Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) constitutes a viral persistence reservoir that sustains chronic infection. Although the DNA damage response (DDR) facilitates cccDNA biogenesis, its role in regulating cccDNA stability remains unclear. By intersecting published cccDNA-associated proteomic datasets with known DDR-related host factors, we identified heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) as a novel restriction factor that binds cccDNA and suppresses HBV replication by promoting cccDNA degradation. Mechanistically, hnRNPA2B1 interacted with the G-quadruplex (G4) structure of cccDNA, with preference for G4-1, G4-7, and G4-10, and leads to the recruitment of the cytidine deaminase APOBEC3B by its prion-like domain (PrLD), thereby inducing C>T and G>A hypermutations and initiating cccDNA decay. Notably, HBV counteracts this defense mechanism through HBx-mediated hnRNPA2B1 polyubiquitination and proteasomal degradation, revealing a viral evasion strategy that perpetuates cccDNA persistence. These findings reveal a G4-dependent surveillance axis wherein hnRNPA2B1 directs APOBEC3B-mediated cytidine deamination to destabilize cccDNA while identifying HBx-induced hnRNPA2B1 ubiquitination as a viral countermeasure. This mechanistic duality not only elucidates a critical virus-host interaction governing cccDNA persistence but also provides a promising therapeutic target for the treatment of HBV infection.

BTB/POZ-MATH (BPM) proteins are key regulators to modulate the stability of their substrates via the 26S proteasome. However, their function in plant immunity, particularly in modulating the activity of nucleotide-binding, leucine-rich repeat (NLR) receptor, remains unknown. Here, we demonstrate that maize ZmBPM1, but not its close homolog ZmBPM2, negatively regulates the autoactive NLR protein Rp1-D21 by promoting its degradation through both the 26S proteasome and the autophagy pathways. ZmBPM1 overexpression inhibits Rp1-D21-mediated hypersensitive response (HR), whereas its mutation enhances the HR strength in maize. Notably, ZmBPM1 is primarily localized in the autophagosome-like punctate structures and facilitates relocation of Rp1-D21 from the nucleo-cytoplasmic compartment to these punctate structures. Furthermore, ZmBPM1 promotes the degradation of Rp1-D21 through autophagy pathway by interacting with the autophagy-related protein ZmATG6a/ZmATG6b, therefore inhibiting Rp1-D21-mediated HR. Strikingly, ZmBPM1 also acts as a negative regulator of resistance against southern corn rust caused by Puccinia polysora, a fungus that appears to enhance ZmBPM1-mediated autophagic activity. Our study thus identifies an autophagy-dependent mechanism by which a BPM protein finely controls NLR homeostasis and plant immunity, revealing a previously unrecognized immune regulation mechanism in plants.

Recognition between nucleotide-binding leucine-rich repeat (NLR) proteins and their cognate pathogen effectors often triggers the hypersensitive response (HR), a localized form of cell death in plants. Although NLR-interacting proteins are known to finely tune the activities of NLRs, the molecular mechanisms by which the Kelch-containing F-box protein (FBK) regulates NLR-mediated defense response remain unclear. Here, we report that maize ZmFBK1, but not its close homologs ZmFBK2 and ZmFBK3, modulates the homeostasis of the NLR protein Rp1-D21 and regulates Rp1-D21-mediated HR. We observed that overexpression of ZmFBK1 suppresses but ZmFBK1 mutation enhances the HR. Interestingly, ZmFBK1 is predominantly located in autophagosome-like dots and relocates Rp1-D21 from the nucleo-cytoplasm to these dots. Moreover, we found that ZmFBK1 interacts with the autophagy-related protein ZmATG6 and facilitates autophagy-mediated degradation of Rp1-D21, thereby suppressing Rp1-D21-mediated HR. Notably, ZmFBK1 also negatively regulates the resistance to southern corn rust caused by Puccinia polysora and southern leaf blight caused by Cochliobolus heterostrophus, and both pathogens appear to promote ZmFBK1-mediated autophagy in maize. In summary, we demonstrate that ZmFBK1 and ZmATG6 suppress Rp1-D21-mediated HR, likely by sequestering Rp1-D21 in autophagosome-like structures for degradation. Our study reveals a novel mechanism underlying how the activity of an NLR protein is precisely regulated by an FBK protein and the autophagy pathway.

