Cell Death & Disease最新文献

Axin1 plays a critical role in regulating the Wnt/β-catenin signaling pathway and cancer progression, and its polymerization is indispensable for the assembly of the β-catenin destruction complex. However, the mechanisms that control Axin1 polymerization are limited. Here, we reveal that TRIM15 interferes with the polymerization of Axin1, thereby promoting Wnt activation and colorectal cancer growth. Mechanistically, TRIM15 strongly interacts with Axin1 through its coiled-coil domain to disrupt the polymerization among Axin1 molecules. Manipulation of TRIM15 expression dramatically weakens Wnt signaling, cell proliferation, and tumor growth. Furthermore, conditional genetic ablation of Trim15 in mice inhibits tumor formation in both AOM/DSS-induced and Apc^Min/+ colorectal cancer models. Notably, TRIM15 is also a Wnt target gene that forms a positive feedback loop in colon cancer cells. TRIM15 is highly expressed and is positively associated with β-catenin in colorectal cancer. More importantly, the simultaneous increase in Axin1 protein levels and its polymerization can synergistically induce apoptosis. Together, our study uncovers an important regulatory mechanism of Axin1 polymerization and implies that targeting TRIM15 provides a therapeutic strategy for colorectal cancer based on inhibiting Wnt signaling.

Tertiary lymphoid structures (TLS) are associated with an improved response to Immune checkpoint therapy (ICT) in head and neck squamous cell carcinoma (HNSCC). Human papillomavirus (HPV) infection constitutes a high-risk factor for HNSCC carcinogenesis. However, its role in TLS formation has yet to be elucidated. Herein, immunohistochemical (IHC) analysis from 59 HNSCC patients revealed a higher prevalence of mature TLS in HPV-positive (HPV⁺) HNSCC compared to HPV-negative (HPV^-) cases. Furthermore, integrated analysis of single-cell RNA sequencing, spatial transcriptomics, and RNA-seq data indicated that TLS-positive tumors were characterized by an expanded population of KRT15^high tumor cells in HNSCC. IHC and cytological experiments confirmed upregulation of KRT15 in HPV⁺HNSCC tumor cells, which also showed high expression of cancer stem cell marker genes. These KRT15^high stem-like tumor cells specifically secreted CCL20, which was related to the infiltration of TLS-associated immune cells in HPV⁺HNSCC. Murine models confirmed that CCL20 treatment promoted TLS formation and enhanced the efficacy of anti-PD-1 therapy. Multiplex immunofluorescence showed that TLS provided specialized microenvironments that supported the proliferation of CD39⁺PD-1⁺CD8⁺T cells. Collectively, our findings proposed that CCL20 secreted by HPV-infected KRT15^high tumor cells promoted TLS formation, thereby enhancing anti-PD-1 therapy responses in HPV⁺HNSCC. This study provides mechanistic insights into HPV-mediated TLS development and supports precision immunotherapeutic strategies for HNSCC.

Pyroptosis, a gasdermin (GSDM)-mediated immunogenic programmed cell death modality, manifests through characteristic membrane permeabilization and proinflammatory cytokine release. Pyroptosis exhibits dual therapeutic advantages by remodeling the tumor microenvironment and potentiating systemic anti-tumor immunity, positioning it as a pivotal focus in cancer immunotherapy. However, researchers still focus current pyroptosis induction strategies predominantly on single molecular targets and have not sufficiently analyzed the inter-organelle communication networks that govern pyroptotic signaling cascades. This review provides a systematic exploration of organelle-specific ultrastructural alterations during pyroptosis progression and the molecular machinery regulating organelle-mediated pyroptotic pathways. We synthesize recent advances in organelle-targeted pyroptosis induction strategies, elucidating how inter-organelle crosstalk networks to enhance therapeutic efficacy. We aim to provide translational approaches for optimizing cancer treatment paradigms.

Vanishing White Matter Disease (VWMD) is a devastating, currently incurable neurodevelopmental disorder primarily affecting white matter. The prevailing view attributes VWMD to the activation of the canonical integrated stress response (c-ISR). However, recent studies have identified a novel, distinct pathway called the split ISR (s-ISR), though its activation has so far only been documented in mouse stem cells harboring a single eIF2B mutation, leaving uncertainty about whether it occurs in human cells, whether other mutations can trigger it, and what role it plays in the disease. Here, we used prime editing (PE) to engineer multiple eIF2B pathogenic mutations into HEK293T and induced pluripotent stem cells (iPSCs), generating human models. We demonstrated PE's effectiveness and safety, marking the first successful application of PE for modeling VWMD. We found that all modeled mutations activate the s-ISR, indicating that this response is a common feature across VWMD mutations, and that it can be further amplified by stress-induced c-ISR and effectively suppressed by ISRIB. Mechanistically, we show that s-ISR hinders mutant iPSCs from achieving the high protein synthesis levels necessary for proper differentiation, expecially into astrocytes. This impairment disrupts their maturation process, directly linking s-ISR activation to the white matter abnormalities of VWMD.

