Search Results (31)

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy where endogenous steroid excess may foster immune evasion. However, whether this hormonal axis directly modulates the antigen presentation machinery remains unclear. Methods: We applied an immunoinformatics approach to the TCGA-ACC cohort (n = 79) to investigate relationships among steroid phenotype, HLA expression, tumor microenvironment (TME), and patient outcome. Key findings were assessed in an independent validation cohort (ENSAT-ACC, n = 44) using C1A/C1B molecular subtypes corresponding to the steroid phenotypes. Results: Stratification by steroid phenotype revealed two distinct immunological profiles. The high steroid production (HSP) phenotype was associated with suppressed HLA expression and a lymphocyte-depleted “cold” TME. In contrast, the low steroid production (LSP) phenotype displayed elevated HLA expression, enriched T-cell infiltration, and upregulation of immune checkpoints (e.g., PDCD1, CTLA4), consistent with an inflamed but exhausted TME. The core signature of HLA downregulation in the HSP-like phenotype (C1A) and the significant survival advantage of the LSP-like phenotype (C1B) were confirmed in the validation cohort, demonstrating biological robustness despite platform and sample size differences. Conclusions: These findings identify the steroid phenotype as a critical regulator of immune escape in ACC. Our results support incorporating this stratification as a biomarker for patient selection, identifying LSP tumors as the subgroup most likely to benefit from immune checkpoint blockade due to their “hot” yet exhausted microenvironment. Full article

Copper (Cu) is an essential element required by all living cells, where it supports critical enzymatic and signaling functions. In cancer, this balance is often disrupted, creating vulnerabilities that can be therapeutically exploited. Changes in Cu availability have been shown to influence key immunoregulatory pathways, including those involved in inflammation, cell death, and immune evasion. Notably, Cu can drive expression of programmed death ligand 1 (PD-L1), contributing to immunosuppression, while also promoting immunogenic cell death, which stimulates adaptive immune responses. These dual effects highlight the complexity and therapeutic potential of Cu-based interventions, particularly in the context of immune modulation and toxicity. This review argues that Cu-based nanomedicines can selectively deliver high concentrations of bioactive Cu to tumor cells, inducing cell death and triggering adaptive immune responses. We summarize current knowledge on Cu’s roles in cancer and immunity, emphasizing recent insights into how these intersect through Cu-mediated modulation of anticancer immune pathways. Finally, we explore the clinical potential of Cu-based nanomedicines to convert immunologically “cold” tumors into “hot” ones, thereby improving responses to immunotherapy. Realizing this potential will depend on the thoughtful integration of Cu delivery approaches with existing immunotherapeutic strategies. Full article

Background: Melanoma is a highly heterogeneous neoplasia in which transcriptional profile encodes much of the biological diversity that determines tumor progression and therapeutic response. To refine its molecular stratification and profiles characterization, we conducted an in silico transcriptomic analysis. Methods: Public microarray datasets from the GEO and ArrayExpress were examined, and the E-MTAB-6697 expression dataset was selected. We used a K-Means clustering algorithm to stratify 194 tumor samples into expression-driven subgroups and analyzed each one to define their transcriptional and biological profiles. Differential expression analysis between identified clusters and controls was performed. Additionally, we applied Weighted-Gene correlation analysis to identify coordinated expression hubs in the tumor dataset and tested the resulting modules for correlation with the identified clusters. Results: Unsupervised clustering of melanoma transcriptomic profiles identified three distinct molecular subtypes characterized by divergent biological programs. While all clusters shared the dysregulation of pathways involved in epidermal differentiation, immune response, and lipid metabolism, they diverged in proliferation, phenotypic plasticity, metabolic adaptation, and apoptotic regulation. Cluster A was characterized by enrichment in DNA replication, repair, and mitochondrial metabolism modules, suggesting a proliferative yet genomically stable state. Cluster B showed enrichment in immune and cytokine signaling pathways alongside reduced proliferative activity, consistent with a quiescent or transitional phenotype. Cluster C displayed coordinated enrichment in cell-cycle, DNA-maintenance, and neuroectodermal reprogramming pathways, indicating a highly plastic and proliferative subtype. Despite these molecular distinctions, all clusters retained an “immunologically hot” profile (IPS 7–8), indicating potential responsiveness to immunotherapy. Conclusions: These findings provide an overview of the functional characteristics of melanoma heterogeneity and identify biological processes that could be targeted by drugs for the development of tailored therapies for each subtype. Nevertheless, future studies in independent clinically annotated cohorts would be required. Full article

