The Seventh Affiliated Hospital of Sun Yat-sen University

2019-nCoV is a newly identified coronavirus with high similarity to SARS-CoV. We performed a structural analysis of the receptor binding domain (RBD) of spike glycoprotein responsible for entry of coronaviruses into host cells. The RBDs from the two viruses share 72% identity in amino acid sequences, and molecular simulation reveals highly similar ternary structures. However, 2019-nCoV has a distinct loop with flexible glycyl residues replacing rigid prolyl residues in SARS-CoV. Molecular modeling revealed that 2019-nCoV RBD has a stronger interaction with angiotensin converting enzyme 2 (ACE2). A unique phenylalanine F486 in the flexible loop likely plays a major role because its penetration into a deep hydrophobic pocket in ACE2. ACE2 is widely expressed with conserved primary structures throughout the animal kingdom from fish, amphibians, reptiles, birds, to mammals. Structural analysis suggests that ACE2 from these animals can potentially bind RBD of 2019-nCoV, making them all possible natural hosts for the virus. 2019-nCoV is thought to be transmitted through respiratory droplets. However, since ACE2 is predominantly expressed in intestines, testis, and kidney, fecal-oral and other routes of transmission are also possible. Finally, antibodies and small molecular inhibitors that can block the interaction of ACE2 with RBD should be developed to combat the virus.

The accelerating and thorough treatment of chronic wounds still represents a major unmet medical need owing to the complex symptoms resulting from metabolic disorder of the wound microenvironment. Although numerous strategies and bioactive hydrogels are developed, an effective and widely used method of chronic wound treatment remains a bottleneck. With the aim to accelerate chronic wound healing, many hydrogel dressings with antioxidant functions have emerged and are proven to accelerate wound healing, especially for chronic wound repair. The new strategy in chronic wound treatment brought by antioxidant hydrogels is of great significance to human health. Here, the application of antioxidant hydrogels in the repair of chronic wounds is discussed systematically, aiming to provide an important theoretical reference for the further breakthrough of chronic wound healing.

Abstract The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1 + TIM-3 + T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3 + cytotoxic CD8 T cells and immunosuppressive regulatory T cells (T reg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes T reg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon β and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.

Abstract Until now there has been no fundamental theory applicable for biodegradable metals (BMs). First, this paper optimizes the definition of BMs given in 2014. Second, the dual criteria of biodegradability and biocompatibility are proposed for BMs, and all metallic elements in the periodic table with accessible data are screened on the basis of these criteria. Regarding biodegradability, electrode potential, reactivity series, galvanic series, Pilling–Bedworth ratio, and Pourbaix diagrams are all adopted as parameters to classify the degradable and nondegradable nature of a material, especially in a physiological environment. Considering the biocompatibility at different levels, cellular biocompatibility, tissue biocompatibility, and human/clinical related biocompatibility parameters are put forward to comprehensively evaluate the biosafety of BMs. Third, for the material design of BMs, mechanical properties, chemical properties, physical properties and biological properties should be considered and balanced to guarantee that the degradation behavior of BMs match well with a tissue regeneration/repair procedure as the function of time and spatial location. Besides the selected metallic elements, some nonmetallic elements are selected as suitable alloying elements for BMs. Finally, five classification/research directions for future BMs are proposed: biodegradable pure metals, crystalline alloys, bulk metallic glasses, high entropy alloys, and metal matrix composites.

Abstract The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically 1,2 . This results in substantial accumulation of lacate, the end product of anaerobic glycolysis, in cancer cells 3 . However, how cancer metabolism affects chemotherapy response and DNA repair in general remains incompletely understood. Here we report that lactate-driven lactylation of NBS1 promotes homologous recombination (HR)-mediated DNA repair. Lactylation of NBS1 at lysine 388 (K388) is essential for MRE11–RAD50–NBS1 (MRN) complex formation and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. Furthermore, we identify TIP60 as the NBS1 lysine lactyltransferase and the ‘writer’ of NBS1 K388 lactylation, and HDAC3 as the NBS1 de-lactylase. High levels of NBS1 K388 lactylation predict poor patient outcome of neoadjuvant chemotherapy, and lactate reduction using either genetic depletion of lactate dehydrogenase A (LDHA) or stiripentol, a lactate dehydrogenase A inhibitor used clinically for anti-epileptic treatment, inhibited NBS1 K388 lactylation, decreased DNA repair efficacy and overcame resistance to chemotherapy. In summary, our work identifies NBS1 lactylation as a critical mechanism for genome stability that contributes to chemotherapy resistance and identifies inhibition of lactate production as a promising therapeutic cancer strategy.

