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Search Results (3,409)

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Keywords = tumor–immune system

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30 pages, 1325 KiB  
Review
Molecular Targets for Pharmacotherapy of Head and Neck Squamous Cell Carcinomas
by Robert Sarna, Robert Kubina, Marlena Paździor-Heiske, Adrianna Halama, Patryk Chudy, Paulina Wala, Kamil Krzykawski and Ilona Nowak
Curr. Issues Mol. Biol. 2025, 47(8), 609; https://doi.org/10.3390/cimb47080609 (registering DOI) - 1 Aug 2025
Abstract
Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold [...] Read more.
Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold standard but is limited by toxicity and tumor resistance. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), has improved overall survival, especially in patients with high PD-L1 expression. In parallel, targeted therapies such as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors—which impair DNA repair and increase replication stress—have shown promising activity in HNSCC. Cyclin-dependent kinase (CDK) inhibitors are also under investigation due to their potential to correct dysregulated cell cycle control, a hallmark of HNSCC. This review aims to summarize current and emerging pharmacotherapies for HNSCC, focusing on chemotherapy, immunotherapy, and PARP and CDK inhibitors. It also discusses the evolving role of targeted therapies in improving clinical outcomes. Future research directions include combination therapies, nanotechnology-based delivery systems to enhance treatment specificity, and the development of diagnostic tools such as PARP1-targeted imaging to better guide personalized treatment approaches. Full article
(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers: 2nd Edition)
13 pages, 1293 KiB  
Article
Integration of an OS-Based Machine Learning Score (AS Score) and Immunoscore as Ancillary Tools for Predicting Immunotherapy Response in Sarcomas
by Isidro Machado, Raquel López-Reig, Eduardo Giner, Antonio Fernández-Serra, Celia Requena, Beatriz Llombart, Francisco Giner, Julia Cruz, Victor Traves, Javier Lavernia, Antonio Llombart-Bosch and José Antonio López Guerrero
Cancers 2025, 17(15), 2551; https://doi.org/10.3390/cancers17152551 (registering DOI) - 1 Aug 2025
Abstract
Background: Angiosarcomas (ASs) represent a heterogeneous and highly aggressive subset of tumors that respond poorly to systemic treatments and are associated with short progression-free survival (PFS) and overall survival (OS). The aim of this study was to develop and validate an immune-related [...] Read more.
Background: Angiosarcomas (ASs) represent a heterogeneous and highly aggressive subset of tumors that respond poorly to systemic treatments and are associated with short progression-free survival (PFS) and overall survival (OS). The aim of this study was to develop and validate an immune-related prognostic model—termed the AS score—using data from two independent sarcoma cohorts. Methods: A prognostic model was developed using a previously characterized cohort of 25 angiosarcoma samples. Candidate genes were identified via the Maxstat algorithm (Maxstat v0.7-25 for R), combined with log-rank testing. The AS score was then computed by weighing normalized gene expression levels according to Cox regression coefficients. For external validation, transcriptomic data from TCGA Sarcoma cohort (n = 253) were analyzed. The Immunoscore—which reflects the tumor immune microenvironment—was inferred using the ESTIMATE package (v1.0.13) in R. All statistical analyses were performed in RStudio (v 4.0.3). Results: Four genes—IGF1R, MAP2K1, SERPINE1, and TCF12—were ultimately selected to construct the prognostic model. The resulting AS score enabled the classification of angiosarcoma cases into two prognostically distinct groups (p = 0.00012). Cases with high AS score values, which included both cutaneous and non-cutaneous forms, exhibited significantly poorer outcomes, whereas cases with low AS scores were predominantly cutaneous. A significant association was observed between the AS score and the Immunoscore (p = 0.025), with higher Immunoscore values found in high-AS score tumors. Validation using TCGA sarcoma cohort confirmed the prognostic value of both the