This is the first work to screen an optimal extraction method for Citrus reticulata Blanco cv. Tankan peel polysaccharides (CPP). The CPP was extracted using hot water extraction (HWE), acid extraction (AAE), enzyme extraction (EAE), high-pressure extraction (HPE), and ultrasound extraction (UAE), named CPP-W, CPP-A, CPP-E, CPP-P, and CPP-U, respectively. Results showed that CPP-A and CPP-P had higher extraction yields than other CPPs. The five CPPs varied chemically in molecular weight, monosaccharide composition, and microstructure, but shared similar IR spectra and core glycosidic linkages, indicating differential degradation while preserving core structures during extraction. Among these CPPs, CPP-A, CPP-E, and CPP-U exhibited stronger immunological activities, attributed to high galacturonic acid and low molecular weight. Moreover, CPPs significantly promoted secretion of cytokines (nitric oxide, NO; prostaglandin E₂, PGE₂; interleukin-6, IL-6; tumor necrosis factor-α, TNF-α) by activating downstream inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)-related mitogen-activated protein kinases (MAPK) pathways. Overall, CPP-E possessed high extraction yield, low molecular weight, and strong immuno-stimulatory activity, suggesting that enzyme-assisted extraction was the optimal approach for extracting CPP. Full article

To investigate the immunomodulatory activity of polysaccharides derived from the rhizome of Imperata cylindrica, polysaccharides (IRPs-H) were extracted using hot water extraction and further purified via DEAE-52 ion-exchange chromatography, yielding three fractions: IRPs-H1, IRPs-H2, and IRPs-H3. The structural features of these fractions were characterized by Fourier-transform infrared spectroscopy (FT-IR), high-performance gel permeation chromatography (HPGPC), atomic force microscopy (AFM), and thermogravimetric analysis (TGA). Their immunological activities were evaluated in vitro. All three fractions were identified as neutral pyranose-type polysaccharides, primarily composed of glucose and xylose, exhibiting good thermal stability and lacking long-chain structures. In vitro assays using RAW264.7 macrophages demonstrated that these polysaccharides promoted cell proliferation (50–800 μg/mL), enhanced phagocytic activity, and induced morphological changes characteristic of macrophage activation, including irregular shapes and pseudopod formation. ELISA and flow cytometry analyses revealed dose-dependent increases in nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) levels. Notably, the IRPs-H3 fraction stimulated TNF-α and IL-6 production to levels of 438.02 ± 14.14 pg/mL and 30.13 ± 1.27 pg/mL, respectively, which were comparable to those induced by lipopolysaccharide (LPS), the positive control (460.83 ± 16.10 pg/mL and 31.87 ± 1.72 pg/mL, respectively). These results suggest that polysaccharides extracted from the rhizome of Imperata cylindrica possess significant immunostimulatory properties and hold potential for development as functional food ingredients or immune-enhancing agents. Full article

