include humanized zebrafish, testing of next-generation immunotherapies, such as CAR T/CAR NK and novel checkpoint inhibitors (LAG-3, TIM-3, and TIGIT). We conclude by outlining the key challenges and future opportunities for integrating zebrafish into the immuno-oncology pipeline to accelerate clinical translation. Full article

Tonsils are secondary lymphoid organs that play a crucial role in the immunological response, with B cells being a major component involved in both innate and adaptive immunity. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome and obstructive sleep apnea syndrome (OSAS) are both common pediatric conditions involving tonsillar pathology. In both syndromes, the molecular pathways dysregulated in tonsillar B cells are still to be understood. The study aimed to unravel and compare the proteomic profiles of tonsillar CD19+ B cells isolated from pediatric patients with PFAPA (n = 6) and OSAS (n = 6) to identify disease-specific molecular signatures. B cells were isolated from the tonsillar tissue using magnetic microbeads (with a purity of 93.50%). Proteomic analysis was performed by nanoLC-MS/MS with both data-dependent (DDA) and data-independent acquisition (DIA) methods, followed by comprehensive bioinformatic analysis. By merging DDA and DIA datasets, a total of 18.078 unique proteins were identified. Differential expression analysis revealed 83 proteins increased and 49 proteins decreased in OSAS B cells compared to PFAPA B cells (fold change ≥ 1.5 or ≤0.6, p < 0.05). Distinct pathway enrichments were highlighted, including alterations in the regulation of PTEN gene transcription, circadian gene expression, inflammasome pathways (IPAF and AIM2), and the metabolism of angiotensinogen to angiotensin. Specific proteins such as p53, Hdac3, RPTOR, MED1, Caspase-1, Cathepsin D, Chymase, and TLR2 (validated by WB) were shown to be differentially expressed. These findings reveal distinct proteomic signatures in tonsillar B cells from patients with PFAPA and OSAS, offering novel insights into the pathophysiology and potential avenues for biomarker discovery. Full article

Mandarin fish (Siniperca chuatsi) are known to exhibit distinct physiological and immunological adaptations to environmental stressors, but the underlying molecular and microbial mechanisms remain unclear. In this study, we integrated transcriptome and microbiome analyses to investigate adaptations across three geographically distinct mandarin fish groups: Guangdong (G), Qiupu (Q), and native Taihu (T). Liver RNA sequencing revealed 5339 differentially expressed genes (DEGs) between T and G and 1531 DEGs between T and Q. Functional enrichment analysis revealed group-specific responses. Specifically, DEGs from T vs. G were linked to small-molecule metabolism and innate immunity whereas the DEGs from T vs. Q were related to immune regulation and chromatin organization. The concurrent 16S rRNA sequencing of the intestinal microbiota identified 2680 amplicon sequence variants, with principal coordinate analysis showing distinct clustering (31.77% variance). Group T had higher Firmicutes abundance whereas groups G and Q had a higher relative abundance of Fusobacteriota. Correlation networks revealed key microbe–gene interactions, including positive links between Lactobacillus and immune genes in group T and negative associations with Romboutsia. These findings suggest that enhanced immune homeostasis and metabolic flexibility in group T may result from coordinated host gene expression and Lactobacillus-driven microbiome modulation. We provide new insights into the mechanisms of adaptation in mandarin fish and identify potential biomarkers for enhancing aquaculture resilience. Full article

Human endogenous retroviruses (HERVs), as remnants of ancient exogenous retroviruses in the human genome, have received increased attention regarding their pathogenic effects caused by abnormal activation. In normal somatic cells, HERVs are tightly regulated by epigenetic mechanisms and are rarely expressed. In cancer cells, likely due to epigenetic dysregulation, HERVs become abnormally activated and are transcribed and expressed. The innate and adaptive immune responses triggered by HERV activation are closely associated with cancer initiation and progression. Melanoma, as a malignant tumor, often exhibits a poor prognosis in advanced-stage patients. HERVs have been found to be expressed in melanoma and linked to its malignant transformation. Here, we review the potential roles HERVs may play in melanoma development. As promising therapeutic targets for melanoma, research on HERVs could facilitate the development of novel treatment strategies. Full article