Abstract Cuproptosis, a newly identified form of regulated cell death that is copper‐dependent, offers great opportunities for exploring the use of copper‐based nanomaterials inducing cuproptosis for cancer treatment. Here, a glucose oxidase (GOx)‐engineered nonporous copper(I) 1,2,4‐triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], for starvation‐augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be “turned on” for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@[Cu(tz)]‐mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper‐induced toxicity. The increased intracellular hydrogen peroxide (H 2 O 2 ) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@[Cu(tz)]. The in vivo experimental results indicate that GOx@[Cu(tz)] produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis.

Hydrogels based on natural polymers have bright application prospects in biomedical fields due to their outstanding biocompatibility and biodegradability. However, the poor mechanical performances of pure natural polymer-based hydrogels greatly limit their application prospects. Recently, a variety of strategies has been applied to prepare natural polymer-based hydrogels with enhanced mechanical properties, which generally exhibit stiffening, strengthening, and stretchable behaviors. This article summarizes the recent progress of natural polymer-based hydrogels with enhanced mechanical properties. From a structure point of view, four kinds of hydrogel are reviewed; double network hydrogels, nanocomposite hydrogels, click chemistry-based hydrogels, and supramolecular hydrogels. For each typical hydrogel, its preparation, structure, and mechanical performance are introduced in detail. At the end of this article, the current challenges and future prospects of hydrogels based on natural polymers are discussed and it is pointed out that 3D printing may offer a new platform for the development of natural polymer-based hydrogels.

Skin cancer has emerged as the fifth most commonly reported cancer in the world, causing a burden on global health and the economy. The enormously rising environmental changes, industrialization, and genetic modification have further exacerbated skin cancer statistics. Current treatment modalities such as surgery, radiotherapy, conventional chemotherapy, targeted therapy, and immunotherapy are facing several issues related to cost, toxicity, and bioavailability thereby leading to declined anti-skin cancer therapeutic efficacy and poor patient compliance. In the context of overcoming this limitation, several nanotechnological advancements have been witnessed so far. Among various nanomaterials, nanoparticles have endowed exorbitant advantages by acting as both therapeutic agents and drug carriers for the remarkable treatment of skin cancer. The small size and large surface area to volume ratio of nanoparticles escalate the skin tumor uptake through their leaky vasculature resulting in enhanced therapeutic efficacy. In this context, the present review provides up to date information about different types and pathology of skin cancer, followed by their current treatment modalities and associated drawbacks. Furthermore, it meticulously discusses the role of numerous inorganic, polymer, and lipid-based nanoparticles in skin cancer therapy with subsequent descriptions of their patents and clinical trials.

Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.

Resistance to cancer therapies has been a commonly observed phenomenon in clinical practice, which is one of the major causes of treatment failure and poor patient survival. The reduced responsiveness of cancer cells is a multifaceted phenomenon that can arise from genetic, epigenetic, and microenvironmental factors. Various mechanisms have been discovered and extensively studied, including drug inactivation, reduced intracellular drug accumulation by reduced uptake or increased efflux, drug target alteration, activation of compensatory pathways for cell survival, regulation of DNA repair and cell death, tumor plasticity, and the regulation from tumor microenvironments (TMEs). To overcome cancer resistance, a variety of strategies have been proposed, which are designed to enhance the effectiveness of cancer treatment or reduce drug resistance. These include identifying biomarkers that can predict drug response and resistance, identifying new targets, developing new targeted drugs, combination therapies targeting multiple signaling pathways, and modulating the TME. The present article focuses on the different mechanisms of drug resistance in cancer and the corresponding tackling approaches with recent updates. Perspectives on polytherapy targeting multiple resistance mechanisms, novel nanoparticle delivery systems, and advanced drug design tools for overcoming resistance are also reviewed.

