Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 18, 2024

PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into action sites. Herein, based on ultra-pH-sensitive enzyme-sensitive nanotechnology, a type polymer PROTAC conjugated pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following construction for Cyclin-dependent kinase 4 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds many treatments even immune checkpoint blockades was selected as tumor model in this study. As result, PSRNs were found maintain nanostructure (40 nm) circulation efficiently accumulated tumors via enhanced permeation retention effect. Then, they dissociated unimers (<10 response an acidic microenvironment, facilitating internalization. Eventually, CDK4/6 degrading released intracellularly cleavage cathepsin B. Importantly, led degradation target protein vitro vivo. The also augmented blockades, through upregulation programmed cell death-ligand 1 (PD-L1) expression cells suppression regulatory T proliferation microenvironment. By combination with α-PD-1, anti-tumor outcome well achieved CT26 model. Overall, our study verifies significance precise intracellular delivery introduces promising therapeutic strategy targeted treatment CRC.

Язык: Английский

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Improvement strategy for immune checkpoint blockade: A focus on the combination with immunogenic cell death inducers

Cancer Letters, Год журнала: 2023, Номер 562, С. 216167 - 216167

Опубликована: Апрель 7, 2023

Cancer immunotherapies have yielded promising outcomes in various malignant tumors by blocking specific immune checkpoint molecules, such as programmed cell death 1 and cytotoxic T lymphocyte antigen 4. However, only a few patients respond to blockade therapy because of the poor immunogenicity tumor cells immune-suppressive microenvironment. Accumulating evidence suggests that chemotherapeutic agents, including oxaliplatin doxorubicin, not mediate direct cytotoxicity but also induce immunogenic cancer stimulate powerful anti-cancer response In this review, we summarize recent advances combination based on inhibitors plus inducers. Despite some clinical failures challenges, inducers displayed great potential when combined with for treatment both preclinical studies trials.

Язык: Английский

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Pleckstrin-2 promotes tumour immune escape from NK cells by activating the MT1-MMP-MICA signalling axis in gastric cancer

Cancer Letters, Год журнала: 2023, Номер 572, С. 216351 - 216351

Опубликована: Авг. 15, 2023

Immune escape is a major challenge in tumour immunotherapy. Pleckstrin-2(PLEK2) plays critical role progression, but its immune gastric cancer (GC) remains uncharacterized. RNA sequencing was used to explore the differentially expressed genes GC cell line that resistant antitumor effect of Natural killer (NK) cells. Apoptosis and expression IFN-γ TNF-α were detected by flow cytometry (FCM). PLEK2 examined Western blotting immunohistochemistry (IHC). upregulated MGC803R cells NK knockout increased sensitivity killing. negatively correlated with MICA positively MT1-MMP both vitro vivo. promoted Sp1 phosphorylation through PI3K-AKT pathway, thereby upregulating expression, which ultimately led shedding. In mouse xenograft models, inhibited intraperitoneal metastasis infiltration. summary, suppressed surveillance promoting shedding, serves as potential therapeutic target for GC.

Язык: Английский

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Gut microbiota interactions with antitumor immunity in colorectal cancer: From understanding to application

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 165, С. 115040 - 115040

Опубликована: Июнь 25, 2023

Colorectal cancer (CRC) is one of highly prevalent cancer. Immunotherapy with immune checkpoint inhibitors (ICIs) has dramatically changed the landscape treatment for many advanced cancers, but CRC still exhibits suboptimal response to immunotherapy. The gut microbiota can affect both anti-tumor and pro-tumor responses, further modulate efficacy immunotherapy, particularly in context therapy ICIs. Therefore, a deeper understanding how modulates responses crucial improve outcomes patients receiving immunotherapy overcome resistance nonresponders. present review aims describe relationship between microbiota, CRC, antitumor particular focus on key studies recent findings effect activity. We also discuss potential mechanisms by which influences host as well prospective role intestinal flora treatment. Furthermore, therapeutic limitations different modulation strategies are discussed. These insights may facilitate better comprehend interplay provide new research pathways enhance expand patient population that could be benefited

Язык: Английский

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Research hotspots and frontiers in the tumor microenvironment of colorectal cancer: a bibliometric study from 2014 to 2024

Frontiers in Oncology, Год журнала: 2025, Номер 15

Опубликована: Фев. 5, 2025

Background Colorectal cancer (CRC) is the second leading cause of deaths globally, which poses a heavy burden on our healthcare and economy. In recent years, increasing researches suggest that tumor microenvironment (TME) influences onset, progression, metastasis, treatment. This has become popular direction for researching attacking cancer. However, to date, there no bibliometric analysis colorectal from 2014 2024. study aims provide comprehensive picture current research status, hotspots, future trends in this field perspective. Methods study, publications about 2024 were searched based Web Science Core Collection database. Then we analyzed visualized data using CiteSpace, VOSviewer, bibliometrix package, Microsoft Excel 2019. Results A total 748 included number entered period rapid growth after China United States are major collaboration centers field. Elkord, Eyad most prolific author, Frontiers Immunology journal published papers TME CRC. addition, keyword cluster showed immune checkpoint inhibitors, cancer-associated fibroblasts, macrophage polarization, intestinal microbiota, liver drug resistance, scRNA-seq, etc. may be hotspots Conclusions developmental stage, strengthening international cooperation can help drive forward. The main components signaling TME, CRC immunotherapy, new techniques hot directions domain. Our findings will scholars with an up-to-date perspective state research,

