Salicylic Acid's impact on Sedum alfredii growth and cadmium tolerance: Comparative physiological, transcriptomic, and metabolomic study.

With the acceleration of industrialization, Cd pollution has emerged as a major threat to soil ecosystem health and food safety. Hyperaccumulating plants like Sedum alfredii Hance are considered to be used as part of an effective strategy for the ecological remediation of Cd polluted soils. This study delved deeply into the physiological, transcriptomic, and metabolomic responses of S. alfredii under cadmium (Cd) stress when treated with exogenous salicylic acid (SA). We found that SA notably enhanced the growth of S. alfredii and thereby increased absorption and accumulation of Cd, effectively alleviating the oxidative stress caused by Cd through upregulation of the antioxidant system. Transcriptomic and metabolomic data further unveiled the influence of SA on photosynthesis, antioxidant defensive mechanisms, and metal absorption enrichment pathways. Notably, the interactions between SA and other plant hormones, especially IAA and JA, played a central role in these processes. These findings offer us a comprehensive perspective on understanding how to enhance the growth and heavy metal absorption capabilities of hyperaccumulator plants by regulating plant hormones, providing invaluable strategies for future environmental remediation efforts.

Prognostic value and immunological function of cuproptosis-related genes in lung adenocarcinoma.

Background: Lung cancer is one of the malignant tumors with the highest morbidity and fatality rates worldwide. The overall survival (OS) of lung adenocarcinoma (LUAD) is poor. Cuproptosis is a copper-triggered modality of mitochondrial cell death, however, its contribution to the emergence of lung cancer is unknown. The clinical implication and immunological function of cuproptosis-related genes (CRGs) in LUAD has yet to be established. Methods: TCGA, HPA, GEPIA, Kaplan-Meier, TIMER and CancerSEA database were used to explore the prognostic value and biological function of CRGs in LUAD. Results: CRGs are primarily involved in copper ion transport, the citrate cycle (TCA cycle) and central carbon metabolism in LUAD. The mRNA expression of COA6, UBE2D1, DLAT, SLC25A3, and DBH was significantly increased. The expression of COA6, DLAT, SLC25A3, DBH, and LOXL2 were all strongly associated with the clinicopathological stages in LUAD. Moreover, high expression of COA6, UBE2D1, DLAT, SLC25A3 and LOXL2 was related to poor OS. The expression of SLC25A3 and LOXL2 showed different association with immune cell infiltration. The single cell sequencing demonstrated that CRGs play important roles in the regulation of DNA damage response, inflammation and metastasis in LUAD. Conclusions: In summary, this study comprehensively uncovered that CRGs could be identified as potential prognostic and immunological biomarkers in LUAD. Our current research could provide a solid theoretical basis for LUAD survival research and clinical decision-making.

An evolutionarily conserved ubiquitin ligase drives infection and transmission of flaviviruses.

Mosquito-borne flaviviruses such as dengue (DENV) and Zika (ZIKV) cause hundreds of millions of infections annually. The single-stranded RNA genome of flaviviruses is translated into a polyprotein, which is cleaved equally into individual functional proteins. While structural proteins are packaged into progeny virions and released, most of the nonstructural proteins remain intracellular and could become cytotoxic if accumulated over time. However, the mechanism by which nonstructural proteins are maintained at the levels optimal for cellular fitness and viral replication remains unknown. Here, we identified that the ubiquitin E3 ligase HRD1 is essential for flaviviruses infections in both mammalian hosts and mosquitoes. HRD1 directly interacts with flavivirus NS4A and ubiquitylates a conserved lysine residue for ER-associated degradation. This mechanism avoids excessive accumulation of NS4A, which otherwise interrupts the expression of processed flavivirus proteins in the ER. Furthermore, a small-molecule inhibitor of HRD1 named LS-102 effectively interrupts DENV2 infection in both mice and Aedes aegypti mosquitoes, and significantly disturbs DENV transmission from the infected hosts to mosquitoes owing to reduced viremia. Taken together, this study demonstrates that flaviviruses have evolved a sophisticated mechanism to exploit the ubiquitination system to balance the homeostasis of viral proteins for their own advantage and provides a potential therapeutic target to interrupt flavivirus infection and transmission.

A naturally isolated symbiotic bacterium suppresses flavivirus transmission by Aedes mosquitoes.

