Cell Communication and Signaling最新文献

Many viral proteins undergo liquid-liquid phase separation (LLPS) to form biomolecular condensates known as viral inclusion bodies (VIBs), which are utilized for genome replication and virion assembly, thus serving as potential targets for antiviral drugs. However, the role of VIBs in viral immune evasion has rarely been explored. In this study, we demonstrated that VP35 protein of type II grass carp reovirus (GCRV-II) formed VIBs through LLPS in cells and in vitro. Moreover, we identified a host interaction partner of GCRV-II VP35, DEAH (Asp-Glu-Ala-His)-box helicase 15 (DHX15), which promoted expression of GCRV-II- or poly(I: C)-induced interferon (IFN) and interferon-stimulated genes (ISGs) via promoting phosphorylation of TBK1 (TANK-binding kinase 1) and stabilizing TBK1 to prevent it from degradation through autophagy pathway. To evade host anti-viral immunity, GCRV-II VP35 sequesters DHX15 from nucleus to the cytoplasm VIBs and degrades DHX15 via lysosomal pathway. Our findings provide a novel immune evasion strategy of GCRV-II, of which VP35 protein recruits DHX15, a positive regulator of host anti-viral immunity, to VIBs and degrades DHX15 via lysosomal pathway, which provides novel insights for the development of anti-viral drugs against GCRV-II infection.

Colorectal cancer (CRC) liver metastases remain refractory to immunotherapy due to a profoundly immunosuppressive tumor microenvironment. Here, we conducted a prospective clinical study enrolling 18 patients with microsatellite-stable CRC liver metastases treated with high-dose radiotherapy (RT) followed by anti-PD-1 immune checkpoint inhibitors (RT-ICI). Integrative analysis of single-cell RNA-sequencing, spatial transcriptomics, and peripheral immune profiling revealed that RT-ICI therapy reprograms both tumor-intrinsic and immune compartments. RT triggered the emergence of an APOA2⁺ tumor cell state characterized by enhanced lipid metabolic activity and transient elevation of circulating HDL. This metabolic reprogramming, in turn, promoted systemic activation of CETP⁺ M2-like macrophages, a population marked by high LXR/RXR transcriptional activity and enriched expression of immunosuppressive and lipid-processing genes. Despite their expansion, CETP⁺ macrophages localized preferentially to non-irradiated tumor regions, suggesting a distal immunometabolic effect driven by HDL-mediated signaling. Concurrently, combination therapy expanded GZMB⁺ effector T cells and induced a novel population of inflammatory-toxic T cells (IT_T), which exhibited high cytotoxicity and spatial co-localization with CXCL10⁺ macrophages. Ligand-receptor analysis and pseudotime modeling revealed that irradiated tumor cells acted as "in situ vaccines" by enhancing MHC-TCR interactions and promoting T cell differentiation along non-exhausted cytotoxic lineages. Together, these findings reveal a dual mechanism by which RT-ICI therapy enhances local anti-tumor immunity while modulating systemic lipid metabolism and macrophage polarization, offering insights for combinatorial immunotherapy design in immunologically "cold" tumors.

Background: Delayed detection of recurrence significantly contributes to colorectal cancer (CRC) mortality, underscoring the need for robust prognostic biomarkers. Although extrachromosomal circular DNA (eccDNA) is a known oncogenic driver, its prognostic utility in CRC remains largely unexplored.

Methods: In this 6-year prospective cohort study, full-length eccDNA profiling of 153 plasma samples was performed using Nanopore sequencing. Differential eccDNA signatures between recurrence (R, n = 20) and non-recurrence (NR, n = 133) patients enabled construction of predictive models for recurrence and mortality. Functional validation of eccDNAs was conducted in HCT116 cells.

Results: Compared to NR patients, R patients exhibited enrichment of eccDNAs derived from chromosome 9, shorter median eccDNA lengths, and reduced variability in eccDNA length. All 4.9-5.0 kb eccDNAs derived from CKM, while other eccDNAs showed a strong genomic distribution correlation between groups (Spearman's ρ = 0.73). Promoter-derived eccDNAs were enriched in R patients, particularly from the promoter of CARD9 (eccPromoter-CARD9, 10.4-fold increase). Overexpression of eccPromoter-CARD9 significantly promoted CRC cell proliferation and migration. R patients exhibited elevated eccDNAs harboring the hsa-mir-374c cluster in plasma and tissues, and their corresponding miRNAs demonstrated exceptional diagnostic accuracy in CRC-related TCGA cohorts. An eccDNA-based random forest classifier achieved superior recurrence prediction accuracy (AUC > 0.8), correlating with shorter time-to-recurrence (HR = 3.79) and elevated CA125 and CEA levels. Additional eccDNA-based models effectively predicted recurrence-associated mortality (AUC ≥ 0.93).

Conclusions: The plasma eccDNA landscape may serve as an early and powerful non-invasive biomarker for CRC prognostication, optimizing risk stratification and guiding personalized treatment.