参考文献

Natural killer (NK) cells are innate immune cells that are crucial for anticancer activity and have been developed as an immune cell therapy for leukemia. However,their limited effectiveness against solid tumors has prompted research into methods to enhance NK cell activity through combination therapies. Health supplements capable of boosting immune surveillance against tumor cells are gaining attention owing to their potential benefits. Resveratrol,a stilbenoid produced by several plants including peanuts and grapes,reportedly exerts anticancer effects and can activate immune cells. The peanut sprout extract cultivated with fermented sawdust medium (PSEFS) is rich in resveratrol,leveraging its health benefits in terms of the dry weight of herbal products,thus maximizing the utilization of resveratrol’s beneficial properties. Our study compared the efficacy of resveratrol and PSEFS and revealed that PSEFS significantly enhanced NK cell activation compared with an equivalent dose of resveratrol. We investigated the ability of PSEFS to potentiate NK cell anticancer activity,focusing on NK cell survival,tumor cell lysis,and NK cell activation in PSEFS-administered mice. Our findings suggest that PSEFS could be a potential NK cell booster for cancer immunotherapy. View Publication

BACKGROUNDSepsis is a severe illness characterized by systemic and multiorgan reactive responses and damage. However,the impact of sepsis on the bone marrow,particularly on bone marrow mesenchymal stem cells (BMSCs),is less reported. BMSCs are critical stromal cells in the bone marrow microenvironment that maintain bone stability and hematopoietic homeostasis; however,the impairment caused by sepsis remains unknown.AIMTo investigate the effects of sepsis on BMSCs and the underlying mechanisms.METHODSBMSCs were obtained from healthy donors and patients with sepsis. We compared the self-renewal capacity,differentiation potential,and hematopoietic supportive ability in vitro. Senescence of septic BMSCs was assessed using β-galactosidase staining,senescence-associated secretory phenotype,intracellular reactive oxygen species levels,and the expression of P16 and P21. Finally,the changes in septic BMSCs after nicotinamide adenine dinucleotide (NAD) treatment were evaluated.RESULTSSeptic BMSCs showed decreased proliferation and self-renewal,bias towards adipogenic differentiation,and weakened osteogenic differentiation. Additionally,hematopoietic supportive capacity declines in sepsis. The levels of aging markers were significantly higher in the septic BMSCs. After NAD treatment,the proliferation capacity of septic BMSCs showed a recovery trend,with increased osteogenic and hematopoietic supportive capacities. Sepsis resulted in decreased expression of sirtuin 3 (SIRT3) in BMSCs,whereas NAD treatment restored SIRT3 expression,enhanced superoxide dismutase enzyme activity,reduced intracellular reactive oxygen species levels,maintained mitochondrial stability and function,and ultimately rejuvenated septic BMSCs.CONCLUSIONSepsis accelerates the aging of BMSCs,as evidenced by a decline in self-renewal and osteogenic capabilities,as well as weakened hematopoietic support functions. These deficiencies can be effectively reversed via the NAD/SIRT3/superoxide dismutase pathway. View Publication

Immune dysregulation-induced inflammation serves as a driving force in the progression of metabolic dysfunction-associated steatohepatitis (MASH),while the underlying cellular and molecular mechanisms remain largely uncharted. A Western diet (WD) is employed to construct mouse models of metabolic dysfunction associated steatotic liver disease (MASLD) or MASH. Mass cytometry identifies a c-kit+ cDC1 subset whose frequency is reduced in the livers of mice and patients with MASH compared with healthy controls. Adoptive cell transfer of c-kit+ cDC1 protects the progression of MASH. Moreover,analysis of gut microbe sequence shows that WD-fed mice and MASLD/MASH patients exhibit gut microbiota dysbiosis,with an elevated abundance of H2S-producing Desulfovibrio_sp. Transplanting of MASH-derived fecal flora,Desulfovibrio_sp.,or injecting H2S intraperitoneally into MASLD mice decreases the c-kit+cDC1 population and exacerbates liver inflammation. Mechanistically,H2S induces autophagic cell death of cDC1 in a c-kit-dependent manner in cDC-specific c-kit-/- and Atg5-/- mice. We thus uncover that microbiota-derived H2S triggers the autophagic cell death of c-kit+ cDC1 and ignites the liver inflammatory cascade in MASH. The immune regulatory mechanism for metabolic dysfunction-associated steatohepatitis (MASH) remains elusive. Here,the authors identify a c-kit+ cDC1 subset,which can be depleted by Desulfovibrio_sp.-induced H2S via autophagic cell death and contributing to uncontrolled inflammation for MASH progression. View Publication

