Cell Communication and Signaling最新文献

With the development of next-generation sequencing methods, the presence of flora has been detected in otherwise sterile tumour tissues, and intratumoural flora has a role in tumour diagnosis suggesting prognosis due to its heterogeneous nature. Studies have shown that intratumoural flora may contribute to cancer development and progression by inducing DNA damage, affecting immune system homeostasis, influencing signalling pathways, affecting barrier effects, and the effects of intratumoural flora metabolites on the organism. Moreover, intratumoural bacteria have been combined with various therapies to play a role in the clinical management of upper gastrointestinal tumours. In addition, immune cells act as either promoters or suppressors of tumours, and there are various crosstalks between intratumoral bacteria and immune cells; intratumoral bacteria enhance anti-tumour immunity through mechanisms such as T and NK cell activation and intratumoral microbiota-derived antigen presentation, and also reduce anti-tumour immune responses and promote cancer progression through the promotion of anti-inflammatory environments, T-cell inactivation and immunosuppression. In recent studies, intratumoral bacteria have been combined with nano-engineering to target not only the tumour tissue but also the tumour microenvironment. In this review, we summarise the roles and mechanisms played by intratumoural flora in cancer development, metastasis and therapy, and hope to provide ideas for follow-up studies.

Exosomes are key mediators of communication between tumor cells and the tumor microenvironment(TME); however, the mechanisms underlying exosome-mediated crosstalk between tumor cells and macrophages remain largely unclear. This study investigated the effect of exosomal RAB10 on macrophage polarization and tumor growth. Mechanistically, RAB10 delivered by breast cancer cells binds to the interferon receptor IFNAR1 and inhibits JAK1/STAT1 pathway phosphorylation, thereby impeding M1 polarization and promoting M2 polarization. RAB10 expression was significantly upregulated in drug-resistant breast cancer cells and was correlated with poor patient prognosis. In vitro assays confirmed that RAB10 enhances cancer cell proliferation. In vivo knockdown of RAB10 suppressed tumor growth and reduced the expression of markers related to proliferation (Ki67, PCNA), invasion (MMP2), and epithelial-mesenchymal transition (Snail, Vimentin). Single-cell RNA sequencing revealed a marked decrease in the proportion of macrophages in the TME following RAB10 knockdown. This phenotypic shift increases the secretion of immunosuppressive factors such as PDL1, leading to reduced activity of CD8⁺ T cells. Animal studies further confirmed that combined targeting of RAB10 and PD-L1 produces a synergistic inhibitory effect on tumor growth. This study demonstrated that breast cancer cells can transfer RAB10 to macrophages via exosomes. RAB10 interacts with IFNAR1 to suppress the JAK1/STAT1 signaling pathway, thereby inhibiting M1 polarization and promoting M2 polarization of macrophages. Inhibition of RAB10, especially in combination with PD-L1 blockade, offers a promising strategy to enhance anti-tumor immunity and overcome therapeutic resistance in breast cancer.

Background: Cisplatin (CP)-induced nephrotoxicity is a major clinical concern. Emerging evidence has revealed the critical role of PANoptosis, a coordinated cell death pathway, and neutrophil extracellular traps (NETs) in renal tubular damage. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has been recognized as a potential modulator of inflammation and cell survival; however, its regulatory function and mechanism in acute kidney injury (AKI), especially CP-induced AKI, particularly concerning NETs and PANoptosis, remain poorly understood. This study investigates the central role of PPARγ and explores the therapeutic potential of its novel activator, O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1L), in this context.

Methods: Cultured renal tubular epithelial cells (mTECs) as well as a CP-induced AKI mouse model (20 mg/kg, 72 h) and renal ischemia-reperfusion injury (IRI) model​ were used. PPARγ heterozygous knockout mice, NET inhibitors (DNase I and GSK484), and pharmacological interventions (including the novel PPARγ agonist HD-1L and rosiglitazone [ROSI]) were used. The molecular mechanisms were assessed using western blotting, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and cellular thermal shift assays (CETSA). PPARγ activity, NET markers (MPO, Cit-H3, and dsDNA), PANoptosis-related proteins (p-MLKL, GSDMD-N, and cleaved caspase-3), and reactive oxygen species (ROS) levels were quantified.

Results: CP triggered robust PANoptosis in the renal tissues, accompanied by elevated NETs and ROS-dependent NETosis. PPARγ activation significantly suppressed ROS production in neutrophils, thereby reducing NET formation. Mechanistically, NETs facilitate the release of cytoplasmic dsDNA, activate the AIM2 inflammasome, and promote PANoptosome assembly. Genetic PPARγ heterozygous knockout exacerbated renal injury and abolished protective effects, confirming the central role of PPARγ. HD-1L-induced activation of PPARγ reduced markers of PANoptosis and improved renal function in CP-AKI models. Furthermore, PPARγ agonism similarly protected against renal injury and suppressed the NETosis-PANoptosis axis in the IRI model.

Conclusion: PPARγ is a pivotal checkpoint in CP-AKI by inhibiting ROS-NETosis-driven AIM2-mediated PANoptosis. This protective mechanism is also applicable to IRI-induced AKI, highlighting its broad relevance. HD-1L confers renoprotection through PPARγ activation, providing a novel therapeutic strategy against AKI.

Background: Nearly half of patients with recurrent pregnancy loss (RPL) link to disrupted maternal immune tolerance. IL-10-production regulatory B cells (Bregs) are functionally impaired in RPL, but the underlying mechanisms remain unclear. This study aimed to identify these mechanisms and test suberoylanilide hydroxamic acid (SAHA) as a potential therapy.

Methods: Peripheral Bregs were isolated from 30 RPL patients and 30 healthy controls (HCs). Epigenetic assays (chromatin immunoprecipitation for DNMT1 occupancy, methylation profiling of the IL10 promoter), ubiquitination analyses (focusing on K48-linked polyubiquitin chains), and functional co-cultures with CD3/CD28-activated effector T cells (Teffs) were performed. SAHA (0.5-5 μM) was tested after validating non-toxicity via cell viability assays.

Results: Compared to HCs, RPL Bregs showed significantly elevated IL10 promoter methylation (HC: 22 ± 5% vs. RPL: 48 ± 8%; p < 0.0001) and overexpression of DNA methyltransferase 1 (DNMT1), which correlated with reduced IL-10 secretion (HC: 325 ± 45 pg/mL vs. RPL: 180 ± 30 pg/mL; p < 0.001) and impaired Teff suppression (suppressive index: HC: 0.52 ± 0.08 vs. RPL: 0.21 ± 0.06; p < 0.001). DNMT1 accumulation in RPL Bregs was driven by reduced binding to the E3 ubiquitin ligase TRIM28, leading to diminished K48-linked polyubiquitination (a signal for proteasomal degradation). Treatment with SAHA restored TRIM28 expression, enhanced DNMT1 ubiquitination and degradation, reversed IL10 promoter hypermethylation, and rescued IL-10 secretion and Breg-mediated Teff suppression. These effects were abolished by TRIM28 siRNA, confirming TRIM28 dependence.

Conclusion: TRIM28 deficiency disrupts DNMT1 degradation, leading to DNMT1-mediated IL10 silencing and Breg dysfunction in RPL. SAHA targets the TRIM28-DNMT1-IL10 axis to restore immune tolerance, representing a precision therapy for immune-mediated RPL.