Purpose This paper aims to assess the trade efficiency and potential of China’s agricultural product exports to Regional Comprehensive Economic Partnership (RCEP) member countries across the entire industry chain while analyzing trends and influencing factors. Design/methodology/approach Using the Chinese customs database, export trade data for China’s agricultural products were collected and segmented by the industry chain. A stochastic frontier gravity model was developed to estimate the export trade efficiency and potential of each segment while exploring the influencing factors. Findings The empirical findings indicate that the export efficiency of China’s agricultural products to RCEP member countries across the entire industry chain significantly improved in 2022. The trade performance of China’s exports to other member countries exhibits varying trends across each segment of the industry chain, influenced by both natural and human factors. In 2023, the most efficient exports were upstream to Malaysia, midstream to Brunei and downstream to Malaysia. Japan, Indonesia and Singapore present the greatest potential for China’s agricultural exports across the entire industry chain. Originality/value This paper transcends the commonly used six-digit harmonized system (HS) coding in previous studies by employing the eight-digit HS coding from China customs to more accurately identify upstream, midstream and downstream agricultural products, offering insights and strategies to boost export efficiency. Key policy recommendations include promoting RCEP’s upgrade and expansion, strengthening strategic cooperation with member countries and implementing tailored strategies to enhance agricultural trade and industry collaboration.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) are a new class of specific antiviral agents that interfere with the capsid assembly process to exert antiviral effects. In this study, we rationally designed and chemically synthesized a series of novel boronic acid (boronate ester)-bearing heteroaryldihydropyrimidine (HAP) derivatives based on a multisite-binding strategy in the solvent-exposed region. Among them, CAB7-3 exhibited significant anti-HBV activity in HBV-integrated HepDES19 (EC50 = 0.07 μM), HepAD38 (EC50 = 0.001 μM) and HBV-infected HLCZ01 cells (EC50 = 0.002 μM), respectively. Additionally, CAB7-3 effectively reduced the level of HBV core protein (Cp) and repressed HBV replication in HBV carrier mice. Preliminary drug-likeness evaluation indicated that CAB7-3 displayed improved water solubility, superior microsomal metabolic stability in liver (T 1/2 = 169.0 min) and lower hERG cardiotoxicity (IC50 = 6.5375 μM) compared to GLS4. All data demonstrated that CAB7-3 may be used as a potential candidate for further drug development.

Atherosclerosis involves inflammatory and thrombotic mechanisms, to which both platelets and transforming growth factor β (TGFβ) contribute. The effect of platelet-derived TGFβ on atherosclerosis is, however, unknown and therefore investigated. Murine platelet-selective TGFβ-deficiency (plt-TGFβ -/- ) was created by a Pf4 -Cre approach, and an atherosclerotic mouse model was established by functional abrogation of Ldlr and 10-15 weeks of a high-fat diet in plt-TGFβ -/- mice and their non-plt-TGFβ -/- littermates. En face Oil Red O staining of the aorta showed more atherosclerotic lesion formation in plt-TGFβ -/- mice, with significant increases in both lesion size and lesion coverage of the total aortic area. Cryosections of the aortic root confirmed the aggravation of atherogenesis. Platelet-derived TGFβ deficiency increased circulating platelets and plasma levels of total cholesterol, LDL-cholesterol, and triglycerides after a 10 or 15 week high-fat diet period. RNA sequencing and proteomic analyses of the aorta showed signs of CD4 + T effector cell and macrophage activation in plt-TGFβ -/- mice. In conclusion, platelet-specific TGFβ deficiency aggravates atherosclerosis, via increasing arterial inflammation and plasma levels of cholesterol. Our findings demonstrate that platelet-derived TGFβ is prominently athero-protective. Key points Platelet-specific transforming growth factor β (TGFβ) deficiency markedly enhances atherosclerosis in a high-fat diet-fed murine model. Platelet TGFβ deficiency aggravates hyperlipidemia, with further elevations of total cholesterol, LDL-cholesterol, and triglycerides.