Histone deacetylase 3 (HDAC3) has emerged as a critical epigenetic regulator in tumor progression and immune modulation, positioning it as a promising target for enhancing cancer immunotherapy. This work comprehensively explores HDAC3’s multifaceted roles, focusing on its regulation of key immune-modulatory pathways such as cGAS-STING, ferroptosis, and the Nrf2/HO-1 axis. These pathways are central to tumor immune evasion, antigen presentation, and immune cell activation. Additionally, the distinct effects of HDAC3 on various immune cell types—including its role in enhancing T cell activation, restoring NK cell cytotoxicity, promoting dendritic cell maturation, and modulating macrophage polarization—are thoroughly examined. These findings underscore HDAC3’s capacity to reshape the tumor immune microenvironment, converting immunologically “cold tumors” into “hot tumors” and thereby increasing their responsiveness to immunotherapy. The therapeutic potential of HDAC3 inhibitors is highlighted, both as standalone agents and in combination with immune checkpoint inhibitors, to overcome resistance and improve treatment efficacy. Innovative strategies, such as the development of selective HDAC3 inhibitors, advanced nano-delivery systems, and integration with photodynamic or photothermal therapies, are proposed to enhance treatment precision and minimize toxicity. By addressing challenges such as toxicity, patient heterogeneity, and resistance mechanisms, this study provides a forward-looking perspective on the clinical application of HDAC3 inhibitors. It highlights its significant potential in personalized cancer immunotherapy, paving the way for more effective treatments and improved outcomes for cancer patients. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a notably poor response to therapy due to its immunosuppressive tumor microenvironment (TME) and intrinsic drug resistance. The oncolytic virus (OV) represents a promising therapeutic strategy capable of transforming the “cold” immunological profile of PDAC tumors to a “hot” one by reshaping the TME. 4-1BB (CD137), a crucial member of the tumor necrosis factor receptor superfamily, plays a significant role in T-cell activation and function. Methods: In this study, we constructed an oncolytic herpes simplex virus armed with 4-1BBL (oHSV-4-1BBL), the ligand for the 4-1BB receptor, and investigated its therapeutic effects in two mouse models of pancreatic cancer, Pan02_HVEM and KPC. Results: We found that oHSV-4-1BBL remarkably inhibited tumor growth and extended the median survival time in both models. To amplify the therapeutic effect, we further combined oHSV-4-1BBL with PD-1 antibody. This combination therapy not only further suppressed tumor growth but also extended the median survival time by an additional 11 days compared to oHSV (armed with GFP as a control) combined with PD-1 antibody treatment, with some mice achieving complete tumor regression. Conclusions: Our findings confirm the potential of combining oncolytic viral therapy with 4-1BB targeting in enhancing the treatment of pancreatic cancer. Full article

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically “cold” tumors to “hot” tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients. Full article

Cancer immunotherapy has revolutionized oncology by harnessing the patient’s immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically ‘cold’ tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy. Full article

The success of cancer immunotherapy is largely associated with immunologically hot tumors. Approaches that promote the infiltration of immune cells into tumor beds are urgently needed to transform cold tumors into hot tumors. Oncolytic viruses can transform the tumor microenvironment (TME), resulting in immunologically hot tumors. Cytokines are good candidates for arming oncolytic viruses to enhance their function in this transformation. Here, we used the oncolytic vaccinia virus (oVV) to deliver interleukin-9 (IL-9) into the tumor bed and explored its antitumor effects in colon and lung tumor models. Our data show that IL-9 prolongs viral persistence, which is probably mediated by the up-regulation of IL-10. The vvDD-IL-9 treatment elevated the expression of Th1 chemokines and antitumor factors such as IFN-γ, granzyme B, and perforin. IL-9 expression increased the percentages of CD4⁺ and CD8⁺ T cells in the TME and decreased the percentage of oVV-induced immune suppressive myeloid-derived suppressor cells (MDSC), leading to potent antitumor effects compared with parental virus treatment. The vvDD-IL-9 treatment also increased the percentage of regulatory T cells (Tregs) in the TME and elevated the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4, but not GITR. The combination therapy of vvDD-IL-9 and the anti-CTLA-4 antibody, but not the anti-GITR antibody, induced systemic tumor-specific antitumor immunity and significantly extended the overall survival of mice, indicating a potential translation of the IL-9-expressing oncolytic virus into a clinical trial to enhance the antitumor effects elicited by an immune checkpoint blockade for cancer immunotherapy. Full article

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5–10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy. Full article

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients’ T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10–20 Gy/fractions) converts immunologically “cold” tumors into “hot” ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5–10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors. Full article