AS score (p = 0.0066) and the Immunoscore (p = 0.0029), with a strong correlation between their continuous values (p = 2.9 × 10−8). Further survival analysis, integrating categorized scores into four groups, demonstrated robust prognostic significance (p = 0.00021). Notably, in tumors with a low Immunoscore, AS score stratification was not prognostic. In contrast, among cases with a high Immunoscore, the AS score effectively distinguished outcomes (p < 0.0001), identifying a subgroup with poor prognosis but potential sensitivity to immunotherapy. Conclusions: This combined classification using the AS score and Immunoscore has prognostic relevance in sarcoma, suggesting that angiosarcomas with an immunologically active microenvironment (high Immunoscore) and poor prognosis (high AS score) may be prime candidates for immunotherapy and this approach warrants prospective validation. Full article
(This article belongs to the Special Issue Genomics and Transcriptomics in Sarcoma)
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22 pages, 3527 KiB  
Review
Applications of Organoids and Spheroids in Anaplastic and Papillary Thyroid Cancer Research: A Comprehensive Review
by Deepak Gulwani, Neha Singh, Manisha Gupta, Ridhima Goel and Thoudam Debraj Singh
Organoids 2025, 4(3), 18; https://doi.org/10.3390/organoids4030018 - 1 Aug 2025
Abstract
Organoid and spheroid technologies have rapidly become pivotal in thyroid cancer research, offering models that are more physiologically relevant than traditional two-dimensional culture. In the study of papillary and anaplastic thyroid carcinomas, two subtypes that differ both histologically and clinically, three-dimensional (3D) models [...] Read more.
Organoid and spheroid technologies have rapidly become pivotal in thyroid cancer research, offering models that are more physiologically relevant than traditional two-dimensional culture. In the study of papillary and anaplastic thyroid carcinomas, two subtypes that differ both histologically and clinically, three-dimensional (3D) models offer unparalleled insights into tumor biology, therapeutic vulnerabilities, and resistance mechanisms. These models maintain essential tumor characteristics such as cellular diversity, spatial structure, and interactions with the microenvironment, making them extremely valuable for disease modeling and drug testing. This review emphasizes recent progress in the development and use of thyroid cancer organoids and spheroids, focusing on their role in replicating disease features, evaluating targeted therapies, and investigating epithelial–mesenchymal transition (EMT), cancer stem cell behavior, and treatment resistance. Patient-derived organoids have shown potential in capturing individualized drug responses, supporting precision oncology strategies for both differentiated and aggressive subtypes. Additionally, new platforms, such as thyroid organoid-on-a-chip systems, provide dynamic, high-fidelity models for functional studies and assessments of endocrine disruption. Despite ongoing challenges, such as standardization, limited inclusion of immune and stromal components, and culture reproducibility, advancements in microfluidics, biomaterials, and machine learning have enhanced the clinical and translational potential of these systems. Organoids and spheroids are expected to become essential in the future of thyroid cancer research, particularly in bridging the gap between laboratory discoveries and patient-focused therapies. Full article
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23 pages, 2510 KiB  
Article
Variations in Circulating Tumor Microenvironment-Associated Proteins in Non-Muscle Invasive Bladder Cancer Induced by Mitomycin C Treatment
by Benito Blanco Gómez, Francisco Javier Casas-Nebra, Daniel Pérez-Fentes, Susana B. Bravo, Laura Rodríguez-Silva and Cristina Núñez
Int. J. Mol. Sci. 2025, 26(15), 7413; https://doi.org/10.3390/ijms26157413 (registering DOI) - 1 Aug 2025
Abstract
Mitomycin C (MMC) is a widely employed chemotherapeutic agent, particularly in non-muscle invasive bladder cancer (NMIBC), where it functions by inducing DNA cross-linking and promoting tumor cell apoptosis. However, the tumor microenvironment (TME) significantly influences the therapeutic efficacy of MMC. Among the key [...] Read more.
