Search Results (304)

Hepatocellular carcinoma (HCC) ranks among the top causes of cancer-related mortality worldwide, and its complex tumor microenvironment (TME) contributes to poor responses to immunotherapy. Although PD-1/PD-L1 blockade has emerged as an effective treatment strategy, therapeutic resistance frequently limits its clinical benefit. Here, we uncover a distinct macrophage population associated with anti-PD-1 resistance in HCC. Single-cell transcriptomic profiling reveals an NFKBIZ⁺ M0 macrophage subset predominantly present in non-responders. Notably, these macrophages exhibit a hypoxia-induced phenotype characterized by the secretion of VEGFA and HBEGF, which cooperatively enhance tumor angiogenesis, alongside an elevated expression of the inflammatory chemokines CXCL2, CXCL3, and CXCL8 that consolidate an immunosuppressive, pro-tumorigenic microenvironment. Transcriptional regulatory network analysis further identified FOSB–VEGFA and FOS–HBEGF axes as key drivers of this pathogenic macrophage phenotype. Our findings define a distinct NFKBIZ⁺ macrophage population that mechanistically links hypoxia, angiogenesis, and immune evasion to PD-1 blockade resistance. This work provides new insights into the cellular and molecular basis of immunotherapy failure in HCC and highlights potential targets for overcoming treatment resistance. Full article

Background: Hypertrophic cardiomyopathy (HCM) is increasingly recognized as a disorder shaped not only by sarcomeric mutations but also by complex immunogenetic and metabolic interactions. Emerging transcriptomic and single-cell analyses implicate immune dysregulation, RNA methylation, and necroptosis as critical modulators of myocardial remodeling. Objectives: This scoping review synthesizes bioinformatic, transcriptomic, and experimental data to delineate the immunogenetic architecture of HCM and identify candidate molecular targets for immune–metabolic modulation. Methods: Following Joanna Briggs Institute and PRISMA-ScR guidelines, we systematically searched PubMed, Embase, Web of Science, and GEO through September 2025 for studies evaluating immune infiltration, RNA regulation, and necroptosis in human HCM. Data were narratively synthesized across histologic, clinical, and multi-omics domains. Results: Among 8191 screened records, 25 studies met the inclusion criteria. Key immune–epigenetic regulators included the lncRNA–mRNA pair MIR210HG–BPIFC, m6A readers IGFBP3 and YTHDC1, and necroptosis gene JAK2. The HCM myocardium exhibited the depletion of reparative M2 macrophages and Tregs; enrichment of cytotoxic CD8⁺ T cells; and activation of the TNFα–NFκB, IL-6–JAK–STAT3, and PI3K–Akt pathways. Machine learning biomarkers (RASD1, FCN3, and PIK3R1) exhibited diagnostic accuracy (AUC > 0.85). Drug target predictions identified ruxolitinib and celecoxib as potential immunometabolic modulators (agents predicted to modulate both immune and metabolic pathways based on gene expression signatures). Conclusions: These findings support a hypothesis that HCM may involve immunogenetic mechanisms, rather than being exclusively sarcomeric in nature, although this remains to be validated. The integration of molecular and imaging biomarkers may enable precision immunotherapy, redefining HCM from a structural cardiomyopathy to a biologically stratified condition. Full article

The intratumoral microbiota, comprising bacteria, fungi, and viruses within the tumor microenvironment, actively influences carcinogenesis. Key mechanisms include the induction of host DNA damage, modulation of critical oncogenic signaling pathways such as WNT-β-catenin, NF-κB, and PI3K, and the orchestration of inflammatory processes. The microbiome’s interaction with the host immune system is complex and bidirectional. On one hand, specific microbes can foster a pro-tumorigenic niche by suppressing the activity of cytotoxic T cells and natural killer (NK) cells or by promoting the accumulation of immunosuppressive cell types like tumor-associated macrophages (TAMs). On the other hand, microbial components can serve as neoantigens for T cell recognition or produce metabolites that reprogram the immune landscape to enhance anti-tumor responses. The composition of this microbiome is emerging as a crucial factor influencing the outcomes of immunotherapies. Prospective investigations in cancer immunotherapy ought to prioritize mechanistic inquiry employing integrative multi-omics methodologies. The execution of meticulously designed clinical trials for the validation of microbial biomarkers, and the systematic, evidence-based development of microbiome-targeted therapeutic interventions aimed at enhancing antitumor immune responses. Full article