COVID-19 has a significant impact on public health and poses a challenge to medical staffs, especially to front-line medical staffs who are exposed to and in direct contact with patients. To understand the psychological stress status of medical staffs during the outbreak of COVID-19, random sample questionnaire survey was conducted among 2110 medical staffs and 2158 college students in all provinces of China through a questionnaire, which was compiled and completed through the Questionnaire Star platform relying on Wechat, QQ, and other social software. The differences in psychological stress status of different groups were compared through the analysis of the questionnaire. Results revealed that in all provinces of China, medical staffs scored significantly higher on all items of psychological stress than college students (P < .001). In Wuhan, medical staffs scored significantly higher than college students in all items of psychological stress (P < .001). While among medical staffs, the group in Wuhan area scored significantly higher than the group outside Wuhan on the following items: "Thought of being in danger," "The possibility of self-illness," "Worrying about family infection" (P < .05), "Poor sleep quality," "Needing psychological guidance," and "Worrying about being infected" (P < .01) in the Psychological Stress Questionnaire, but on the item "Confidence in the victory of the epidemic," the group in Wuhan area scored significantly lower than the group outside Wuhan (P < .05). The emotion, cognition, physical, and mental response of front-line medical staff showed obvious "exposure effect", which calls for a psychological crisis intervention strategy that can be helpful.

Current treatment approaches for spinal cord injuries (SCIs) are mainly based on cellular transplantation. Induced pluripotent stem cells (iPSCs) without supply constraints and ethical concerns have emerged as a viable treatment option for repairing neurological disorders. However, the primarily limitations in the neuroregeneration field are uncontrolled cell differentiation, and low cell viability caused by the ischemic environment. The mechanical property of three-dimensional (3D) hydrogel can be easily controlled and shared similar characteristics with nerve tissue, thus promoting cell survival and controlled cell differentiation. We propose the combination of a 3D gelatin methacrylate (GelMA) hydrogel with iPSC-derived NSCs (iNSCs) to promote regeneration after SCI. In vitro, the iNSCs photoencapsulated in the 3D GelMA hydrogel survived and differentiated well, especially in lower-moduli hydrogels. More robust neurite outgrowth and more neuronal differentiation were detected in the soft hydrogel group. To further evaluate the in vivo neuronal regeneration effect of the GelMA hydrogels, a mouse spinal cord transection model was generated. We found that GelMA/iNSC implants significantly promoted functional recovery. Further histological analysis showed that the cavity areas were significantly reduced, and less collagen was deposited in the GelMA/iNSC group. Furthermore, the GelMA and iNSC combined transplantation decreased inflammation by reducing activated macrophages/microglia (CD68-positive cells). Additionally, GelMA/iNSC implantation showed striking therapeutic effects of inhibiting GFAP-positive cells and glial scar formation while simultaneously promoting axonal regeneration. Undoubtedly, use of this 3D hydrogel stem cell-loaded system is a promising therapeutic strategy for SCI repair.

This study aimed to evaluate the global incidence and mortality trends of breast cancer among females by region and age in the past decade. We retrieved country-specific incidence and mortality data from the Global Cancer Observatory up to 2018 and Cancer Incidence in Five Continents volumes I-XI, the Nordic Cancer Registries, the Surveillance, Epidemiology, and End Results, and WHO mortality database up to 2016. The temporal patterns were using Average Annual Percent Change (AAPC) with the 95% confidence interval (CI) by joinpoint regression analysis. Most countries showed an increasing trend in incidence. For the older population aged ≥ 50 years, Japan (5.63, 4.90-6.36), Slovakia (3.63, 3.03-4.22), China (2.86, 2.00-3.72) reported the most prominent increase. For young females (<50 years), Japan (AAPC=3.81, 95% CI=2.71-4.93), Germany (AAPC=2.60, 95% CI=1.41-3.81) and Slovakia (1.91, 1.13-2.69) reported the most drastic rise. Similarly, 12 countries showed an incidence increase among women aged <40 years. As for mortality, the Philippines (4.36, 3.65-5.07), Thailand (4.35, 3.12-5.59), Colombia (0.75, 0.08-1.42), and Brazil (0.44, 0.19-0.68) reported a significant increase. The disease burden of breast cancer showed an increasing trend in a large number of populations. More preventive efforts are recommended for these countries. Further research should explore the underlying reasons for these epidemiological trends.