Mitomycin C (MMC) is a widely employed chemotherapeutic agent, particularly in non-muscle invasive bladder cancer (NMIBC), where it functions by inducing DNA cross-linking and promoting tumor cell apoptosis. However, the tumor microenvironment (TME) significantly influences the therapeutic efficacy of MMC. Among the key regulators within the TME, the complement system and the coagulation pathway play a crucial role in modulating immune responses to cancer therapies, including MMC. This article explores the interaction between platinum nanoparticles (PtNPs) with human serum (HS) of NMIBC patients (T1 and Ta subtypes) at three different points: before the chemotherapy instillation of MMC (t0) and three (t3) and six months (t6) after the treatment with MMC. This novel nanoproteomic strategy allowed the identification of a TME proteomic signature associated with the response to MMC treatment. Importantly, two proteins involved in the immune response were found to be deregulated across all patients (T1 and Ta subtypes) during MMC treatment: prothrombin (F2) downregulated and complement component C7 (C7) upregulated. By understanding how these biomarker proteins interact with MMC treatment, novel therapeutic strategies can be developed to enhance treatment outcomes and overcome resistance in NMIBC. Full article
(This article belongs to the Special Issue Omics-Driven Unveiling of the Structure and Function of Nanoparticles)
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19 pages, 4365 KiB  
Article
Fecal Virome Transplantation Confirms Non-Bacterial Components (Virome and Metabolites) Participate in Fecal Microbiota Transplantation-Mediated Growth Performance Enhancement and Intestinal Development in Broilers with Spatial Heterogeneity
by Shuaihu Chen, Tingting Liu, Junyao Chen, Hong Shen and Jungang Wang
Microorganisms 2025, 13(8), 1795; https://doi.org/10.3390/microorganisms13081795 - 31 Jul 2025
Abstract
Fecal microbiota transplantation (FMT) promotes growth performance and intestinal development in yellow-feathered broilers, but whether the virome and metabolites contribute to its growth-promoting effect remains unclear. This study removed the microbiota from FMT filtrate using a 0.45 μm filter membrane, retaining the virome [...] Read more.
Fecal microbiota transplantation (FMT) promotes growth performance and intestinal development in yellow-feathered broilers, but whether the virome and metabolites contribute to its growth-promoting effect remains unclear. This study removed the microbiota from FMT filtrate using a 0.45 μm filter membrane, retaining the virome and metabolites to perform fecal virome transplantation (FVT), aiming to investigate its regulatory role in broiler growth. Healthy yellow-feathered broilers with high body weights (top 10% of the population) were used as FVT donors. Ninety-six 8-day-old healthy male yellow-feathered broilers (95.67 ± 3.31 g) served as FVT recipients. Recipient chickens were randomly assigned to a control group and an FVT group. The control group was gavaged with 0.5 mL of normal saline daily, while the FVT group was gavaged with 0.5 mL of FVT solution daily. Growth performance, immune and antioxidant capacity, intestinal development and related gene expression, and microbial diversity were measured. The results showed that FVT improved the feed utilization rate of broilers (the feed conversion ratio decreased by 3%; p < 0.05), significantly increased jejunal length (21%), villus height (69%), and crypt depth (84%) (p < 0.05), and regulated the jejunal barrier: insulin-like growth factor-1 (IGF-1) (2.5 times) and Mucin 2 (MUC2) (63 times) were significantly upregulated (p < 0.05). FVT increased the abundance of beneficial bacteria Lactobacillales. However, negative effects were also observed: Immunoglobulin A (IgA), Immunoglobulin G (IgG), Immunoglobulin M (IgM), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interferon-gamma (IFN-γ) in broilers were significantly upregulated (p < 0.05), indicating immune system overactivation. Duodenal barrier-related genes Mucin 2 (MUC2), Occludin (OCLN), Claudin (CLDN1), and metabolism-related genes solute carrier family 5 member 1 (SLC5A1) and solute carrier family 7 member 9 (SLC7A9) were significantly downregulated (p < 0.05). The results of this trial demonstrate that, besides the microbiota, the gut virome and metabolites are also functional components contributing to the growth-promoting effect of FMT. The differential responses in the duodenum and jejunum reveal spatial heterogeneity and dual effects of FVT on the intestine. The negative effects limit the application of FMT/FVT. Identifying the primary functional components of FMT/FVT to develop safe and targeted microbial preparations is one potential solution. Full article
(This article belongs to the Section Veterinary Microbiology)
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34 pages, 6899 KiB  
Review
The Exposome Perspective: Environmental and Infectious Agents as Drivers of Cancer Disparities in Low- and Middle-Income Countries
by Zodwa Dlamini, Mohammed Alaouna, Tebogo Marutha, Zilungile Mkhize-Kwitshana, Langanani Mbodi, Nkhensani Chauke-Malinga, Thifhelimbil E. Luvhengo, Rahaba Marima, Rodney Hull, Amanda Skepu, Monde Ntwasa, Raquel Duarte, Botle Precious Damane, Benny Mosoane, Sikhumbuzo Mbatha, Boitumelo Phakathi, Moshawa Khaba, Ramakwana Chokwe, Jenny Edge, Zukile Mbita, Richard Khanyile and Thulo Molefiadd Show full author list remove Hide full author list
Cancers 2025, 17(15), 2537; https://doi.org/10.3390/cancers17152537 - 31 Jul 2025
Abstract
Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for [...] Read more.
Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for understanding these disparities. In LMICs, populations are disproportionately affected by air and water pollution, occupational hazards, and oncogenic infections, including human papillomavirus (HPV), hepatitis B virus (HBV), Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), and neglected tropical diseases, such as schistosomiasis. These infectious agents contribute to increased cancer susceptibility and poor outcomes, particularly in immunocompromised individuals. Moreover, climate change, food insecurity, and barriers to healthcare access exacerbate these risks. This review adopts a population-level exposome approach to explore how environmental and infectious exposures intersect with genetic, epigenetic, and immune mechanisms to influence cancer incidence and progression in LMICs. We highlight the critical pathways linking chronic exposure and inflammation to tumor development and evaluate strategies such as HPV and HBV vaccination, antiretroviral therapy, and environmental regulation. Special attention is given to tools such as exposome-wide association studies (ExWASs), which offer promise for exposure surveillance, early detection, and public health policy. By integrating exposomic insights into national health systems, especially in regions such as sub-Saharan Africa (SSA) and South Asia, LMICs can advance equitable cancer prevention and control strategies. A holistic, exposome-informed strategy is essential for reducing global cancer disparities and improving outcomes in vulnerable populations. Full article
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12 pages, 3463 KiB  
Case Report
Immunologic Alteration After Total En-Bloc Spondylectomy with Anterior Spinal Column Reconstruction with Frozen Tumor-Containing Bone Autologous Grafts: A Case Report in a Prospective Study
by Hisaki Aiba, Hiroaki Kimura, Ryu Terauchi, Nobuyuki Suzuki, Kenji Kato, Kiyoshi Yagi, Makoto Yamaguchi, Kiyoka Murakami, Shogo Suenaga, Toshiharu Shirai, Ayano Aso, Costantino Errani and Hideki Murakami
Curr. Oncol. 2025, 32(8), 432; https://doi.org/10.3390/curroncol32080432 (registering DOI) - 31 Jul 2025
Abstract
Cryotherapy could stimulate immune responses and induce abscopal effects. A novel technique was developed for treating spinal bone tumors involving the use of frozen tumor-containing autologous bone grafts for anterior spinal reconstruction following total en-bloc spondylectomy, with the aim of activating cryoimmunity. This [...] Read more.
Cryotherapy could stimulate immune responses and induce abscopal effects. A novel technique was developed for treating spinal bone tumors involving the use of frozen tumor-containing autologous bone grafts for anterior spinal reconstruction following total en-bloc spondylectomy, with the aim of activating cryoimmunity. This study focused on analyzing changes in the T-cell receptor (TCR) repertoire after surgery to evaluate T-cell diversity. Blood samples were collected pre- and post-operatively, with subsequent RNA extraction and immunosequencing. Compared to pre-surgery samples, the diversity and abundance of the Complementarity-Determining Region 3, regions of the TCR α and β chains decreased, suggesting that more selective clones may have emerged and influenced immune responses. Through TCR repertoire analysis, this study demonstrated that transplantation of frozen tumor-containing autologous bone impacted the immune system. This study is expected to provide a foundation for developing treatments that may enhance immune activation. Full article
(This article belongs to the Special Issue 2nd Edition: Treatment of Bone Metastasis)
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16 pages, 1540 KiB  
Article
The Role of Drug Resistance in Candida Inflammation and Fitness
by Gabriella Piatti, Alberto Vitale, Anna Maria Schito, Susanna Penco and Daniele Saverino
Microorganisms 2025, 13(8), 1777; https://doi.org/10.3390/microorganisms13081777 - 30 Jul 2025
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Abstract
Drug resistance in Candida may result in either a fitness cost or a fitness advantage. Candida auris, whose intrinsic drug resistance remains unclear, has emerged as a significant human pathogen. We aimed to investigate whether Candida fitness, including early interaction with the host [...] Read more.