Язык: Английский

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Prolyl isomerase Pin1 sculpts the immune microenvironment of colorectal cancer

Cellular Signalling, Год журнала: 2024, Номер 115, С. 111041 - 111041

Опубликована: Янв. 8, 2024

Язык: Английский

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Identification of Immune Infiltration-Associated CC Motif Chemokine Ligands as Biomarkers and Targets for Colorectal Cancer Prevention and Immunotherapy

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 625 - 625

Опубликована: Янв. 13, 2025

Colorectal cancer (CRC) is the third most common globally, with limited effective biomarkers and sensitive therapeutic targets. An increasing number of studies have highlighted critical role tumor microenvironment (TME) imbalances, particularly immune escape due to impaired chemokine-mediated trafficking, in tumorigenesis progression. Notably, CC chemokines (CCLs) been shown either promote or inhibit angiogenesis, metastasis, responses tumors, thereby influencing development patient outcomes. However, diagnostic prognostic significance CCLs CRC remains unclear. In this study, multiple online tools for bioinformatics analyses were utilized. The findings revealed that mRNA expression levels CCL3, CCL4, CCL26 significantly elevated tissues compared normal tissues, whereas CCL2, CCL5, CCL11, CCL21, CCL28 markedly downregulated. Additionally, dysregulation CCL21 was strongly associated clinical staging, linked prolonged survival patients. Functional enrichment analysis indicated cellular roles predominantly chemokine, Wnt, Toll-like receptor signaling pathways, as well protein kinase activity. Furthermore, transcriptional regulation involved RELA NFKB1. Key downstream targets included members SRC family tyrosine kinases (HCK, LYN, LCK), serine/threonine (ATR ATM), others such CSNK1G2, NEK2, CDK2. Moreover, (CCL2, CCL28) exhibited strong correlations major infiltration-related cells, including B CD8+ T CD4+ macrophages, neutrophils, dendritic cells. conclusion, our study provides novel insights into potential utility prevention immunotherapy.

Язык: Английский

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Gamma Knife Stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: A Phase II Trial Analysis

Опубликована: Янв. 21, 2025

An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.In this phase II trial, received Gamma Knife SBRT combined Tislelizumab. P Biomarker analysis was performed pre- post-treatment. From November 2022 to July 2024, 13 20 achieved PR, 6 SD. mPFS 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse included nausea (65%), anemia (55%), fatigue (45%). For who had not responded first second-line therapies, combo tislelizumab showed high reasonable safety. Significant post-radiotherapy improvements in tumor’s microenvironment. These results imply that pMMR/MSS/MSI-L were unresponsive chemotherapy, provides a safe powerful later-line treatment alternative.

Язык: Английский

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Gamma Knife Stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: A Phase II Trial Analysis

Опубликована: Янв. 21, 2025

An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.In this phase II trial, received Gamma Knife SBRT combined Tislelizumab. P Biomarker analysis was performed pre- post-treatment. From November 2022 to July 2024, 13 20 achieved PR, 6 SD. mPFS 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse included nausea (65%), anemia (55%), fatigue (45%). For who had not responded first second-line therapies, combo tislelizumab showed high reasonable safety. Significant post-radiotherapy improvements in tumor’s microenvironment. These results imply that pMMR/MSS/MSI-L were unresponsive chemotherapy, provides a safe powerful later-line treatment alternative.

Язык: Английский

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Folate Metabolism in Colorectal Cancer Reveals Links Between Clinical and Immune Traits, Identifying CYP26A1 as a Target

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

Background:Folic acid plays a key role in cellular regulation and metabolism, commonly found dietary supplements. However, its complex colorectal cancer (CRC), particularly metabolism immune evasion, remains unclear. Methods:We developed the FMRG_score system using machine learning algorithms based on TCGA GEO databases to assess modification patterns influencing CRC patients' clinical characteristics. The system’s reliability was validated multiple external cohorts receiving immunotherapy. We further explored relationships between FMRGs-related features traits, mutation profiles, biological functions, infiltration, therapy response, drug sensitivity. Results:By combining vitro experiments bioinformatics analysis, we established 9-gene risk model associated with folate predict prognosis. Notably, CYP26A1, component of model, upregulated tissues, promoting cell proliferation, migration, invasion. Significant differences checkpoint expression, sensitivity were observed groups. Conclusion:The scoring can prognosis, tumor microenvironment, response. This is first study proposing CYP26A1 as an oncogene CRC.

Язык: Английский

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