The commensal microbiota of the mosquito gut plays a complex role in determining the vector competence for arboviruses. In this study, we identified a bacterium from the gut of field Aedes albopictus mosquitoes named Rosenbergiella sp. YN46 (Rosenbergiella_YN46) that rendered mosquitoes refractory to infection with dengue and Zika viruses. Inoculation of 1.6 × 103 colony forming units (CFUs) of Rosenbergiella_YN46 into A. albopictus mosquitoes effectively prevents viral infection. Mechanistically, this bacterium secretes glucose dehydrogenase (RyGDH), which acidifies the gut lumen of fed mosquitoes, causing irreversible conformational changes in the flavivirus envelope protein that prevent viral entry into cells. In semifield conditions, Rosenbergiella_YN46 exhibits effective transstadial transmission in field mosquitoes, which blocks transmission of dengue virus by newly emerged adult mosquitoes. The prevalence of Rosenbergiella_YN46 is greater in mosquitoes from low-dengue areas (52.9 to ~91.7%) than in those from dengue-endemic regions (0 to ~6.7%). Rosenbergiella_YN46 may offer an effective and safe lead for flavivirus biocontrol.

Co-delivery of siAEG-1 and doxorubicin to treat osteosarcoma via nanomicelles for azide-alkyne "click" conjugation of poly(l-lysine) dendrons onto Zein.

Astrocyte elevated gene-1 (AEG-1) oncogene is a notorious and evolving target in a variety of human malignancies including osteosarcoma. The RNA interference (RNAi) has been clinically proven to effectively knock down specific genes. To successfully implement RNAi in vivo, protective vectors are required not only to protect unstable siRNAs from degradation, but also to deliver siRNAs to target cells with controlled release. Here, we synthesized a Zein-poly(l-lysine) dendrons non-viral modular system that enables efficient siRNA-targeted AEG-1 gene silencing in osteosarcoma and encapsulation of antitumor drugs for controlled release. The rational design of the ZDP integrates the non-ionic and low immunogenicity of Zein and the positive charge of the poly(l-lysine) dendrons (DPLL) to encapsulate siRNA and doxorubicin (DOX) payloads via electrostatic complexes and achieve pH-controlled release in a lysosomal acidic microenvironment. Nanocomplexes-directed delivery greatly improves siRNA stability, uptake, and AEG-1 sequence-specific knockdown in 143B cells, with transfection efficiencies comparable to those of commercial lipofectamine but with lower cytotoxicity. This AEG-1-focused RNAi therapy supplemented with chemotherapy inhibited, and was effective in inhibiting the growth in of osteosarcoma xenografts mouse models. The combination therapy is an alternative or combinatorial strategy that can produce durable inhibitory responses in osteosarcoma patients.

A Novel Laryngopharyngeal Reflux Disease Model for Bama Pigs.

OBJECTIVE: To develop a novel Laryngopharyngeal Reflux Disease (LPRD) model in Bama pigs through endoscopic cricopharyngeal myotomy. METHODS: A total of eight 8-month-old Bama pigs were randomly assigned to either the control or surgery group. Prior to intervention, upper esophageal sphincter (UES) manometry and laryngopharyngeal Dx-pH monitoring were conducted to establish baseline physiological parameters for each pig. Subsequently, the surgery group underwent endoscopic cricopharyngeal myotomy, while the control group did not. Two weeks postintervention, these procedures were repeated to evaluate changes in UES contractility and the occurrence of reflux events. At week eight postsurgery, mucosal tissues from both groups were harvested for histological analysis. Hematoxylin and eosin (H&E) staining was used to assess inflammation, while transmission electron microscopy (TEM) examined alterations in intercellular spaces and desmosomes. RESULTS: The mean UES pressures in the control and surgery groups were 59 ± 9 mmHg and 68 ± 12 mmHg, respectively. In the surgery group, there was a significant decrease in UES pressure 2weeks after the operation compared to preoperative values (P = 0.005), whereas no significant change was observed in the control group (P = 0.488). Laryngopharyngeal reflux (LPR) was successfully induced in the surgery group as evidenced by reflux events with pH <5.0, which were not detected in the control group. HE staining revealed marked inflammatory cell infiltration and submucosal gland expansion in throat tissues of the surgery group Bama pigs. TEM further showed enlarged intercellular spaces and reduced desmosome numbers in the laryngopharyngeal epithelium compared to controls. CONCLUSION: Given analogous throat epithelial structures to humans, Bama pigs are an appropriate species for an LPRD animal model. Endoscopic cricopharyngeal myotomy effectively induces LPR and observable pathological changes in Bama pigs, providing a valuable platform for further research into LPRD pathophysiology.