Drug resistance in Candida may result in either a fitness cost or a fitness advantage. Candida auris, whose intrinsic drug resistance remains unclear, has emerged as a significant human pathogen. We aimed to investigate whether Candida fitness, including early interaction with the host innate immune system, depends on the antifungal susceptibility phenotype and putative-associated resistance mutations. We compared interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor α production by human colorectal adenocarcinoma cells stimulated by fluconazole-susceptible and fluconazole-resistant strains of Candida albicans, C. parapsilosis, C. tropicalis, and C. glabrata, as well as fluconazole-resistant C. auris strains. Sensitive Candida strains induced lower cytokine levels compared with C. auris and resistant strains, except for TNF a. Resistant strains induced cytokine levels like C. auris, except for higher IL-1β and lower TNF-α. Susceptible strains exhibited cytokine profiles distinct from those of resistant strains. C. auris induced cytokine levels comparable to resistant strains but displayed profiles resembling those of susceptible strains. This study highlights the relationship among antifungal susceptibility, fungal fitness and host early immunity. C. auris behavior appears to be between fluconazole-sensitive and fluconazole-resistant strains. Understanding these dynamics may enhance the knowledge of the survival and reproduction of resistant Candida and the epidemiology of fungal infections. Full article
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17 pages, 1500 KiB  
Article
Comprehensive Receptor Repertoire and Functional Analysis of Peripheral NK Cells in Soft Tissue Sarcoma Patients
by Luana Madalena Sousa, Jani-Sofia Almeida, Tânia Fortes-Andrade, Patrícia Couceiro, Joana Rodrigues, Rúben Fonseca, Manuel Santos-Rosa, Paulo Freitas-Tavares, José Manuel Casanova and Paulo Rodrigues-Santos
Cancers 2025, 17(15), 2508; https://doi.org/10.3390/cancers17152508 - 30 Jul 2025
Viewed by 55
Abstract
Background: Soft tissue sarcomas (STSs) are a rare and heterogeneous group of mesenchymal tumors with limited response to current therapies, particularly in advanced stages. STS tumors were traditionally considered “cold” tumors, characterized by limited immune infiltration and low immunogenicity. However, emerging evidence is [...] Read more.
Background: Soft tissue sarcomas (STSs) are a rare and heterogeneous group of mesenchymal tumors with limited response to current therapies, particularly in advanced stages. STS tumors were traditionally considered “cold” tumors, characterized by limited immune infiltration and low immunogenicity. However, emerging evidence is challenging this perception, highlighting a potentially critical role for the immune system in STS biology. Objective: Building on our previous findings suggesting impaired natural killer (NK) cell activity in STS patients, we aimed to perform an in-depth characterization of peripheral NK cells in STS. Methods: Peripheral blood samples from STS patients and sex- and age-matched healthy donors were analyzed to assess NK cell degranulation, IFNγ production, and receptor repertoire. Results: Functional assays revealed a notable reduction in both degranulation and IFNγ production in NK cells from STS patients. STS patients also exhibited dysregulated expression of activating and inhibitory NK cell receptors. Principal component analysis (PCA) identified CD27 and NKp44 as critical markers for distinguishing STS patients from healthy donors. Increased CD27 expression represents a shift towards a more regulatory NK cell phenotype, and we found that CD27 expression was negatively correlated with NK cell degranulation and IFNγ production. ROC curve analysis demonstrated strong potential to distinguish between the groups for both CD27 (AUC = 0.85) and NKp44 (AUC = 0.94). Conclusion: In conclusion, STS patients exhibited impaired NK cell function, altered receptor repertoire, and a shift towards a less cytotoxic and more regulatory phenotype. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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18 pages, 2125 KiB  
Article
A Replication-Defective Myxoma Virus Inducing Pro-Inflammatory Responses as Monotherapy and an Adjuvant to Chemo- and DC Immuno-Therapy for Ovarian Cancer
by Martin J. Cannon and Jia Liu
Viruses 2025, 17(8), 1058; https://doi.org/10.3390/v17081058 - 29 Jul 2025
Viewed by 192
Abstract
Myxoma virus (MYXV), a rabbit-specific poxvirus and non-pathogenic in humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor-associated macrophages (TAMs) are key to inhibiting antitumor immunity while hindering therapeutic [...] Read more.