Immune checkpoint blockade (ICB) therapy is one of the cornerstones of cancer treatment regimens, but the overall response rates remain low because of suppressive immune cells, such as myeloid-derived suppressor cells (MDSC). Therefore, it is unmet need to target MDSC to achieve better outcomes of ICB therapy. Inositol-requiring enzyme 1α (IRE1α) is identified as a key regulator for the generation of MDSC. Here, we evaluated the potential of KIRA6, an inhibitor for IREα kinase activity and RNase activity, to abrogate MDSC-mediated immune suppression. KIRA6 significantly suppressed 4T1 tumor growth, decreased MDSC population and enhanced T cell infiltration. Two dosages of KIRA6 treatment directly inhibited extramedullary myelopoiesis and MDSC generation in vivo. KIRA6 abrogated the induction of MDSC from bone marrow cells and abolished the immunosuppressive capability of MDSC in vitro. Meanwhile, KIRA6 not only attenuated G-CSF production from tumor cells thereby blocking the induction of MDSC, but also caused apoptosis of tumor cells. Moreover, KIRA6 treatment diminished MDSC generation, restored T cell proportion in both local and systemic immune landscapes and eventually overcame resistance to anti-PD-1 therapy. Our work establishes the evidence for KIRA6 as an impressive agent for abrogating MDSC-mediated immune suppression, killing tumor, and overcoming ICB resistance.

RNaseT2-deficient cystic leukoencephalopathy (CLE) presents with severe psychomotor retardation, cystic brain lesions, white matter alterations, and cerebral atrophy. The Rnaset2^-/- mouse mirrors key features of this disease and represents the first murine model with a distinct neurological phenotype for type I interferonopathies. Rnaset2^-/- mice exhibit activated microglia, perivascular monocyte and CD8 + T cell infiltration, and hippocampal accentuated atrophy. However, the mechanisms linking interferon-driven neuroinflammation to neurodegeneration remain unclear, underscoring the need to clarify which molecular processes contribute to tissue injury in a time-dependent manner. We found a sustained upregulation of interferon-stimulated genes (IRF9, RIG-I) over three to 28 weeks of age in the brains of Rnaset2^-/- mice compared to controls. Expression of the chemokines Ccl2, Ccl5, and Cxcl10 peaked early but declined thereafter. Pyroptosis-related markers (ASC, CASP1, GSDMD) were significantly increased already at three to 6 weeks of age and decreased thereafter, whereas apoptotic markers such as Bax, Bad, Bid, CASP3, CASP8, and PARP were not differentially expressed compared to controls. Finally, Cd3e as well as Tnf peaked later (at 17 weeks of age) and declined at 28 weeks. Interestingly, double IHC confirmed the co-localization of the pyroptosis-related marker ASC with the microglia marker IBA-1. Taken together, these findings support the notion that pyroptosis is an early, disease-associated event restricted to microglia that likely contributes to establishing a proinflammatory milieu prior to T cell infiltration and brain atrophy. Targeting pyroptosis could therefore represent a potential strategy to attenuate neurodegeneration in type I interferon-driven neuroinflammatory disorders.

Pancreatic ductal adenocarcinoma is a highly malignant solid tumor of the digestive tract, and chemoresistance to gemcitabine is an important cause of shortened survival time in patients. Upregulation of deoxypyrimidine synthesis is one of the important reasons for pancreatic cancer cells to be resistant to gemcitabine, however, the specific mechanism leading to increased deoxypyrimidine synthesis in pancreatic cancer cells is still unclear. Ribonucleotide reductase M2 subunit (RRM2) is overexpressed through unclear mechanisms in many types of human cancer significantly affects sensitivity to various chemotherapy treatments. Here, we found that high expression of enolase-1 (ENO1) is closely related to gemcitabine resistance in pancreatic cancer patients. Cellular experiments and in vivo experiments confirmed that ENO1 increases the resistance of pancreatic cancer to gemcitabine without relying on its glycolytic enzyme activity. Mechanistically, ENO1 competitively binds to RRM2 with ubiquitin E3 ligase STUB1, thereby weakening the ubiquitination and degradation of RRM2 by STUB1. This ENO1-mediated aggregation of RRM2 protein increases the synthesis of dNTPs in pancreatic cancer cells, enhancing the resistance of pancreatic cancer to gemcitabine. Our study reveals a role of ENO1 in pancreatic cancer via RRM2-STUB1 axis and provides a scientific basis for the development of new therapeutic strategies targeting ENO1.

