Two Key Descriptors for Designing Second Near-Infrared Dyes and Experimental Validation.

Second near-infrared (NIR-II) optical imaging technology has emerged as a powerful tool for diagnostic and image-guided surgery due to its higher imaging contrast. However, a general strategy for efficiently designing NIR-II organic molecules is still lacking, because NIR-II dyes are usually difficult to synthesize, which has impeded the rapid development of NIR-II bioprobes. Herein, based on the theoretical calculations on 62 multiaryl-pyrrole (MAP) systems with spectra ranging from the visible to the NIR-II region, a continuous red shift of the spectra toward the NIR-II region could be achieved by adjusting the type and site of substituents on the MAPs. Two descriptors (ΔEgs and µgs) were identified as exhibiting strong correlations with the maximum absorption/emission wavelengths, and the descriptors could be used to predict the emission spectrum in the NIR-II region only if ΔEgs ≤ 2.5 eV and µgs ≤ 22.55 D. The experimental absorption and emission spectra of ten MAPs fully confirmed the theoretical predictions, and biological imaging in vivo of newly designed MAP23-BBT showed high spatial resolution in the NIR-II region in deep tissue angiography. More importantly, both descriptors of ΔEgs and µgs have shown general applicability to most of the reported donor-acceptor-donor-type non-MAP NIR-II dyes. These results have broad implications for the efficient design of NIR-II dyes.

Novel inhalation therapy in pulmonary fibrosis: principles, applications and prospects.

Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.

Traditional Chinese medicine inspired dual-drugs loaded inhalable nano-therapeutics alleviated idiopathic pulmonary fibrosis by targeting early inflammation and late fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a highly debilitating and fatal chronic lung disease that is difficult to cure clinically. IPF is characterized by a gradual decline in lung function, which leads to respiratory failure and severely affects patient quality of life and survival. Oxidative stress and chronic inflammation are believed to be important pathological mechanisms underlying the onset and progression of IPF, and the vicious cycle of NOX4-derived ROS, NLRP3 inflammasome activation, and p38 MAPK in pulmonary fibrogenesis explains the ineffectiveness of single-target or single-drug interventions. In this study, we combined astragaloside IV (AS-IV) and ligustrazine (LIG) based on the fundamental theory of traditional Chinese medicine (TCM) of "tonifying qi and activating blood" and loaded these drugs onto nanoparticles (AS_LIG@PPGC NPs) that were inhalable and could penetrate the mucosal barrier. Our results suggested that inhalation of AS_LIG@PPGC NPs significantly improved bleomycin-induced lung injury and fibrosis by regulating the NOX4-ROS-p38 MAPK and NOX4-NLRP3 pathways to treat and prevent IPF. This study not only demonstrated the superiority, feasibility, and safety of inhalation therapy for IPF intervention but also confirmed that breaking the vicious cycle of ROS and the NLRP3 inflammasome is a promising strategy for the successful treatment of IPF. Moreover, this successful nanoplatform is a good example of the integration of TCM and modern medicine.

Biomimetic Nanovesicle with Mitochondria-Synthesized Sonosensitizer and Mitophagy Inhibition for Cancer Sono-Immunotherapy.

Mitochondria are crucial for both sonodynamic therapy and antitumor immunity. However, how to accurately damage mitochondria and meanwhile prevent the mitophagy and immune checkpoint inhibition is still a great challenge. Herein, hexyl 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) are loaded into the tumor cell-derived microparticle (X-MP), which can direct the target delivery of the prepared HAL/3MA@X-MP to the tumor cells. HAL induces the confined biosynthesis and accumulation of sonosensitizer PpIX in mitochondria, leading to the localized generation of reactive oxygen species (ROS) upon ultrasound irradiation and, thus, the efficient mitochondrial damage. Meanwhile, 3MA not only inhibits mitophagy but also down-regulates the PD-L1 expression, promoting the immunogenic cell death (ICD) while blocking the immune checkpoint recognition. The smart synergism of precise mitochondrial damage, mitophagy inhibition and antitumor immunity results in potent therapeutic efficacy without obvious side effects.

Proteomic profiling of gastric cancer with peritoneal metastasis identifies a protein signature associated with immune microenvironment and patient outcome.