Myxoma virus (MYXV), a rabbit-specific poxvirus and non-pathogenic in humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor-associated macrophages (TAMs) are key to inhibiting antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macrophages/monocytes, we examined the therapeutic potential of MYXV against TAMs. We found previously that a replication-defective MYXV with targeted deletion of an essential gene, M062R, designated ΔM062R MYXV, activated both the host DNA sensing pathway and the SAMD9 pathway. Treatment with ΔM062R confers therapeutic benefit comparable to that of wild-type replicating MYXV in preclinical models. Here we found that ΔM062R MYXV, when integrated with cisplatin and DC immunotherapy, further improved treatment benefit, likely through promoting tumor antigen-specific T cell function. Moreover, we also tested ΔM062R MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that ΔM062R treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4+ T cells. Overall, ΔM062R presents a promising immunotherapeutic platform as a beneficial adjuvant to chemotherapy and DC vaccine. Full article
(This article belongs to the Special Issue Women in Virology 2025)
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28 pages, 2854 KiB  
Article
Real-Time Functional Stratification of Tumor Cell Lines Using a Non-Cytotoxic Phospholipoproteomic Platform: A Label-Free Ex Vivo Model
by Ramón Gutiérrez-Sandoval, Francisco Gutiérrez-Castro, Natalia Muñoz-Godoy, Ider Rivadeneira, Adolay Sobarzo, Jordan Iturra, Ignacio Muñoz, Cristián Peña-Vargas, Matías Vidal and Francisco Krakowiak
Biology 2025, 14(8), 953; https://doi.org/10.3390/biology14080953 - 28 Jul 2025
Viewed by 155
Abstract
The development of scalable, non-invasive tools to assess tumor responsiveness to structurally active immunoformulations remains a critical unmet need in solid tumor immunotherapy. Here, we introduce a real-time, ex vivo functional system to classify tumor cell lines exposed to a phospholipoproteomic platform, without [...] Read more.
The development of scalable, non-invasive tools to assess tumor responsiveness to structurally active immunoformulations remains a critical unmet need in solid tumor immunotherapy. Here, we introduce a real-time, ex vivo functional system to classify tumor cell lines exposed to a phospholipoproteomic platform, without relying on cytotoxicity, co-culture systems, or molecular profiling. Tumor cells were monitored using IncuCyte® S3 (Sartorius) real-time imaging under ex vivo neutral conditions. No dendritic cell components or immune co-cultures were used in this mode. All results are derived from direct tumor cell responses to structurally active formulations. Using eight human tumor lines, we captured proliferative behavior, cell death rates, and secretomic profiles to assign each case into stimulatory, inhibitory, or neutral categories. A structured decision-tree logic supported the classification, and a Functional Stratification Index (FSI) was computed to quantify the response magnitude. Inhibitory lines showed early divergence and high IFN-γ/IL-10 ratios; stimulatory ones exhibited a proliferative gain under balanced immune signaling. The results were reproducible across independent batches. This system enables quantitative phenotypic screening under standardized, marker-free conditions and offers an adaptable platform for functional evaluation in immuno-oncology pipelines where traditional cytotoxic endpoints are insufficient. This approach has been codified into the STIP (Structured Traceability and Immunophenotypic Platform), supporting reproducible documentation across tumor models. This platform contributes to upstream validation logic in immuno-oncology workflows and supports early-stage regulatory documentation. Full article
(This article belongs to the Section Cancer Biology)
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27 pages, 6405 KiB  
Article
PDMS Membranes Drilled by Proton Microbeam Writing: A Customizable Platform for the Investigation of Endothelial Cell–Substrate Interactions in Transwell-like Devices
by Vita Guarino, Giovanna Vasco, Valentina Arima, Rosella Cataldo, Alessandra Zizzari, Elisabetta Perrone, Giuseppe Gigli and Maura Cesaria
J. Funct. Biomater. 2025, 16(8), 274; https://doi.org/10.3390/jfb16080274 - 28 Jul 2025
Viewed by 457
Abstract
Cell migration assays provide valuable insights into pathological conditions, such as tumor metastasis and immune cell infiltration, and the regenerative capacity of tissues. In vitro tools commonly used for cell migration studies exploit commercial transwell systems, whose functionalities can be improved through engineering [...] Read more.