Neuroinflammation, a key contributor to neurodegenerative diseases, results from excessive microglial activation. Microglia that respond to pathogenic molecules switch to the M1 type and secrete various immune cytokines, which can cause neuronal damage. Therefore, our study focused on molecules that can enhance the neuroprotective role of microglia and reduce neuronal damage. The adipocyte enhancer-binding protein 1 (AEBP1) gene is known for its role in regulating immune responses in macrophages. However, its role in neuroinflammation has not been fully explored. Therefore, we investigated the role of AEBP1 in microglial cells activated by lipopolysaccharide (LPS). First, we confirmed that AEBP1 is expressed in LPS-activated microglia and demonstrated that downregulation of AEBP1 using shRNA in activated microglia reduced the immune response via the nuclear factor-kappa-B (NFκB) pathway. These results promote a shift toward neuroprotective M2 microglia, thereby reducing neuronal damage. Next, we confirmed that the expression of AEBP1 was elevated in the brains of Alzheimer’s disease (AD) mice. Additionally, animal experiments to assess the therapeutic effects of AEBP1 showed that microglia gathered around amyloid beta (Aβ) and reduced its size. Taken together, our results provide the first evidence that AEBP1 can reduce inflammatory activity in microglia, suggesting its potential as a target molecule for immunotherapy. Full article

The tumor microenvironment (TME) plays an important role in the development, progression, and treatment response of pediatric cancers, yet remains less elucidated compared to adult malignancies. Pediatric tumors are unique with a low mutational burden, an immature immune landscape, and unique stromal interactions. The resultant “cold” immune microenvironments limits the effectiveness of conventional immunotherapies. This review summarizes the key cellular and non-cellular components of the pediatric TME—including T cells, NK cells, tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix remodeling, angiogenesis, and hypoxia—and describes how these elements shape tumor behavior and therapy resistance. The role of TME in common pediatric cancers like leukemia, lymphoma, neuroblastoma, brain tumors, renal tumors, and sarcomas is discussed. Emerging therapeutic strategies targeting immune checkpoints, macrophage polarization, angiogenic pathways, and stromal barriers are discussed. Full article

Novel adjuvants are key to making allergen-specific immunotherapy (AIT) safer and more effective. Their development is crucial for moving AIT into a new generation of precision medicine. N-glycosylation of protein antigens plays a pivotal role in modulating innate immune responses through enhanced recognition by pattern recognition receptors. New AIT vaccine strategies aim to exploit this by using innate-targeting adjuvants, modifying allergen structures, and routing early responses toward tolerance. Thus, we engineered five distinct N-glycosylated adjuvant configurations, composed of the receptor-binding domain of hemagglutinin (H1s) and Der p 2 (D2) allergen, to explore how glycan profile affects innate immune response for the application in therapeutic strategies for Type 1 hypersensitivity. Glycoengineered proteoforms produced in Pichia pastoris were structurally verified by mass spectrometry. Using M0 and M2 THP-1-derived macrophages, binding of all H1sD2 proteoforms to DC-SIGN was confirmed via confocal microscopy and flow cytometry. Stimulation of PBMCs with these proteoforms led to increased IL-10 and IFN-γ levels, indicating a shift toward regulatory immune responses. Notably, the M2 glycovariant elicited the strongest immunomodulatory signature, suggesting significant promise as a therapeutic candidate. These findings support the potential of glycoengineered allergen-adjuvant proteoforms to fine-tune innate immunity and improve the safety and efficacy of AIT. Full article

M2-like tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, particularly for cancer patients who are refractory to current immune checkpoint inhibitors (ICIs). Previously, we showed that prostaglandin E1 (PGE1) enhances the expression of M1 markers, including HLA-DR, on macrophages and induces the M1 polarization of TAMs in vivo. This study investigated the pharmacological mechanisms by which PGE1 and its derivatives suppress the expression of M2 markers, including TREM2 and CXCR2. Macrophages were cultured in ultralow attachment dishes either alone or in combination with liver cancer cell lines to generate homospheroids or heterospheroids. Cell surface marker expression was assessed by flow cytometry. Compared with homospheroids, M2 marker expression on macrophages in heterospheroids was significantly increased, suggesting that heterospheroid culture promotes M2 polarization. PGE1 decreased M2 marker expression in heterospheroids more effectively compared with PGE2, PGE3, misoprostol, and 13,14-dihydro-15-keto-PGE1, whereas the suppressive effects of 15-keto- and 13,14-dihydro-PGE1s, and lubiprostone were comparable to that of PGE1. Pharmacological inhibition of prostaglandin receptors revealed that EP2 and EP4 receptors are involved in the PGE1-induced reprogramming of M2-like macrophages to M1 macrophages. In summary, PGE1 and its derivatives are promising TAM-targeting immunotherapeutics. Full article