OBJECTIVE:T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of membrane-bound TIM-3 by the A disintegrin and metalloprotease, however its precise role in inflammation remains largely unclear. This study aims to define the specific function of sTIM-3. METHODS:In this study, the role of sTIM-3 was investigated using in vivo models of experimental autoimmune encephalomyelitis (EAE) and septic shock. Mechanistic insights were gained through biochemical analyses of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome pathway. RESULTS:We found that sTIM-3 alleviated disease severity in both EAE and septic shock. This protective effect was achieved through the inhibition of NLRP3 inflammasome activation. Mechanistically, sTIM-3 interacted with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC), thereby dampening its oligomerization and subsequent assembly of the active NLRP3 inflammasome complex. CONCLUSION:Our findings establish sTIM-3 as a promising therapeutic candidate for mitigating inflammation caused by excessive NLRP3 inflammasome activation, providing novel insights into potential interventions for various inflammatory diseases.

BACKGROUND:Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS:VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS:VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS:VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence, however, how the host innate immune system responds to cccDNA is still less known. Here, based on cccDNA-hepatic proteins interaction profiling, DNA sensor ATP-binding cassette subfamily F member 1 (ABCF1) is identified as a novel cccDNA-binding protein and host restriction factor for HBV replication. Mechanistically, ABCF1 recognizes cccDNA by KKx4 motif and forms phase-separated condensates by the poly-glutamine (PolyQ) region of the N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. In turn, to sustain viral replication, HBV reduces ABCF1 expression by HBx-mediated ubiquitination and degradation of SRY-box transcription factor 4(SOX4), leading to defects in SOX4-mediated upregulation of ABCF1 transcription. Taken together, the study shows that ABCF1 interacts with cccDNA to form phase separation that dually drives innate immune signaling and HBV transcriptional inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection.

Inadequate β-cell mass and insulin secretion are essential for the development of type 2 diabetes (T2D). TNF-α-induced protein 8-like 1 (Tipe1) plays a crucial role in multiple diseases, however, a specific role in T2D pathogenesis remains largely unexplored. Herein, Tipe1 as a key regulator in T2D, contributing to the maintenance of β cell homeostasis is identified. The results show that the β-cell-specific knockout of Tipe1 (termed Ins2-Tipe1BKO) aggravated diabetic phenotypes in db/db mice or in mice with high-fat diet-induced diabetes. Notably, Tipe1 improves β cell mass and function, a process that depends on Gαs, the α subunit of the G-stimulating protein. Mechanistically, Tipe1 inhibited the K48-linked ubiquitination degradation of Gαs by recruiting the deubiquitinase USP5. Consequently, Gαs or cAMP agonists almost completely restored the dysfunction of β cells observed in Ins2-Tipe1BKO mice. The findings characterize Tipe1 as a regulator of β cell function through the Gαs/cAMP pathway, suggesting that Tipe1 may emerge as a novel target for T2D intervention.

Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8+ T cell response to PD-1 blockade through carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). Moreover, the ADAM10 inhibitor GI254023X, which blocks sTim-3 production, reduces tumor progression in Tim-3 humanized mice and reverses anti-PD-1 resistance in human tumor-infiltrating lymphocytes (TILs). Overall, human sTim-3 holds great predictive and therapeutic potential in onco-immunotherapy.

Resistance to PD-1 blockade in onco-immunotherapy greatly limits its clinical application. T cell immunoglobulin and mucin domain containing-3 (Tim-3), a promising immune checkpoint target, is cleaved by ADAM10/17 to produce its soluble form (sTim-3) in humans, potentially becoming involved in anti-PD-1 resistance. Herein, serum sTim-3 upregulation was observed in non-small cell lung cancer (NSCLC) and various digestive tumors. Notably, serum sTim-3 is further upregulated in non-responding patients undergoing anti-PD-1 therapy for NSCLC and anti-PD-1-resistant cholangiocarcinoma patients. Furthermore, sTim-3 overexpression facilitates tumor progression and confers anti-PD-1 resistance in multiple tumor mouse models. Mechanistically, sTim-3 induces terminal T cell exhaustion and attenuates CD8