BACKGROUND: Peritoneal metastasis (PM) frequently occurs in patients with gastric cancer (GC) and is a major cause of mortality. Risk stratification for PM can optimize decision making in GC treatment. METHODS: A total of 25 GC patients (13 with synchronous, 6 with metachronous PM and 6 PM-free) were included in this study. Quantitative proteomics by high-depth tandem mass tags labeling and whole-exome sequencing were conducted in primary GC and PM samples. Proteomic signature and prognostic model were established by machine learning algorithms in PM and PM-free GC, then validated in two external cohorts. Tumor-infiltrating immune cells in GC were analyzed by CIBERSORT. RESULTS: Heterogeneity between paired primary and PM samples was observed at both genomic and proteomic levels. Compared to primary GC, proteome of PM samples was enriched in RNA binding and extracellular exosomes. 641 differently expressed proteins (DEPs) between primary GC of PM group and PM-free group were screened, which were enriched in extracellular exosome and cell adhesion pathways. Subsequently, a ten-protein signature was derived based on DEPs by machine learning. This signature was significantly associated with patient prognosis in internal cohort and two external proteomic datasets of diffuse and mixed type GC. Tumor-infiltrating immune cell analysis showed that the signature was associated with immune microenvironment of GC. CONCLUSIONS: We characterized proteomic features that were informative for PM progression of GC. A protein signature associated with immune microenvironment and patient outcome was derived, and it could guide risk stratification and individualized treatment.

NAMPT encapsulated by extracellular vesicles from young adipose-derived mesenchymal stem cells treated tendinopathy in a "One-Stone-Two-Birds" manner.

BACKGROUND: Tendinopathy is the leading sports-related injury and will cause severe weakness and tenderness. Effective therapy for tendinopathy remains limited, and extracellular vesicles (EVs) derived from adipose tissue-derived mesenchymal stem cells (ADMSCs) have demonstrated great potential in tendinopathy treatment; however, the influence of aging status on EV treatment has not been previously described. RESULTS: In this study, it was found that ADMSCs derived from old mice (ADMSCold) demonstrated remarkable cellular senescence and impaired NAD+ metabolism compared with ADMSCs derived from young mice (ADMSCyoung). Lower NAMPT contents were detected in both ADMSCold and its secreted EVs (ADMSCold-EVs). Advanced animal experiments demonstrated that ADMSCyoung-EVs, but not ADMSCold-EVs, alleviated the pathological structural, functional and biomechanical properties in tendinopathy mice. Mechanistic analyses demonstrated that ADMSCyoung-EVs improved cell viability and relieved cellular senescence of tenocytes through the NAMPT/SIRT1/PPARγ/PGC-1α pathway. ADMSCyoung-EVs, but not ADMSCold-EVs, promoted phagocytosis and M2 polarization in macrophages through the NAMPT/SIRT1/Nf-κb p65/NLRP3 pathway. The macrophage/tenocyte crosstalk in tendinopathy was influenced by ADMSCyoung-EV treatment and thus it demonstrated "One-Stone-Two-Birds" effects in tendinopathy treatment. CONCLUSIONS: This study demonstrates an effective novel therapy for tendinopathy and uncovers the influence of donor age on curative effects by clarifying the detailed biological mechanism.

Efficacy of emergency extracorporeal shock wave lithotripsy in the treatment of ureteral stones: a meta-analysis.

OBJECTIVE: To compare the clinical efficiency and safety of emergency extracorporeal shock wave lithotripsy (eESWL) and delayed extracorporeal shock wave lithotripsy (dESWL) in the treatment of ureteral stones. METHODS: Cochrane Library, PubMed, Google Scholar, and Web of Science were searched from January 1, 1992 to September 30, 2022, and all comparative studies involving eESWL and dESWL for ureteral calculi were included. Statistical analysis was performed using Review Manager 5.3 software. Funnel plot was used to evaluated publication bias. RESULTS: A total of 9 articles involving 976 patients diagnosed with ureteral stones were included. The results showed that the stone-free rate (SFR) after four weeks was significantly higher in the eESWL group than in the dESWL group [relative risk (RR) = 1.22, 95% confidence interval (CI): 1.13-1.32, P < 0.01]. In subgroup analysis of different stone locations, proximal ureteral calculi [RR = 1.25, 95% CI: 1.14-1.38, P < 0.01] and mid-to-distal ureteral calculi [RR = 1.18, 95% CI: 1.03-1.34, P < 0.05] all showed a higher SFR in the eESWL group. eESWL significantly shortened the stone-free time(SFT) [mean difference (MD) = -5.75, 95% CI: -9.33 to -2.17, P < 0.01]. In addition, eESWL significantly reduced auxiliary procedures [RR = 0.53, 95% CI: 0.40-0.70, P < 0.01]. No significant difference in complications was found between the two groups [RR = 0.90, 95% CI: 0.69-1.16, P > 0.05]. CONCLUSION: eESWL can significantly improve SFR, shorten SFT, and reduce auxiliary procedures.