The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8⁺ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article

Candidozyma auris (Candida auris) is an emerging pathogenic yeast of global concern due to its persistence on abiotic and biotic surfaces and the difficulty of treating the severe infections it causes, which are frequently associated with high mortality rates because of its extensive antifungal resistance. Thus, new therapeutic strategies are urgently needed to complement or replace current antifungal drugs. In this study, we evaluated the efficacy of Ca37, a monoclonal antibody (mAb) targeting the alcohol dehydrogenase (Adh) protein of Candida albicans, against C. auris both in vitro and in vivo. Protein electrophoresis and Western Blot analyses demonstrated immunoreactivity of Ca37 mAb with C. auris total protein and cell wall-associated protein extracts, among which Adh was identified. In vitro, incubation with Ca37 mAb significantly reduced the growth of several C. auris strains and enhanced the phagocytic activity of RAW 264.7 murine macrophages. In vivo, Ca37 mAb treatment increased the survival of Galleria mellonella larvae. In a murine model of systemic infection, treated mice displayed improved clinical condition, along with a greater number and larger area of immune-associated foci in the kidneys, suggesting enhanced fungal recognition. These findings support the potential of Ca37 mAb as an antifungal immunotherapy, although further studies in murine models are necessary to establish optimal dosing, efficacy, and mechanisms of action. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy accounting for 3% of adult cancers globally. Despite advances in immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor (VEGF)-targeted therapies, durable disease control remains elusive for many patients. Increasing evidence implicates the acidic tumour microenvironment (TME) as a critical mediator of RCC progression, immune evasion, and therapeutic resistance. Solid tumours, including RCC, exhibit reversed pH gradients, characterised by acidic extracellular (pH 6.2–6.9) and alkaline intracellular conditions. This dysregulation arises from enhanced glycolysis, hypoxia-driven lactate accumulation, and the overexpression of pH-regulating enzymes such as carbonic anhydrase (CA9). Acidic TMEs impair cytotoxic T-cell and NK-cell activity, promote tumour-associated macrophage (TAM) polarisation towards an immunosuppressive phenotype, and upregulate alternative immune checkpoints. These mechanisms collectively undermine ICI efficacy and contribute to primary and secondary treatment resistance. Proton-sensing G-protein-coupled receptors (GPCRs), notably GPR65, have emerged as pivotal mediators linking extracellular acidosis to immune dysfunction. Preclinical studies demonstrate that GPR65 antagonists restore anti-tumour immune activity by reversing acidosis-driven immunosuppression and enhancing antigen processing. In RCC models, selective GPR65 inhibitors have shown the ability to reduce immunosuppressive cytokine IL-10 production, induce immunoproteasome activation, and synergise with anti-PD-1 therapy. The first-in-class GPR65 inhibitor, PTT-4256, is now under evaluation in the Phase I/II RAISIC-1 trial (NCT06634849) in solid tumours, including RCC. Targeting acid-sensing pathways represents a novel and promising therapeutic strategy in RCC, aiming to remodel the TME and overcome ICI resistance. Integrating GPR65 inhibition with existing immunotherapies may define the next era of RCC management, warranting continued translational and clinical investigation. Full article

