Cell Death and Differentiation最新文献

While immunotherapy based on immune checkpoint inhibitors (ICIs) shows limited efficacy in colorectal cancer (CRC) due to its immunosuppressive tumor microenvironment, strategies to activate innate immunity remain underexplored. Here, we identified wild-type p53-induced phosphatase 1 (WIP1/PPM1D) as a critical immunosuppressive driver in CRC, with its expression significantly upregulated in tumor tissues. Genetic or pharmacological inhibition of WIP1 robustly suppressed tumor growth by remodeling the tumor immune microenvironment, marked by increased infiltration of anti-tumor macrophages and cytotoxic T cells. Mechanistically, WIP1 inhibited type I interferon (IFN) signaling by reducing cytoplasmic dsDNA accumulation to inactivate the cGAS-STING-TBK1 axis, and by directly dephosphorylating TBK1 at Ser172 to suppress its kinase activity. Strikingly, combining a WIP1 inhibitor with a STING agonist synergistically enhanced anti-tumor efficacy by amplifying IFNβ production to activate anti-tumor immune response. This combination further potentiated anti-PD-1 immunotherapy. In summary, this study uncovers WIP1 as a pioneering dual-functional suppressor of tumor-intrinsic STING activation and establishes a rationally designed "STING-WIP1 co-targeting" strategy to reverse immunotherapy resistance. Our findings bridge genomic instability with adaptive immune evasion, offering a roadmap for precision immunotherapy in CRC.

Mutations in ZNHIT3 are strongly associated with progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO syndrome), characterized by severe cerebellar atrophy and profound intellectual disability; however, their role in cerebellar development remains unknown. By developing spatiotemporally-regulated conditional Znhit3 knockout mice, we discovered that Znhit3 is essential for granule cell progenitor survival, proliferation, differentiation, and migration. Knockout of Znhit3 caused loss of granule cell progenitors due to apoptosis, premature cell-cycle exit, and migration arrest and resulted in progressive anterior-lobe atrophy and motor deficits. The granule cell progenitor-autonomous defects secondarily impaired Purkinje cell alignment, dendritic maturation, and synaptic organization. Transcriptomic analyses revealed activation of the p53/p21 pathway, rRNA processing defects, and nucleolar stress. Genetic or pharmacologic inhibition of p53/p21 signaling rescued granule cell progenitor development and restored cerebellar architecture in the Znhit3-knockout mice. Thus, ZNHIT3 is a critical regulator of ribosome biogenesis and cerebellar growth, suggesting nucleolar stress-p53/p21 signaling as a potential therapeutic target in ZNHIT3-related disorders.

Epstein-Barr virus (EBV) is a critical epigenetic regulator in nasopharyngeal carcinoma (NPC) pathogenesis, primarily through well-established mechanisms involving DNA methylation and histone modifications. However, the contribution of RNA modifications, especially RNA 5-methylcytosine (m⁵C), to EBV-driven NPC progression remains largely unclear. Here, we performed RNA bisulfite sequencing (RNA-Bis-seq) on NPC cells and observed a global elevation in RNA m⁵C levels following EBV infection. Notably, EBV infection upregulated NSUN2, a known RNA m⁵C methyltransferase ("writer"), through LMP1-mediated activation of the NF-κB signaling pathway, leading to RNA m⁵C elevation. Functional assays confirmed that NSUN2 significantly enhances NPC cell migration and metastasis through its RNA m⁵C catalytic activity. Furthermore, we identified YBX3 as a novel RNA m⁵C-binding protein ("reader") that was simultaneously upregulated upon EBV infection. Mechanistically, NSUN2 catalyzed m⁵C modification on ICAM-1. Subsequently, YBX3 specifically recognized the modified site, recruiting PABPC1 through interacting with its cold shock domain and thereby enhancing ICAM-1 translation. Consistently, ICAM-1 overexpression effectively rescued the metastasis defects induced by NSUN2 knockdown. Additionally, we observed significant positive correlations among NSUN2, YBX3, and ICAM-1 expression levels in NPC tissues, with their expression strongly associated with tumor progression and poor prognosis. Together, our findings reveal the crucial role of RNA m⁵C modification in EBV-associated NPC progression, delineate the LMP1/NSUN2/YBX3/ICAM-1 signaling cascade, and suggest this regulatory axis as a potential therapeutic target for NPC.

Glioblastoma, IDH1 wildtype, aggressive primary brain tumors with a dismal prognosis, promote the recruitment of microglia, brain resident innate immune cells, and ultimately their activation toward a tumor-supportive phenotype that increases gliomal proliferation and invasion capability. Here, we report that upon stimulation by glioma cells, microglia transit via a reactive state holding anti-tumoral properties coupled to reduced DNA methyltransferase 3 A (DNMT3A) chromatin occupancy and DNA demethylation that promote the expression of gene sets related to the transforming growth factor beta (TGF-β)-dependent microglial homeostasis and the microglial sensome. We find that upon repression of Dnmt3a expression in microglia, those cells maintain anti-tumoral attributes in vitro and in vivo. In a syngeneic immunocompetent glioblastoma mouse model, brain delivery of antisense oligonucleotide targeting Dnmt3a expression led to microglial activation and reduced tumor growth. Taken together, our results reveal the involvement of DNA demethylation in the control of glioma cells-induced microglia activation and indicate that microglial DNMT3A is a potentially therapeutic target to treat brain neoplasms such as glioblastoma that include a microglial component.

The lethal effect of injection of the endotoxin, lipopolysaccharide, as a surrogate for sepsis, is known to require both Caspase-8 and Caspase-11 in mice. In this issue, Liu et al. provide compelling evidence that the cleavage of the de-ubiquitinase CYLD by Caspase-8 is required for Caspase-11 expression, thus providing the "missing link" for the role of Caspase-8 in endotoxicity.

Caspase-8, a key protease in cell death and inflammation, plays a significant role in cytokine production during septic shock, although its precise mechanisms remain unclear. In this study, we found that mice with a specific CYLD mutation at D215 (Cyld^D215A/D215A), rendering CYLD resistant to caspase8 cleavage, exhibited marked protection against lethal endotoxic shock. Moreover, deletion of Cyld in Caspase8^-/-Mlkl^-/- mice restored their sensitivity to endotoxic shock, indicating Caspase8 promotes endotoxic shock by cleaving and degrading CYLD, thereby removing its anti-inflammatory function. Mechanistically, CYLD removes of LUBAC-mediated M1-linked ubiquitination of p65 at K301/K303, thereby suppressing its nuclear translocation and activation, and consequently inhibiting NF-κB-driven inflammatory responses. The CYLD D215A mutation exerts anti-inflammatory effects by resisting Caspase-8-mediated cleavage and degradation. Overall, these findings highlight CYLD cleavage as a promising therapeutic target for combating inflammation in endotoxic shock.