Cancer Cell International最新文献

Glioblastoma multiforme (GBM) is a heterogeneous and malignant brain tumor characterized by an immunosuppressive microenvironment, notably with diminished M1 macrophage activity. MicroRNAs serve as post-transcriptional regulators and have been implicated in influencing tumor progression. However, the interaction between microRNAs and tumor-associated macrophages in glioma remains less characterized. CCAAT/enhancer-binding protein delta (CEBPD) could act as an oncogenic factor in GBM and regulate microRNA transcription, thereby impacting tumorigenesis. In this study, we demonstrated that glioma CEBPD directly binds to and activates the promoter regions of miR-4257 and miR-3156, located within the genes ADAMTSL4 and ANKRD30BP3, respectively. These microRNAs are transmitted via small extracellular vesicles (sEVs) and target macrophages, specifically binding to the 3'-untranslated regions (UTRs) of interleukin 12 (IL-12) p35 and p40 mRNAs, thereby reducing IL-12 transcription and expression in macrophages. Furthermore, our results show that sEV antisense miR-4257 and miR-3156 diminish the M1 macrophage phenotype. In animal models, co-inoculation of glioma cells with antisense miR-4257 and miR-3156 or CEBPD knockdown, along with M1 macrophages, leads to reduced tumor growth and enhanced M1 macrophage activation. These findings suggest that glioma CEBPD can contribute to immunosuppression by regulating miR-4257 and miR-3156, which target IL-12 in macrophages through sEV transmission. This research offers new insights into the relationship between glioma and immunosuppression, highlighting potential therapeutic avenues for enhancing anti-tumor immunity in GBM.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have transformed outcomes for the ~ 5% of CRC patients with mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-H) tumors, delivering durable responses in metastatic and early-stage disease. However, the vast majority of CRCs are mismatch repair-proficient and microsatellite stable (pMMR/MSS), characterized by low tumor mutational burden, sparse immune infiltration, and an immunosuppressive tumor microenvironment, features that confer resistance to current immunotherapies. Bridging this efficacy gap requires a translational roadmap focused on "heating up" immune-cold tumors. Promising strategies include combination checkpoint blockade (PD-1 with CTLA-4, LAG-3, or TIGIT inhibitors), tumor microenvironment modulation via VEGF inhibition and anti-angiogenics, integration of targeted therapies (KRAS-G12C, BRAF, MEK inhibitors) with ICIs, neoantigen-based vaccines, oncolytic viruses, and microbiome manipulation. Biomarker-guided patient selection with incorporating circulating tumor DNA, Immunoscore, and Consensus Molecular Subtypes will be critical to optimize therapeutic sequencing and minimize toxicity. Early-phase trials combining these approaches in MSS CRC show encouraging activity, while neoadjuvant and adjuvant immunotherapy in MSI-H disease redefines treatment paradigms, with some patients achieving complete responses without surgery. This review synthesizes the current evidence and emerging innovations in CRC immunotherapy and proposes a structured translational framework to extend immunotherapy benefits beyond the MSI-H subset.