Plants often utilize nucleotide-binding leucine-rich repeat (NLR) proteins to perceive pathogen infections and trigger a hypersensitive response (HR). The endosomal sorting complex required for transport (ESCRT) machinery is a conserved multisubunit complex that is essential for the biogenesis of multivesicular bodies and cargo protein sorting. VPS23 is a key component of ESCRT-I and plays important roles in plant development and abiotic stresses. ZmVPS23L, a homolog of VPS23-like in maize (Zea mays), was previously identified as a candidate gene in modulating HR mediated by the autoactive NLR protein Rp1-D21 in different maize populations. Here, we demonstrate that ZmVPS23L suppresses Rp1-D21-mediated HR in maize and Nicotiana benthamiana. Variation in the suppressive effect of HR by different ZmVPS23L alleles was correlated with variation in their expression levels. ZmVPS23 also suppressed Rp1-D21-mediated HR. ZmVPS23L and ZmVPS23 predominantly localized to endosomes, and they physically interacted with the coiled-coil domain of Rp1-D21 and mediated the relocation of Rp1-D21 from the nucleo-cytoplasm to endosomes. In summary, we demonstrate that ZmVPS23L and ZmVPS23 are negative regulators of Rp1-D21-mediated HR, likely by sequestrating Rp1-D21 in endosomes via physical interaction. Our findings reveal the role of ESCRT components in controlling plant NLR-mediated defense responses.

Objectives: Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) contributes to viral persistence and recurrence. However, it is still less known how the host immune system responds to cccDNA and suppresses HBV replication. Therefore, it is essential to explore host proteins that interact with cccDNA and efficiently suppress HBV replication. Design: The interaction of cccDNA and ABCF1 was assessed by ChIP and pull-down assay. HBV replication was assessed in different cell models, including cccDNA surrogate-transfected and HBV-infected hepatocytes models. Phase separation of recombinant ABCF1 fusion proteins with cccDNA was observed by fluorescence microscopy. Results: Our data found that ABCF1 interacts with cccDNA to form phase-separated condensates via the poly-glutamine (PolyQ) of N-terminal intrinsically disordered low-complexity domain (LCD). Subsequently, ABCF1-cccDNA phase separation not only activates the type I/III interferon (IFN-I/III) pathway but also prevents Pol II accumulation on cccDNA to inhibit HBV transcription. Conclusions: Taken together, our study showed that ABCF1 acts as an antiviral restriction factor of HBV cccDNA by phase-separation-driven innate immune signaling and transcription inhibition. These findings shed new light on the understanding of host defense against cccDNA and provide a novel promising therapeutic strategy for HBV infection. ### Competing Interest Statement The authors have declared no competing interest.

Plants often utilize nucleotide-binding, leucine-rich repeat (NLR) proteins to perceive pathogen infections and trigger a hypersensitive response (HR). The endosomal sorting complex required for transport (ESCRT) machinery is a conserved multi-subunit complex that is essential for the biogenesis of multivesicular bodies and cargo protein sorting. VPS23 is a key component of ESCRT-I and plays important roles in plant development and abiotic stresses. ZmVPS23L, a homolog of VPS23-like in maize (Zea mays), was previously identified as a candidate gene in modulating HR mediated by the autoactive NLR protein Rp1-D21 in different maize populations. Here we demonstrate that ZmVPS23L suppresses Rp1-D21-mediated HR in maize and Nicotiana benthamiana. Variation in the suppressive effect of HR by different ZmVPS23L alleles was correlated with variation in their expression levels. ZmVPS23 also suppressed Rp1-D21-mediated HR. ZmVPS23L and ZmVPS23 predominantly localized to endosomes, and they physically interacted with the coiled-coil domain of Rp1-D21 and mediated the relocation of Rp1-D21 from the nucleo-cytoplasm to endosomes. In summary, we demonstrate that ZmVPS23L and ZmVPS23 are negative regulators of Rp1-D21-mediated HR, likely by sequestrating Rp1-D21 in endosomes via physical interaction. Our findings reveal the role of ESCRT components in controlling plant NLR-mediated defense responses.