BACKGROUND: Many countries and regions have experienced male fertility problems due to various influencing factors, especially in less developed countries. Unlike female infertility, male infertility receives insufficient attention. Understanding the changing patterns of male infertility in the world, different regions and different countries is crucial for assessing the global male fertility and reproductive health. METHODS: We obtained data on prevalence, years of life lived with disability (YLD), age-standardized rates of prevalence (ASPR) and age-standardized YLD rate (ASYR) from the Global Burden of Disease Study 2019. We analyzed the burden of male infertility at all levels, including global, regional, national, age stratification and Socio-demographic Index (SDI). RESULTS: In 2019, the global prevalence of male infertility was estimated to be 56,530.4 thousand (95% UI: 31,861.5-90,211.7), reflecting a substantial 76.9% increase since 1990. Furthermore, the global ASPR stood at 1,402.98 (95% UI: 792.24-2,242.45) per 100,000 population in 2019, representing a 19% increase compared to 1990. The regions with the highest ASPR and ASYR for male infertility in 2019 were Western Sub-Saharan Africa, Eastern Europe, and East Asia. Notably, the prevalence and YLD related to male infertility peaked in the 30-34 year age group worldwide. Additionally, the burden of male infertility in the High-middle SDI and Middle SDI regions exceeded the global average in terms of both ASPR and ASYR. CONCLUSION: The global burden of male infertility has exhibited a steady increase from 1990 to 2019, as evidenced by the rising trends in ASPR and ASYR, particularly in the High-middle and Middle SDI regions. Notably, the burden of male infertility in these regions far exceeds the global average. Additionally, since 2010, there has been a notable upward trend in the burden of male infertility in Low and Middle-low SDI regions. Given these findings, it is imperative to prioritize efforts aimed at improving male fertility and reproductive health.

Background: Accumulating evidence has shown that disorders in the gut microbiota and derived metabolites affect the development of atherosclerotic cardiovascular disease (ASCVD). However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of their alterations remain unclear. Methods: We performed integrated microbiome–metabolome analysis of 30 patients with coronary artery disease (CAD) and 30 age- and sex-matched healthy controls to identify CAD-associated microbial metabolites, which were then assessed in an independent population of patients with ASCVD and controls (n=256). We further investigate the effect of CAD-associated microbial metabolites on atherosclerosis and the mechanisms of the action. Results: Indole-3-propionic acid (IPA), a solely microbially derived tryptophan metabolite, was the most downregulated metabolite in patients with CAD. Circulating IPA was then shown in an independent population to be associated with risk of prevalent ASCVD and correlated with the ASCVD severity. Dietary IPA supplementation alleviates atherosclerotic plaque development in ApoE −/− mice. In murine- and human-derived macrophages, administration of IPA promoted cholesterol efflux from macrophages to ApoA-I through an undescribed miR-142-5p/ABCA1 (ATP-binding cassette transporter A1) signaling pathway. Further in vivo studies demonstrated that IPA facilitates macrophage reverse cholesterol transport, correlating with the regulation of miR-142-5p/ABCA1 pathway, whereas reduced IPA production contributed to the aberrant overexpression of miR-142-5p in macrophages and accelerated the progression of atherosclerosis. Moreover, the miR-142-5p/ABCA1/reverse cholesterol transport axis in macrophages were dysregulated in patients with CAD, and correlated with the changes in circulating IPA levels. Conclusions: Our study identify a previously unknown link between specific gut microbiota-derived tryptophan metabolite and ASCVD. The microbial metabolite IPA/miR-142-5p/ABCA1 pathway may represent a promising therapeutic target for ASCVD.