Although chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable therapeutic effects in treating hematologic cancers, its effectiveness in solid tumors remains significantly restricted. the primary reason is the immunosuppression mediated by the tumor microenvironment (TME), which leads to rapid exhaustion of infiltrating CAR-T cells. To enhance CAR-T cell efficacy against solid tumors, we pursued improvements in two aspects. First, we constructed fibroblast activation protein (FAP)-directed CAR-T cells to enhance their anti-CAF capability within the TME, thereby alleviating the immunosuppressive barrier. Second, we utilized IL-15, an efficient activator of CAR-T cells that inhibits activation-induced cell death, restores effector functions, and increases the proportion of the T stem cell memory (T_SCM) subpopulation. In this study, we report the generation of FAP/IL-15 CAR-T cells, which target FAP and autonomously synthesize and secrete IL-15. Our data demonstrate that treatment with FAP/IL-15 CAR-T cells exhibited stronger activation characteristics in a FAP antigen-dependent manner, selectively targeting CAFs within the solid TME. Moreover, endogenous IL-15 secretion enabled CAR-T cells to adopt a T_SCM-like phenotype with enhanced memory characteristics, thus improving cell survival, proliferation, activation, and therapeutic efficacy against solid tumors.

While the hydrolase activity of soluble epoxide hydrolase (sEH) reduces vascular calcification, it is not known whether the phosphatase activity of sEH (sEH-P) is also involved. Pharmacological and genetic inhibition of sEH-P reduced the increased calcium deposition in rat aortic rings cultured under high-phosphate conditions. This was associated with decreased mRNA expression of the osteochondrogenic markers Msx2 and Sox9. Deendothelialization of the aortic rings abolished this anticalcifying effect, while the calcification of human aortic smooth muscle cells was unaffected by sEH-P inhibition, suggesting a predominant role of the endothelium. Endothelial NO release did not appear to contribute, but an increased level of the calcification inhibitor pyrophosphate anions (PPi) was observed in the culture supernatant of aortic rings when sEH-P was inhibited. In vitro experiments demonstrated that PPi is a substrate of sEH-P, and that inhibiting sEH-P prevented the high-phosphate induced decrease of PPi in human aortic endothelial cells. Furthermore, the aortic calcification related to chronic kidney disease induced by subtotal nephrectomy was reduced in sEH-P-deficient rats compared to wild-type rats. This was associated with an improvement in flow-induced isolated mesenteric artery dilatation and a reduction of cardiac hypertrophy and fibrosis. Vascular calcification is regulated by sEH-P through the metabolism of endothelial PPi. The prevention of vascular calcification, together with the reduction in vascular dysfunction and cardiac remodeling, suggests that inhibiting sEH-P may help to prevent the cardiovascular complications associated with chronic kidney disease.

Tumor-associated macrophages (TAMs) of classic Hodgkin Lymphoma (cHL) contribute to the development of immunosuppressive tumor microenvironment (TME) and are associated with worse treatment outcomes. However, detailed features, functions and therapeutic vulnerabilities of cHL TAMs remain largely unknown. To address this, we analyzed cHL diagnostic biopsies by Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) and assessed transcriptional, proteomic and metabolic profiles of in vitro TAM models. We show that Reed-Sternberg (RS) cells induce a disease-specific TAM phenotype, characterized by elevated expression of factors involved in chemotaxis, angiogenesis, extracellular matrix remodeling and tumor immune escape. RS cell-conditioned TAMs expressed TGFβ, CCL17 and tryptophan catabolizing enzymes, IDO1 and IL4I1, promoting regulatory T cell recruitment and activation. In addition, we identified the expression of PIM1/2/3 kinases in cHL TAMs and characterized PIMs as critical hubs orchestrating RS-macrophage interactions. Pharmacological PIM blockade attenuated the RS-induced TAM transcriptional program. In established TAMs, PIM inhibition or PROTAC-mediated degradation decreased the expression of multiple factors associated with pro-tumoral TAM functions, including IL8, MMP9, CHI3L1/2, CD206, CD209, PD-L1, CCL17, TGFβ, IL4I1 and IDO1. PIM blockade attenuated TAM-dependent eosinophil chemoattraction, extracellular matrix remodeling, angiogenesis and regulatory T-cell development. Taken together, our study highlights the role of PIMs in the regulation of pathogenic TAM functions in cHL, further supporting the rationale of PIM targeting in this disease.