Jasmonic acid's impact on Sedum alfredii growth and cadmium tolerance: A physiological and transcriptomic study.

Soil cadmium (Cd) pollution is escalating, necessitating effective remediation strategies. This study investigated the effects of exogenous jasmonic acid (JA) on Sedum alfredii Hance under Cd stress, aiming to enhance its phytoextraction efficiency. Initially, experiments were conducted to assess the impact of various concentrations of JA added to environments with Cd concentrations of 100, 300, and 500 µmol/L. The results determined that a concentration of 1 µmol/L JA was optimal. This concentration effectively mitigated the level of ROS products by enhancing the activity of antioxidant enzymes. Additionally, JA fostered Cd absorption and accumulation, while markedly improving plant biomass and photosynthetic performance. In further experiments, treatment with 1 µmol/L JA under 300 µmol/L Cd stress was performed and transcriptomic analysis unveiled a series of differentially expressed genes (DEGs) instrumental in the JA-mediated Cd stress response. These DEGs encompass not only pathways of JA biosynthesis and signaling but also genes encoding functions that influence antioxidant systems and photosynthesis, alongside genes pertinent to cell wall synthesis, and metal chelation and transport. This study highlights that JA treatment significantly enhances S. alfredii's Cd tolerance and accumulation, offering a promising strategy for plant remediation and deepening our understanding of plant responses to heavy metal stress.

Application of the 2022 ACR/EULAR criteria to Chinese patients with previously diagnosed eosinophilic granulomatosis with polyangiitis: The concordance rate between the 2022 ACR/EULAR criteria and the 1990 criteria for EGPA in China.

This study aimed to investigate the concordance rate between the 2022 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria and the 1990 criteria for eosinophilic granulomatosis with polyangiitis (EGPA) in Chinese patients. 68 patients were diagnosed with EGPA according to the 1990 ACR criteria in the Department of Respiratory and Critical Care Medicine, Beijing Chao-yang Hospital Department, from May 2005 to December 2022, and those patients were reclassified using the 2022 ACR/EULAR criteria for EGPA. Among the 68 patients, 88.2% (60 cases) met the 2022 ACR/EULAR criteria for EGPA, and 11.8% (8 cases) patients failed to meet the new criteria. Only 66.2% of the patients were detected blood eosinophil count ≥ 1 × 109/L, while more patients (77.9%) met the item blood eosinophil count > 10% in the 1990 criteria. The report rate of nasal polyps was 13.2% in these patients. The concordance rate between the 2022 ACR/EULAR criteria and the 1990 criteria for EGPA was 88.2%. Compared with the 1990 criteria, the 2022 ACR/EULAR put more weighting on the blood eosinophil count and nasal polyps, while the diagnostic rate of them is low in Chinese patients. Thus improving the positive rate is important and routinely screening for nasal polyps should be performed in the future.

DUSP22 suppresses tumor progression by directly dephosphorylating AKT in non-small cell lung cancer.

Protein kinase B (AKT) plays a pivotal in regulating cell migration, proliferation, apoptosis, and survival, making it a prominent target for anticancer therapy. While the kinase activity of AKT has been extensively explored, its dephosphorylation have largely remained uncharted. Herein, we aimed to unravel the molecular mechanisms governing AKT dephosphorylation, with a specific emphasis on dual-specificity phosphatases DUSP22. Our investigation sought to shed light on the potential of DUSP22 as a potential therapeutic target for non-small cell lung cancer (NSCLC). To determine the expression level of DUSP22 in NSCLC cell lines, the gene expression profiling interactive analysis (GEPIA) and Oncomine database were searched. Additionally, the effect of DUSP22 on patient survival was analyzed with Kaplan-Meier database. Antitumor effects of DUSP22 were tested in A549 and H1299 cell lines. Experiments are based on: (1) cell viability determined by the cell counting kit-8 assay and colony-formation assay; (2) cell migratory ability assessed through the scratch assay and the transwell migration assay; (3) the mechanism behind the antitumor effects of DUSP22 dissected with co-immunoprecipitation (Co-IP) and in vitro kinase assays. Our study revealed a significant downregulation of DUSP22 in both NSCLC cell lines and tissues. Meanwhile, survival rate analysis results demonstrated that reduced DUSP22 expression was correlated with poorer overall survival in lung cancer patients. Moreover, DUSP22 exhibited an inhibitory effect on the cell viability and migratory capacity of A549 and H1299 cells. This inhibition was accompanied by the decrease in the phosphorylation of AKT and p38. Mechanistically, the phosphatase domain of DUSP22 interacted with AKT, resulting in the inhibition of AKT phosphorylation. This inhibitory effect was contingent upon the phosphatase activity of DUSP22. These findings provide compelling evidence that DUSP22 directly interacted with AKT, leading to the dephosphorylation of AKT at S473 and T308 residues, ultimately curbing the proliferation and migration of lung cancer cells. Additionally, our results also highlight a preclinical rationale for utilizing DUSP22 as a prognostic marker in NSCLC.