This study aimed to examine the global burden, risk factors, and trends of esophageal cancer based on age, sex, and histological subtype. The data were retrieved from cancer registries database from 48 countries in the period 1980-2017. Temporal patterns of incidence and mortality were evaluated by average annual percent change (AAPC) using joinpoint regression. Associations with risk factors were examined by linear regression. The highest incidence of esophageal cancer was observed in Eastern Asia. The highest incidence of adenocarcinoma (AC) was found in the Netherlands, the United Kingdom, and Ireland. A higher AC/squamous cell carcinoma (SCC) incidence ratio was associated with a higher prevalence of obesity and elevated cholesterol. We observed an incidence increase (including AC and SCC) in some countries, with the Czech Republic (female: AAPC 4.66), Spain (female: 3.41), Norway (male: 3.10), Japan (female: 2.18), Thailand (male: 2.17), the Netherlands (male: 2.11; female: 1.88), and Canada (male: 1.51) showing the most significant increase. Countries with increasing mortality included Thailand (male: 5.24), Austria (female: 3.67), Latvia (male: 2.33), and Portugal (male: 1.12). Although the incidence of esophageal cancer showed an overall decreasing trend, an increasing trend was observed in some countries with high AC/SCC incidence ratios. More preventive measures are needed for these countries.

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.

Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg−1min−1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.

Long noncoding RNAs (lncRNAs) play important roles in regulating the development and progression of many cancers. However, the clinical significance of specific lncRNAs in the context of nasopharyngeal carcinoma (NPC) and the molecular mechanisms by which they regulate this form of cancer remain largely unclear. In this study we found that the lncRNA PVT1 was upregulated in NPC, and that in patients this upregulation was associated with reduced survival. RNA sequencing revealed that PVT1 was responsible for regulating NPC cell proliferation and for controlling a hypoxia-related phenotype in these cells. PVT1 knockdown reduced NPC cell proliferation, colony formation, and tumorigenesis in a subcutaneous mouse xenograft model systems. We further found that PVT1 serves as a scaffold for the chromatin modification factor KAT2A, which mediates histone 3 lysine 9 acetylation (H3K9), recruiting the nuclear receptor binding protein TIF1β to activate NF90 transcription, thereby increasing HIF-1α stability and promoting a malignant phenotype in NPC cells. Overexpression of NF90 or HIF-1α restored the proliferation in cells that had ceased proliferating due to PVT1 or KAT2A depletion. Conversely, overexpression of active KAT2A or TIF1β, but not of KAT2A acetyltransferase activity-deficient mutants or TIF1β isoforms lacking H3K9ac binding sites, promoted a PVT1-mediated increase in NF90 transcription, as well as increased HIF-1α stability and cell proliferation. PVT1 knockdown enhanced the radiosensitization effect in NPC cells via inhibiting binding between H3K9ac and TIF1β in a manner. Taken together, our results demonstrate that PVT1 serves an oncogenic role and plays an important role in radiosensitivity in malignant NPC via activating the KAT2A acetyltransferase and stabilizing HIF-1α.

Both T-cell deprivation and insufficient tumor immunogenicity seriously hinder the efficacy of immune-mediated tumor destruction in melanoma. In this work, an amphiphilic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) copolymer with a thermally sensitive flowable core (mPEG-b-PHEP) was chosen to incorporate IR780 dye and manganese zinc sulfide nanoparticles (ZMS) to form polymer micelles (denoted PPIR780-ZMS), which precisely controlled the release of ZMS after being triggered by near-infrared light (NIR). Mn2+-mediated chemodynamic therapy (CDT) by photothermal trigger boosted the generation of reactive oxygen species (ROS), making the PPIR780-ZMS smart bomblets in vivo. It was demonstrated that PPIR780-ZMS could maximize immunogenic cell death (ICD) in cancer, which is characterized by abundant damage-associated molecular pattern (DAMP) exposure. As a result, the cytotoxic T cells (CD8+) and helper T cells (CD4+) expanded and infiltrated the neoplastic foci, which further reprogrammed the suppressive tumor microenvironment (TME) against the primary tumor and pulmonary metastases with safe systemic cytokine expression. In addition, Mn2+-mediated cGAS-STING signaling pathway activation enhanced the antitumor immunity of this nanocomposite, providing a practical strategy for expanding the use of Mn-based nanostructures.