Comparative studies of immune-active hot and immune-deserted cold tumors are critical for identifying therapeutic targets and strategies to improve immunotherapy outcomes in cancer patients. Tumors with high tumor-infiltrating lymphocytes (TILs) are likely to respond to immunotherapy. We used the human breast cancer RNA-seq data from the cancer genome atlas (TCGA) and classified them into hot and cold tumors based on their lymphocyte infiltration scores. We compared the immune profiles of hot and cold tumors, their corresponding normal tissue adjacent to the tumor (NAT), and normal breast tissues from healthy individuals from the Genotype-Tissue Expression (GTEx) database. Cold tumors showed a significantly lower effector T cells, lower levels of antigen presentation, higher pro-tumorigenic M2 macrophages, and higher expression of extracellular matrix (ECM) stiffness-associated genes. Hot/cold dichotomy was further tested using TIL maps and H&E whole-slide pathology images from the cancer imaging archive (TCIA). Analysis of both datasets revealed that infiltrating ductal carcinoma and estrogen receptor ER-positive tumors were significantly associated with cold features. However, only TIL map analysis indicated lobular carcinomas as cold tumors and triple-negative breast cancers (TNBC) as hot tumors. Thus, RNA-seq data may be clinically relevant to tumor immune signatures when the results are supported by pathological evidence. Full article

Increasing evidence pinpoints metronomic chemotherapy, a frequent and low dose drug administration with no prolonged drug-free intervals, as a potential tool to fight certain types of cancers. The primary identified targets of metronomic chemotherapy were the tumor endothelial cells involved in angiogenesis. After this, metronomic chemotherapy has been shown to efficiently target the heterogeneous population of tumor cells and, more importantly, elicit the innate and adaptive immune system reverting the “cold” to ”hot” tumor immunologic phenotype. Although metronomic chemotherapy is primarily used in the context of a palliative setting, with the development of new immunotherapeutic drugs, a synergistic therapeutic role of the combined metronomic chemotherapy and immune checkpoint inhibitors has emerged at both the preclinical and clinical levels. However, some aspects, such as the dose and the most effective scheduling, still remain unknown and need further investigation. Here, we summarize what is currently known of the underlying anti-tumor effects of the metronomic chemotherapy, the importance of the optimal therapeutic dose and time-exposure, and the potential therapeutic effect of the combined administration of metronomic chemotherapy with checkpoint inhibitors in preclinical and clinical settings. Full article

Intraductal carcinoma of the prostate (IDC-P) is an aggressive histological subtype of prostate cancer (PCa) detected in approximately 20% of radical prostatectomy (RP) specimens. As IDC-P has been associated with PCa-related death and poor responses to standard treatment, the purpose of this study was to explore the immune infiltrate of IDC-P. Hematoxylin- and eosin-stained slides from 96 patients with locally advanced PCa who underwent RP were reviewed to identify IDC-P. Immunohistochemical staining of CD3, CD8, CD45RO, FoxP3, CD68, CD163, CD209 and CD83 was performed. For each slide, the number of positive cells per mm² in the benign tissues, tumor margins, cancer and IDC-P was calculated. Consequently, IDC-P was found in a total of 33 patients (34%). Overall, the immune infiltrate was similar in the IDC-P-positive and the IDC-P-negative patients. However, FoxP3⁺ regulatory T cells (p < 0.001), CD68⁺ and CD163⁺ macrophages (p < 0.001 for both) and CD209⁺ and CD83⁺ dendritic cells (p = 0.002 and p = 0.013, respectively) were less abundant in the IDC-P tissues compared to the adjacent PCa. Moreover, the patients were classified as having immunologically “cold” or “hot” IDC-P, according to the immune-cell densities averaged in the total IDC-P or in the immune hotspots. The CD68/CD163/CD209-immune hotspots predicted metastatic dissemination (p = 0.014) and PCa-related death (p = 0.009) in a Kaplan–Meier survival analysis. Further studies on larger cohorts are necessary to evaluate the clinical utility of assessing the immune infiltrate of IDC-P with regards to patient prognosis and the use of immunotherapy for lethal PCa. Full article