Fabrication and release property of self-assembled garlic essential oil-amylose inclusion complex by pre-gelatinization coupling with high-speed shear.

Our aim was to investigate the preparation of self-assembled garlic essential oil-amylose inclusion complexes (SGAs) using garlic essential oil (GEO) and corn starch (CS), and evaluated their release properties. SGAs were fabricated by pre-gelatinization coupling with high-speed shear at different GEO-CS mass ratios. When the mass ratio of GEO to pre-gelatinized corn starch was set at 15 % (SGA-15 %), with a fixed shear rate of 9000 rpm and a shear time of 30 min, the allicin content was 0.573 ± 0.023 mg/g. X-ray diffraction (XRD) results revealed a starch V-type crystalline structure in SGAs with peaks at 13.0°, 18.0°, and 20.0° (2θ). Fourier Transform Infrared (FTIR) spectra of SGAs displayed a shift in the characteristic peak of diallyl trisulfide from 987.51 cm-1 to 991.45 cm-1. Scanning electron microscope (SEM) images revealed that SGAs exhibited lamellar structures covered with small granules. SGAs exhibited higher residual mass (approximately 12 %) than other samples. The resistant starch content of SGAs increased from 10.1 % to 18.4 % as GEO contents varied from 5 % to 15 %. In vitro digestion tests showed that about 53.21 % of allicin remained in SGA-15 % after 8 h. Therefore, this dual treatment can be a new method for fabricating controlled-release inclusion complexes of guest molecules.

Association of Childhood Adversity With Frailty and the Mediating Role of Unhealthy Lifestyle: A Lifespan Analysis.

OBJECTIVES: Childhood adversity and lifestyle have been associated with frailty in later life, but not much is known about factors that may explain these associations. Therefore, this study aims to investigate the association of childhood adversity with frailty, and the mediating role of unhealthy lifestyle in the association. METHODS: This lifespan analysis included 152,914 adults aged 40-69 years old from the UK Biobank. We measured childhood adversity with five items: physical neglect, emotional neglect, sexual abuse, physical abuse, and emotional abuse through online mental health survey. Frailty was measured by the frailty index; an unhealthy lifestyle score (range: 0-5) was calculated based on unhealthy body mass index, smoking, alcohol consumption, physical inactivity, and unhealthy diet at the baseline survey. Multiple logistic regression and mediation analysis were performed. RESULTS: A total of 10,078 participants (6.6%) were defined as having frailty. Participants with any childhood adversity had higher odds of frailty. For example, in the fully adjusted model, with a one-point increase in cumulative score of childhood adversity, the odds of frailty increased by 38% (odds ratio: 1.38; 95% Confidence Interval: 1.36, 1.40). Unhealthy lifestyle partially mediated the associations of childhood adversity with frailty (mediation proportion: 4.4%-7.0%). The mediation proportions were largest for physical (8.2%) and sexual (8.1%) abuse. CONCLUSIONS: Childhood adversity was positively associated with frailty, and unhealthy lifestyle partially mediated the association. This newly identified pathway highlights the potential of lifestyle intervention strategies among those who experienced childhood adversity (in particular, physical, and sexual abuse) to promote healthy aging.

FRS2 regulated by miR-429 and miR-206 promotes angiogenesis in osteosarcoma.