In a recently published article in the European Journal of Cancer, Jiaoyun Lv et al. reported that immunoglobins were expressed in clinical tissues and cell lines derived from glioma and associated with a poor prognosis. Moreover, this study illustrated how immunoglobins from glioma promote malignant proliferation and migration through the HGF/SF-Met or FAK/Src pathway in vitro and in vivo [ [1] Lv J. Chen S. Chen X. Xie J. He Z. Fan T. et al. Effect of glioma-derived immunoglobulin on biological function of glioma cells. Eur J Cancer. 2022; 175: 86-98 Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar ]. The immunoglobins are widely distributed in the blood, tissue fluid, and exocrine fluid, primarily maintaining humoral immunity by binding to the exogenous antigen. In keeping with that notion, classical immunology theory considered B cells the primary source of immunoglobin in circulation. Since the heavy chains of immunoglobins were detected in cancer cell lines, increasing evidence has demonstrated that solid cancer and benign hyperplasia tissues, in addition to lymphoma, could also express and secrete immunoglobins [ 2 Kimoto Y. Expression of heavy-chain constant region of immunoglobulin and T-cell receptor gene transcripts in human non-hematopoietic tumor cell lines. Genes Chromosomes Cancer. 1998; 22: 83-86 Crossref PubMed Scopus (67) Google Scholar , 3 Li M. Feng D.Y. Ren W. Zheng L. Zheng H. Tang M. et al. Expression of immunoglobulin kappa light chain constant region in abnormal human cervical epithelial cells. Int J Biochem Cell Biol. 2004; 36: 2250-2257 Crossref PubMed Scopus (51) Google Scholar , 4 Niu N. Zhang J. Huang T. Sun Y. Chen Z. Yi W. et al. IgG expression in human colorectal cancer and its relationship to cancer cell behaviors. PLoS One. 2012; 7e47362 Crossref Scopus (43) Google Scholar ]. However, the molecular and biological role of tumor-derived immunoglobins remains largely unknown. Effect of glioma-derived immunoglobulin on biological function of glioma cellsEuropean Journal of CancerVol. 175PreviewGlioma is the most common and most invasive primary central nervous system tumour, and it is urgent to develop new specific therapeutic targets. Studies have confirmed that epithelial-derived tumour cells promote tumour cell proliferation and metastasis by secreting a large number of immunoglobulins (Igs), but the role of tumour-derived Igs in glioma has never been reported. Full-Text PDF

BACKGROUND:Benign prostate hyperplasia (BPH) and prostate cancer (CaP) are among the most frequently occurring prostatic diseases. When CaP progressed to castration-resistant CaP (CRPC), the prognosis is poor. Although CaP/CRPC and BPH frequently coexist in prostate, the inter-relational mechanism between them is largely unknown.METHODS:Single-cell RNA sequencing, bulk-RNA sequencing, and microarray data of BPH, CaP in the Gene Expression Omnibus database were obtained and comprehensively analyzed. Weighted Gene Co-Expression Network Analysis (WGCNA) and lasso regression analysis were performed to explore the potential biomarkers.RESULTS:With WGCNA, five modules in BPH, two in CaP, and three in CRPC were identified as significant modules. Pathway enrichment analysis found that the epigenetics and chromosomal-related signaling were dominantly clustered in the CaP group but not in BPH and CRPC. Lasso regression analysis was used to analyze further the mutual genes between the BPH module and the CRPC module. As a result, DDA1, ERG28, OGFOD1, and OXA1L were significantly correlated with the transcriptomic features in both BPH and CRPC. More importantly, the role of the four gene signatures was validated in two independent anti-PD-1 immunotherapy cohort.CONCLUSION:This study revealed the shared gene signatures and immune microenvironment between BPH and CRPC. The identified hub genes, including DDA1, ERG28, OGFOD1, and OXA1L, might be potential therapeutic targets for facilitating immunotherapy in prostate cancer.