Characterizing the HIV-1 reservoir in blood and tissues is crucial for the development of curative strategies. Using an HIV Tat mRNA-containing lipid nanoparticle (Tat-LNP) in combination with panobinostat,we show that p24+ cells from blood and lymph nodes exhibit distinct phenotypes. Blood p24+ cells are found in both central/transitional (TCM/TTM) and effector memory subsets,mostly lack CXCR5 expression and are enriched in GZMA+ cells. In contrast,most lymph node p24+ cells display a TCM/TTM phenotype,with approximately 50% expressing CXCR5 and nearly all lacking GZMA expression. Furthermore,germinal center T follicular helper cells do not appear to harbor the translation-competent reservoir in long-term suppressed individuals. Near full-length HIV-1 sequencing in longitudinal samples from matched blood,lymph nodes,and gut indicates that clones of infected cells,including those carrying an inducible provirus,persist and spread across various anatomical compartments. Finally,uniform genetic diversity across sites suggests the absence of ongoing replication in tissues under treatment. Here,Pardons and Lambrechts et al show that HIV-1 reservoirs in blood and lymph nodes differ phenotypically. Furthermore, germinal center T follicular helper cells do not harbor the inducible reservoir in long-term suppressed individuals. Infected clones can spread across tissues and persist without active replication. View Publication

Tissue-repair regulatory T cells (trTregs) comprise a specialized cell subset essential for tissue homeostasis and repair. While well-studied in sterile injury models,their role in infection-induced tissue damage and antimicrobial immunity is less understood. We investigated trTreg dynamics during acute Trypanosoma cruzi infection,marked by extensive tissue damage and strong CD8+ immunity. Unlike sterile injury models,trTregs significantly declined in secondary lymphoid organs and non-lymphoid target tissues during infection,correlating with systemic and local tissue damage,and downregulation of function-associated genes in skeletal muscle. This decline was linked to decreased systemic IL-33 levels,a key trTreg growth factor,and promoted by the Th1 cytokine IFN-γ. Early recombinant IL-33 treatment increased trTregs,type 2 innate lymphoid cells,and parasite-specific CD8+ cells at specific time points after infection,leading to reduced tissue damage,lower parasite burden,and improved disease outcome. Our findings not only provide novel insights into trTregs during infection but also highlight the potential of optimizing immune balance by modulating trTreg responses to promote tissue repair while maintaining effective pathogen control during infection-induced injury. Author summaryDuring Chagas’ disease,caused by the protozoan Trypanosoma cruzi,severe organ damage is generated by the interplay between the parasite and the immune response. In our investigation,we examined the role of tissue-repair regulatory T cells (trTregs) during the acute phase of T. cruzi infection in mice. Surprisingly,we observed a reduction in trTregs at the peak of tissue damage,contrary to their usual accumulation after injury in other contexts. This decline aligned with decreased levels of interleukin-33,a critical factor for trTreg survival,and was promoted by the effector cytokine IFN-γ. Administering interleukin-33 at early infection times not only boosted trTregs but also expanded other reparative and antiparasitic immune cells. Consequently,these treated mice exhibited reduced damage and lower parasite levels in tissues. Our findings provide new insights into how trTreg function during infection-related injury,paving the way for strategies that balance the immune response to support tissue repair without weakening the body’s ability to fight the infection. This approach could have broader implications for treating infectious diseases and conditions involving tissue damage. View Publication

Liver metastasis (LM) poses a significant challenge in cancer treatment,with limited available therapeutic options and poor prognosis. Understanding the dynamics of tumor microenvironment (TME) and immune interactions is crucial for developing effective treatments. We find that WNT11 promoted CD8+ T-cell exclusion and suppression,which was correlated with poor prognosis in LM. Mechanistically,WNT11-overexpressing tumor cells directly reduce CD8+ T-cell recruitment and activity by decreasing CXCL10 and CCL4 expression through CAMKII-mediated β-catenin/AFF3 downregulation. WNT11-overexpressing tumor cells promote immunosuppressive macrophage polarization by inducing IL17D expression via the CAMKII/NF-κB pathway,which result in CD8+ T-cell suppression. Moreover,CAMKII inhibition increases the efficacy of anti-PD-1 therapy in mouse model of LM. Serum expression of WNT11 is identified as a potential minimally invasive biomarker in the management of colorectal cancer-LM with immunotherapy. Our findings highlight WNT11/CAMKII axis as a critical regulator of the TME and a promising target for immunotherapy in patients with LM. Activation of the WNT/β-catenin signaling pathway has been associated with immune evasion in several cancer types. Here the authors show that expression of WNT11,a member of the non-canonical WNT signaling pathway,is associated with CD8 + T cell exclusion and resistance to immune checkpoint inhibitors in liver metastasis. View Publication