FRS2 has demonstrated oncogenic roles in various malignancies, including liposarcoma and giant cell tumor of bone. However, its role in osteosarcoma remains less understood, and the upstream regulatory molecules influencing FRS2 remain unclear. This study aims to explore the clinical implications and biological function of FRS2 in osteosarcoma, and the potential regulatory microRNAs (miRNAs) governing its expression. Our study indicated significant upregulation of FRS2 in osteosarcoma cells and tissues by Western blotting and immunohistochemical staining. Elevated FRS2 expression correlated positively with increased angiogenesis and poor prognosis, possibly serving as an independent prognostic indicator for osteosarcoma patients. Functional assays revealed that attenuating FRS2 in osteosarcoma cells could mitigate proliferation, migration, and angiogenesis of vascular endothelial cells. Further investigations revealed that miR-429 and miR-206 directly targeted FRS2, exerting a negative regulation on its expression. Furthermore, FRS2 played a role in repressing osteosarcoma advancement influenced by miR-429 or miR-206. In summary, FRS2, influenced by miR-429 and miR-206, emerges as a promising therapeutic candidate for antiangiogenic osteosarcoma treatments.

A co-carrier for plasmid DNA and curcumin delivery to treat pancreatic cancer via dendritic poly(l-lysine) modified amylose.

Pancreatic cancer is one of the most lethal malignancies in the world and remains one of the leading causes of cancer related death. For its treatment, a lot of investigations have dealt not only with individual chemotherapy by using polymeric carriers to deliver anticancer drugs, but also with individual gene therapy by using polymeric carriers to deliver nucleic acids such as small interfering RNA (siRNA) and plasmid DNA. However, relatively few studies have been focused on the co-delivery of gene and anticancer drug by multifunctional polymeric carriers for its synergistic therapy. In this work, a DPLL-functionalized amylose (ADP) was prepared by the click reaction between azidized amylose and propargyl focal point poly(l-lysine) dendrons, and then used to co-deliver plasmid pIRES2-EGFP-TNFα and curcumin for pancreatic cancer treatment. Due to the internal hydrophobic cavity of amylose component, ADP could load efficiently curcumin with anticancer activity and showed a sustained release behavior. Moreover, the curcumin-loaded ADP could form colloidally stable nanocomplexes with plasmid DNA in aqueous system due to the existence of cationic poly(l-lysine) dendrons and exhibited high gene transfection efficiency. The in vitro and in vivo tests confirmed the effectiveness of using ADP to co-deliver plasmid pIRES2-EGFP-TNFα and curcumin for synergistic therapy of pancreatic cancer.

Eosinophilia in a patient with aggressive systemic mastocytosis harboring a KIT D816V mutation: A case report.

Eosinophilia may result from three main causes: secondary (reactive), primary (clonal), and/or idiopathic. The diagnosis of idiopathic eosinophilia must be made based on excluding all reactive or clonal causes. However, some causes may be very rare so as to be misdiagnosed as idiopathic. We present the case of eosinophilia caused by aggressive systemic mastocytosis, originally recognized as idiopathic. Lymphadenopathy, dysmyelopoiesis, and hepatosplenomegaly gradually appeared and deteriorated with increasing eosinophils. This case carried KIT D816V mutation. The BCR::ABL fusion gene and the mutations in JAK2 V617F, PDGFRα, and PDGFRß in bone marrow were all negative. PHF6, PPM1D, and TET2 mutations were demonstrable. The patient was prescribed to avapritinib. The condition was effectively controlled. However, the patient discontinued medication for economic reasons 5 months later. Disease progression happened and died 10 months after diagnosis. Our study indicates that gene mutation detection at diagnosis is helpful for patient accurate diagnosis and targeted therapy of such patients.

Particulate matter promotes the epithelial to mesenchymal transition in human lung epithelial cells via the ROS pathway.