Immunotherapy has demonstrated significant efficacy in colorectal cancer (CRC), but its therapeutic effects remain limited in microsatellite stable (MSS) patients, indicating the critical role of the tumor immune microenvironment (TIME) in regulating immune responses. Lipid rafts, dynamic membrane microdomains enriched in cholesterol and sphingolipids, have emerged as potential targets for TIME remodeling through their integration of immune signal transduction, enrichment of cell death receptors, and regulation of immune cell functionality. This review outlines the pivotal mediating roles of lipid rafts in cellular survival, death, and tumor progression. Specifically, MSS-type CRC exhibits lipid raft structural remodeling driven by dysregulated lipid metabolism, which fosters multiple immune escape mechanisms through exosome-mediated immunosuppressive signaling, promotion of tumor-associated macrophage (TAM) M2 polarization, enhanced infiltration of regulatory T cells (Tregs), and functional exhaustion of effector cells, such as CD8⁺ T cells and NK cells. Finally, we discuss targeted therapeutic strategies based on lipid raft characteristics and CRC molecular profiles, proposing an innovative multidimensional treatment framework combining immune checkpoint inhibitors with lipid raft-targeted interventions and chemoradiotherapy. This approach provides theoretical and strategic support for overcoming CRC immunotherapy resistance and advancing clinical translation. Full article

Bacterial metabolites play a dual role in hepatocellular carcinoma (HCC), exhibiting both tumor-promoting and tumor-suppressing activities dictated by their structural diversity. This review synthesizes recent advances in understanding how key microbial metabolites—such as bile acids, short-chain fatty acids, and polyamines—remodel the tumor immune microenvironment through mechanisms including immunometabolic reprogramming, epigenetic modification, and regulation of signaling pathways (e.g., FXR, TLR, and mTOR). We highlight their roles in modulating the function of T cells, NK cells, and tumor-associated macrophages and discuss emerging strategies that target these metabolites—including probiotic interventions, fecal microbiota transplantation, and metabolite-based adjuvants—to enhance immunotherapy efficacy and overcome resistance. By integrating mechanistic insight into translational potential, this work outlines a metabolite–immunometabolism–hepatocarcinogenesis framework and proposes novel combinatorial approaches for HCC treatment. Full article

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG–PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG–PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving apoptosis and autophagy, while miR-142 suppressed PD-L1 expression and epithelial–mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4⁺ and CD8⁺ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors. Full article

In response to growing clinical demands for more targeted and effective immunotherapies to treat cancer, biomaterial-based strategies have emerged as powerful tools for locally regulating immune responses. Among these, hydrogels, a class of biocompatible and tunable polymeric networks, are increasingly being leveraged for their high versatility and adaptability for creating tailored immune environments. By enabling controlled delivery of immune cues and direct cellular engineering, hydrogels utilized in vivo can precisely regulate both innate and adaptive immune responses while minimizing systemic toxicity. In this review, we outline essential hydrogel design features necessary for in vivo functionality including injectability, degradation kinetics, and immune-specific functionalization. Building on these principles, we explore how hydrogels have been employed to enhance T cell activation and dendritic cell maturation and guide macrophage reprogramming. Beyond cellular modulation, we further examine the use of hydrogels for cytokine and immunoregulatory agent delivery, tumor microenvironment remodeling, and the creation of tertiary-like lymphoid structures. Finally, we review recently completed and ongoing clinical trials of hydrogels in the cancer immunotherapy space. Together, these insights underscore the growing potential of in vivo hydrogel systems as immuno-interactive platforms capable of reshaping immune responses across diverse disease contexts. Full article

Recent studies propose that nanomaterials, either independently or coupled with biomolecular conjugates, have the ability to influence immune activity directly, creating new opportunities for advancing immunotherapies targeting infections and cancer. This review highlights current findings on how functionalized carbon nanotubes (f-CNTs), graphene, and carbon nanohorns interact with immune cells. Among these, f-CNTs have been the most thoroughly explored, though research interest in graphene has been rising steadily. Analysis of published work shows that macrophages are the most frequently studied immune cells (56%), followed by lymphocytes (30%), particularly T cells (22%). Investigations into monocytes and dendritic cells represent 7%, mixed populations such as peripheral blood mononuclear cells make up 6%, and studies on B cells and natural killer (NK) cells remain minimal (1%). Much of the available research has focused on assessing cytotoxicity and compatibility rather than uncovering precise mechanisms of immune modulation. Nonetheless, recent large-scale gene expression profiling has revealed novel immunomodulatory properties of f-CNTs, including stimulation of certain inflammatory signaling pathways. Research on graphene’s immune interactions is still developing. Overall, this review consolidates evidence on the immunological potential of biocompatible f-CNTs and graphene, offering groundwork for their future application in immunology and medicine. Full article