Type I Interferons (IFN-I) are central to host protection against viral infections,with plasmacytoid dendritic cells (pDC) being the most significant source,yet pDCs lose their IFN-I production capacity following an initial burst of IFN-I,resulting in susceptibility to secondary infections. The underlying mechanisms of these dynamics are not well understood. Here we find that viral infection reduces the capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically,we identify lactate dehydrogenase B (LDHB) as a positive regulator of pDC IFN-I production in mice and humans; meanwhile,LDHB deficiency is associated with suppressed IFN-I production,pDC metabolic capacity,and viral control following infection. In addition,preservation of LDHB expression is sufficient to partially retain the function of otherwise exhausted pDCs,both in vitro and in vivo. Furthermore,restoring LDHB in vivo in pDCs from infected mice increases IFNAR-dependent,infection-associated pathology. Our work thus identifies a mechanism for balancing immunity and pathology during viral infections,while also providing insight into the highly preserved infection-driven pDC inhibition. Plasmacytoid dendritic cells (pDC) are the major IFN-I-producing cells,but this production returns to baseline soon after viral infection. Here the authors show that this decrease in IFN-I production and related pDC functions may be attributed to suppressed oxidative and glycolytic metabolism of pDCs,with lactate dehydrogenase B identified as a regulator. View Publication

Regulatory T cells (Treg) play an important role in regulating immune homeostasis in health and disease. Traditionally their suppressive function has been assayed by mixing purified cell populations,which does not provide an accurate picture of a physiologically relevant response. To overcome this limitation,we here develop ‘single cell suppression profiling of human Tregs’ (scSPOT). scSPOT uses a 52-marker CyTOF panel,a cell division detection algorithm,and a whole PBMC system to assess the effect of Tregs on all other cell types simultaneously. In this head-to-head comparison,we find Tregs having the clearest suppressive effects on effector memory CD8 T cells through partial division arrest,cell cycle inhibition,and effector molecule downregulation. Additionally,scSPOT identifies a Treg phenotypic split previously observed in viral infection and propose modes of action by the FDA-approved drugs Ipilimumab and Tazemetostat. scSPOT is thus scalable,robust,widely applicable,and may be used to better understand Treg immunobiology and screen for therapeutic compounds. Traditional regulatory T cell (Tregs) assays utilize mixture of purified cell population. Here the authors develop a ‘single cell suppression profiling of human Tregs’ (scSPOT) with 52-marker CyTOF panel,a cell division detection algorithm,and a whole PBMC system to assess Treg suppressive function on all cell types simultaneously. View Publication

Single-cell RNA-seq methods can be used to delineate cell types and states at unprecedented resolution but do little to explain why certain genes are expressed. Single-cell ATAC-seq and multiome (ATAC + RNA) have emerged to give a complementary view of the cell state. It is however unclear what additional information can be extracted from ATAC-seq data besides transcription factor binding sites. Here,we show that ATAC-seq telomere-like reads counter-inituively cannot be used to infer telomere length,as they mostly originate from the subtelomere,but can be used as a biomarker for chromatin condensation. Using long-read sequencing,we further show that modern hyperactive Tn5 does not duplicate 9 bp of its target sequence,contrary to common belief. We provide a new tool,Telomemore,which can quantify nonaligning subtelomeric reads. By analyzing several public datasets and generating new multiome fibroblast and B-cell atlases,we show how this new readout can aid single-cell data interpretation. We show how drivers of condensation processes can be inferred,and how it complements common RNA-seq-based cell cycle inference,which fails for monocytes. Telomemore-based analysis of the condensation state is thus a valuable complement to the single-cell analysis toolbox. View Publication

BackgroundLung cancer,particularly non-small cell lung cancer (NSCLC),has high recurrence rates and remains a leading cause of cancer-related death,despite recent advances in its treatment. Emerging therapies,such as chimeric antigen receptor (CAR)-T cell therapy,have shown promise but face significant challenges in targeting solid tumors. This study investigated the potential of combining receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeting CAR-T cells with ferroptosis inducers to promote ferroptosis of tumor cells and enhance anti-tumor efficacy.MethodsRNA-seq data and immunofluorescence analysis of relapsed NSCLC patient samples were used to explore ROR1 expression. In addition,ROR1-targeting CAR-T cells were developed to assess cytotoxic activity against ROR1+ tumor cells,and the effect of cytokine stimulation on their efficacy was evaluated. Lipidomics,immunofluorescent histochemistry,and western blotting were used to explore the observed effects. Ferroptosis indicators,including levels of reactive oxygen species,were used to detect the combined effect of CAR-T cells and ferroptosis-inducing drugs. Finally,tumor-bearing mice were used to validate the in vivo efficacy of the combination therapy strategy.ResultsTumor cells treated with ferroptosis inducers showed increased sensitivity to Interferon gamma (IFN-γ) secreted by ROR1 CAR-T cells. Furthermore,ROR1 CAR-T cells enhanced the production of phosphatidylcholine with diacyl-polyunsaturated fatty acid tails (PC-PUFA2) by working in tandem with IFN-γ. This enhancement promoted the expression of acyl-CoA synthetase long chain family member 4 (ACSL4),which in turn strengthened the overall anti-tumor response.ConclusionsCombining ROR1 CAR-T cells with ferroptosis inducers enhanced anti-tumor efficacy in NSCLC by promoting ferroptosis through increased lipid peroxidation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40364-025-00730-0. View Publication