OBJECTS: Epidemiologic studies have linked exposure to airborne pollutant particulate matter (PM) with increased rates of chronic cardiopulmonary diseases, including asthma and idiopathic pulmonary fibrosis (IPF). Several investigations have suggested that the epithelial-to-mesenchymal transition (EMT) may contribute to the complex pathobiology of environmental exposure-mediated pulmonary fibrosis. The present study was designed to characterize the mechanisms of PM-mediated EMT in human lung epithelial cells (HBECs). METHODS AND RESULTS: PM induced significant dose (0-100 µg/ml) and time (0-72 h)-dependent increases in transforming growth factor ß (TGFß) and fibronectin (FN) protein levels in HBECs lysates. PM-activated TGFß and FN protein production in HBECs was prevented by the antioxidant N-acetyl-cysteine (NAC, 5 mM). Furthermore, the NF-κB inhibitor BAY11-7082 (5 µM) abolished PM-induced FN production in HBECs. Biomarkers of EMT (ACTA2, SNAIL1 and SNAIL2) in PM-treated HBECs were significantly increased at the mRNA level compared to control cells. CONCLUSIONS: These results demonstrate that PM increases protein levels of TGFß and FN via reactive oxygen species (ROS)-dependent pathways. In addition, PM exposure induces EMT in human lung epithelial cells, supporting a novel mechanism for PM-induced pulmonary fibrosis.

Misdiagnosis of renal pelvic unicentric Castleman disease: a case report.

Castleman disease is a rare heterogeneous lymphoproliferative disorder of unknown etiology. Unicentric Castleman disease (UCD) is more common. UCD can occur at any site where lymphatic tissue exists, most commonly in the mediastinum, neck, and abdominal cavity, etc. in the current study, we reported a 46-year-old woman, who has left low back pain and discomfort. Magnetic resonance imaging (MRI) of the kidneys showed the left renal pelvis was occupied, left hydronephrosis, and the left renal hilum and retroperitoneal lymph nodes were enlarged. Enhanced kidney CT showed that the "pelvic tumor" was moderately enhanced in the bottom part in corticomedullary phase, while in nephrogenic phase, it was unevenly enhanced with a highly enhanced bottom part and weakly enhanced upper part. In excretory phase, reinforcement was decreased. "left renal pelvis tumor" was diagnosed and she underwent surgical treatment with left nephrectomy. However, histopathological examination indicated the UCD. We suggest that for renal pelvic tumors having imaging characteristics of homogeneous soft tissue density and heterogeneous CT enhancement, the hyaline vascular type of UCD could be taken into consideration for differential diagnosis.

Lysosome blockade induces divergent metabolic programs in macrophages and tumours for cancer immunotherapy.

BACKGROUND: Platinum-drugs based chemotherapy in clinic increases the potency of tumor cells to produce M2 macrophages, thus leading to poor anti-metastatic activity and immunosuppression. Lysosome metabolism is critical for cancer cell migration and invasion, but how it promotes antitumor immunity in tumours and macrophages is poorly understood and the underlying mechanisms are elusive. The present study aimed to explore a synergistic strategy to dismantle the immunosuppressive microenvironment of tumours and metallodrugs discovery by using the herent metabolic plasticity. METHODS: Naphplatin was prepared by coordinating an active alkaline moiety to cisplatin, which can regulate the lysosomal functions. Colorectal carcinoma cells were selected to perform the in vivo biological assays. Blood, tumour and spleen tissues were collected and analyzed by flow cytometry to further explore the relationship between anti-tumour activity and immune cells. Transformations of bone marrow derived macrophage (BMDM) and M2-BMDM to the M1 phenotype was confirmed after treatment with naphplatin. The key mechanisms of lysosome-mediated mucolipin-1(Mcoln1) and mitogen-activated protein kinase (MAPK) activation in M2 macrophage polarization have been unveiled. RNA sequencing (RNA-seq) was used to further explore the key mechanism underlying high-mobility group box 1(HMGB1)-mediated Cathepsin L(CTSL)-lysosome function blockade. RESULTS: We demonstrated that naphplatin induces divergent lysosomal metabolic programs and reprograms macrophages in tumor cells to terminate the vicious tumour-associated macrophages (TAMs)-MDSCs-Treg triangle. Mechanistically, macrophages treated with naphplatin cause lysosome metabolic activation by triggering Ca2+ release via Mcoln1, which induces the activation of p38 and nuclear factor-κB (NF-κB) and finally results in polarizing M2 macrophages. In contrast, HMGB1-mediated lysosome metabolic blockade in cancer cells is strongly linked to antitumor effects by promoting cytoplasmic translocation of HMGB1. CONCLUSIONS: This study reveals the crucial strategies of macrophage-based metallodrugs discovery that are able to treat both immunologically "hot" and "cold" cancers. Different from traditional platinum-based antitumour drugs by inhibition of DNAs, we also deliver a strong antitumour strategy by targeting lysosome to induce divergent metabolic programs in macrophages and tumours for cancer immunotherapy.