Cell migration assays provide valuable insights into pathological conditions, such as tumor metastasis and immune cell infiltration, and the regenerative capacity of tissues. In vitro tools commonly used for cell migration studies exploit commercial transwell systems, whose functionalities can be improved through engineering of the pore pattern. In this context, we propose the fabrication of a transwell-like device pursued by combining the proton beam writing (PBW) technique with wet etching onto thin layers of polydimethylsiloxane (PDMS). The resulting transwell-like device incorporates a PDMS membrane with finely controllable pore patterning that was used to study the arrangement and migration behavior of HCMEC/D3 cells, a well-established human brain microvascular endothelial cell model widely used to study vascular maturation in the brain. A comparison between commercial polycarbonate membranes and the PBW-holed membranes highlights the impact of the ordering of the pattern and porosity on cellular growth, self-organization, and transmigration by combining fluorescent microscopy and advanced digital processing. Endothelial cells were found to exhibit distinctive clustering, alignment, and migratory behavior close to the pores of the designed PBW-holed membrane. This is indicative of activation patterns associated with cytoskeletal remodeling, a critical element in the angiogenic process. This study stands up as a novel approach toward the development of more biomimetic barrier models (such as organ-on-chips). Full article
(This article belongs to the Collection Feature Papers in Biomaterials for Healthcare Applications)
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33 pages, 1777 KiB  
Review
Immunomodulatory Natural Products in Cancer Organoid-Immune Co-Cultures: Bridging the Research Gap for Precision Immunotherapy
by Chang-Eui Hong and Su-Yun Lyu
Int. J. Mol. Sci. 2025, 26(15), 7247; https://doi.org/10.3390/ijms26157247 - 26 Jul 2025
Viewed by 502
Abstract
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We [...] Read more.
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We conducted a comprehensive literature analysis examining natural products tested in cancer organoids, immunomodulatory mechanisms from traditional models, technical advances in organoid-immune co-cultures, and standardization requirements for clinical translation. Our analysis reveals a critical research gap: no published studies have investigated natural product-mediated immunomodulation using organoid-immune co-culture systems. Even though compounds like curcumin, resveratrol, and medicinal mushroom polysaccharides show extensive immunomodulatory effects in two-dimensional (2D) cultures, and organoid technology achieves high clinical correlation for drug response prediction, all existing organoid studies focus exclusively on direct cytotoxicity. Technical challenges include compound stability, limited matrix penetration requiring substantially higher concentrations than 2D cultures, and maintaining functional immune populations in three-dimensional (3D) systems. The convergence of validated organoid-immune co-culture platforms, Food and Drug Administration (FDA) regulatory support through the Modernization Act 2.0, and extensive natural product knowledge creates unprecedented opportunities. Priority research directions include systematic screening of immunomodulatory natural products in organoid-immune co-cultures, development of 3D-optimized delivery systems, and clinical validation trials. Success requires moving beyond cytotoxicity-focused studies to investigate immunomodulatory mechanisms in physiologically relevant 3D systems, potentially unlocking new precision cancer immunotherapy approaches. Full article
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20 pages, 25333 KiB  
Article
Regulatory Effects of Codonopsis pilosula Alkali-Extracted Polysaccharide Induced Intestinal Lactobacillus Enrichment on Peripheral Blood Proteomics in Tumor-Bearing Mice
by Yuting Fan, Chenqi Yang, Yiran Zhao, Xiao Han, Hongfei Ji, Zhuohao Ren, Wenjie Ding and Haiyu Ji
Microorganisms 2025, 13(8), 1750; https://doi.org/10.3390/microorganisms13081750 - 26 Jul 2025
Viewed by 232
Abstract
Codonopsis pilosula polysaccharides have demonstrated multiple biological activities including immune regulation, antitumor, and antioxidant properties. The rapid development and integrated application of multi-omics can facilitate the unraveling of the complex network of immune system regulation. In this study, C. pilosula alkali-extracted polysaccharide (CPAP) [...] Read more.