Introduction:A primary impediment to the efficacy of immune checkpoint inhibitors is the lack of biomarkers for therapeutic responses and prognosis. Although patients with clear cell renal cell carcinoma (ccRCC) could be precisely selected for targeted therapy based on somatic mutations, it remains controversial to choose the suitable patients with a high response rate to immune checkpoint inhibitors (ICIs). The immune-dependent roles of tumor suppressor PTEN in the formation of tumor immune microenvironment remain elusive.Methods:We comprehensively analyzed the genomic and transcriptomic data from multiple ccRCC datasets, including bulk-RNA sequencing and single-cell RNA sequencing data. In vitro, immunoblotting, qRT-PCR, and RNA sequencing were conducted in ccRCC cell lines upon PTEN depletion. Gene ontology and gene set enrichment analysis were performed to screen the critical pathway and molecules in response to PTEN deletion. Immunohistochemistry staining and further bioinformatic analysis were used to validate our data.Results:Based on multi-omics analysis of public datasets of renal cancer, the frequently mutated or deleted PTEN was found to be correlated with a suppressive tumor immune microenvironment in ccRCC. Furthermore, we depleted PTEN via CRISPR-Cas9 in Caki-1 cells, which led to the upregulation of multiple neutrophil chemokines, particularly CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8. The roles of neutrophil chemokines and neutrophil markers were further validated and investigated for the association with prognosis in vitro, clinical samples, and the publicly available databases. The expression of CXCL1, CXCL8, and neutrophil markers, S100A9 and BCL2A1, were significantly associated with a poor immunotherapy-related prognosis in public dataset of renal cancer patients receiving ICIs treatment.Conclusion:These results add a new layer to understanding the association between PTEN status and the role of neutrophil infiltration in ccRCC. Moreover, our findings propose low expression of PTEN as candidate factor of resistance to anti-PD-1-based immunotherapy in ccRCC.

Platelets are an able regulator of CD4+ T cell immunity. Herein, the mechanisms underlying platelet-regulated effector responses of naïve CD4+ T (Tn) cells were investigated. Platelet–Tn cell co-cultures of human cells, genetically modified murine models, and high-throughput bioinformatic analyses were combined to elucidate molecular mechanisms of platelet-dependent regulation. Platelets exerted sophisticated regulation on effector responses of type 1, 2, and 17 T helper (Th1/Th2/Th17) and regulatory T (Treg) cells, in time-, concentration-, and organ-dependent manners and with close cooperation of transforming growth factor β (TGFβ) and platelet factor 4 (PF4). PF4 at low concentrations reinforced TGFβ signaling by heteromerizing with type III TGFβ receptor (TGFBRIII), and subsequently enhanced TGFBRII expression and TGFβ signaling. High-concentration PF4 had, however, opposite effects by directly binding to TGFBRII, blocking TGFβ–TGFBRII ligation, and thus inhibiting TGFβ signaling. Furthermore, platelet depletion markedly hampered Treg and Th17 responses in the spleen but not in the lymph nodes, blockade of platelet–Tn cell contact diminished platelet effects, while spleen injection of PF4-immobilized microparticles in PF4-deficient mice mimicked platelet effects, suggesting the importance of direct platelet–Tn contact and platelet-bound PF4 for the optimal regulatory effects by platelets. Platelets exert context-dependent regulations on effector responses of Tn cells via PF4-TGFβ duet, suggesting new possibilities of platelet-targeted interventions of T cell immunity.

Hepatitis B virus (HBV) infection remains a major challenge to global health due to unsatisfactory treatment efficacy, side effects of current therapies, and immune tolerance. Toll-like receptors 7/8 (TLR7/8) agonists have shown great potential in chronic hepatitis B (CHB) cure, but systemic administration often induces severe side effects due to rapid dispersion into the microvasculature. Herein, we encapsulate an imidazoquinoline-based TLR7/8 agonist (IMDQ) into zeolitic imidazolate framework 8 nanoparticles (IMDQ@ZIF-8 NPs) for HBV immunotherapy. Compared with free IMDQ, IMDQ@ZIF-8 NPs efficiently accumulate in the liver and are selectively taken up by antigen-presenting cells (APCs), leading to enhanced APC activation and efficient viral elimination in HBV-infected models. Strikingly, MDQ@ZIF-8 NP treatment results in the obvious production of anti-HBs antibody and seroconversion in HBV-infected mice. Overall, this study on the convergence of a facile assembly approach and efficient therapeutic effects represents a promising strategy for HBV treatment.