Codonopsis pilosula polysaccharides have demonstrated multiple biological activities including immune regulation, antitumor, and antioxidant properties. The rapid development and integrated application of multi-omics can facilitate the unraveling of the complex network of immune system regulation. In this study, C. pilosula alkali-extracted polysaccharide (CPAP) were prepared, and their effects on gut microbiota compositions, metabolic pathways, and protein expressions in peripheral blood and solid tumors in mice were further evaluated. The 16S rDNA sequencing results showed that CPAP could effectively promote the enrichment of intestinal Lactobacillus in tumor-bearing mice. In addition, it could be inferred from peripheral blood and solid tumor proteomics results that CPAP might activate T cell-mediated antitumor immune functions by regulating purine metabolism and alleviate tumor-caused inflammation by promoting neutrophil degranulation, finally inducing apoptosis in tumor cells by increasing oxidative stress. These results will provide a theoretical foundation and data support for the further development of CPAP as dietary adjuvants targeting immune deficiency-related diseases. Full article
(This article belongs to the Section Food Microbiology)
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21 pages, 1208 KiB  
Review
Combination of Irreversible Electroporation and Clostridium novyi-NT Bacterial Therapy for Colorectal Liver Metastasis
by Zigeng Zhang, Guangbo Yu, Qiaoming Hou, Farideh Amirrad, Sha Webster, Surya M. Nauli, Jianhua Yu, Vahid Yaghmai, Aydin Eresen and Zhuoli Zhang
Cancers 2025, 17(15), 2477; https://doi.org/10.3390/cancers17152477 - 26 Jul 2025
Viewed by 223
Abstract
Colorectal liver metastasis (CRLM) poses a significant challenge in oncology due to its high incidence and poor prognosis in unresectable cases. Current treatments, including surgical resection, systemic chemotherapy, and liver-directed therapies, often fail to effectively target hypoxic tumor regions, which are inherently more [...] Read more.
Colorectal liver metastasis (CRLM) poses a significant challenge in oncology due to its high incidence and poor prognosis in unresectable cases. Current treatments, including surgical resection, systemic chemotherapy, and liver-directed therapies, often fail to effectively target hypoxic tumor regions, which are inherently more resistant to these interventions. This review examines the potential of a novel therapeutic strategy combining irreversible electroporation (IRE) ablation and Clostridium novyi-nontoxic (C. novyi-NT) bacterial therapy. IRE is a non-thermal tumor ablation technique that uses high-voltage electric pulses to create permanent nanopores in cell membranes, leading to cell death while preserving surrounding structures, and is often associated with temporary tumor hypoxia due to disrupted perfusion. C. novyi-NT is an attenuated, anaerobic bacterium engineered to selectively germinate and proliferate in hypoxic tumor regions, resulting in localized tumor cell lysis while sparing healthy, oxygenated tissue. The synergy between IRE-induced hypoxia and hypoxia-sensitive C. novyi-NT may enhance tumor destruction and stimulate systemic antitumor immunity. Furthermore, the integration of advanced imaging and artificial intelligence can support precise treatment planning and real-time monitoring. This integrated approach holds promise for improving outcomes in patients with CRLM, though further preclinical and clinical validation is needed. Full article
(This article belongs to the Section Cancer Metastasis)
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