Phytochemical Engineered Bacterial Outer Membrane Vesicles for Photodynamic Effects Promoted Immunotherapy.

Cancer vaccines are emerging as an attractive modality for tumor immunotherapy. However, their practical application is seriously impeded by the complex fabrication and unsatisfactory outcomes. Herein, we construct bacterial outer membrane vesicles (OMVs)-based in situ cancer vaccine with phytochemical features for photodynamic effects-promoted immunotherapy. By simply fusing thylakoid membranes with OMVs, bacteria-plant hybrid vesicles (BPNs) are prepared. After systemic administration, BPNs can target tumor tissues and stimulate the activation of immune cells, including dendritic cells (DCs). The photodynamic effects derived from thylakoid lead to the disruption of local tumors and then the release of tumor-associated antigens that are effectively presented by DCs, inducing remarkable tumor-specific CD8+T cell responses. Moreover, BPNs can efficiently ameliorate the immunosuppressive tumor microenvironment and further boost immune responses. Therefore, both tumor development and metastasis can be efficiently prevented. This work provides a novel idea for developing a versatile membrane-based hybrid system for highly efficient tumor treatment.

Multiple Bioactivities of Peptides from Hydrolyzed Misgurnus anguillicaudatus.

Misgurnus anguillicaudatus (loach) is a widely distributed benthic fish in Asia. In this study, the alkaline protease was used to hydrolyze loach, and the hydrolysate products of different molecular weights were obtained by membrane separation. In vitro antioxidant assays showed that the <3 kDa fraction (SLH-1) exhibited the strongest antioxidant activity (DPPH, hydroxyl radical and superoxide radical scavenging ability, and reducing power), while SLH-1 was purified by gel filtration chromatography, and peptide sequences were identified by LC-MS/MS. A total of six peptides with antioxidant activity were identified, namely SERDPSNIKWGDAGAQ (D-1), TVDGPSGKLWR (D-2), NDHFVKL (D-3), AFRVPTP (D-4), DAGAGIAL (D-5), and VSVVDLTVR (D-6). In vitro angiotensin-converting enzyme (ACE) inhibition assay and pancreatic cholesterol esterase (CE) inhibition assay, peptide D-4 (IC50 95.07 µg/mL, 0.12 mM) and D-2 inhibited ACE, and peptide D-2 (IC50 3.19 mg/mL, 2.62 mM), D-3, and D-6 acted as pancreatic CE inhibitors. The inhibitory mechanisms of these peptides were investigated by molecular docking. The results showed that the peptides acted by binding to the key amino acids of the catalytic domain of enzymes. These results could provide the basis for the nutritional value and promote the type of healthy products from hydrolyzed loach.

Monitoring the Cascade of Tumor-specific Immune Response in vivo via Chemoenzymatic Proximity Labeling.

Monitoring the highly dynamic and complex immune response remains a great challenge owing to the lack of reliable and specific approaches. Here, we develop a strategy to monitor the cascade of tumor immune response through the cooperation of pore-forming alginate gel with chemoenzymatic proximity-labeling. A macroporous gel containing tumor-associated antigens, adjuvants, and pro-inflammatory cytokines is utilized to recruit endogenous DCs and enhance their maturation in vivo. The mature DCs are then modified with GDP-fucose-fucosyltransferase (GDP-Fuc-Fuct) via the self-catalysis of fucosyltransferase (Fuct). Following the migration of the obtained Fuct-DCs to the draining lymph nodes (dLNs), the molecular recognition mediated interaction of DCs and T cells leads to the successful decoration of T cells with GDP-Fuc-azide through the Fuct catalyzed proximity-labeling. Therefore, the activated tumor-specific T cells in dLNs and tumors can be identified through bioorthogonal labeling, opening up a new avenue for studying the immune mechanism of tumors in situ.

Smart Tumor-Cell-Derived Microparticles Provide On-Demand Photosensitizer Synthesis and Hypoxia Relief for Photodynamic Therapy.

Positioning essential elements of photodynamic therapy (PDT) near to mitochondria can conquer the rigorous spatiotemporal limitations of reactive oxygen species (ROS) transfer and make considerable differences in PDT. However, precise accumulation of photosensitizer (PS) and oxygen within mitochondria is still challenging. We simultaneously encapsulated hexyl 5-aminolevulinate hydrochloride (HAL) and 3-bromopyruvic acid (3BP) into microparticles collected from X-ray-irradiated tumor cells (X-MP). After systemic administration, the developed HAL/3BP@X-MP can specifically target and recognize tumor cells, where HAL induces efficient accumulation of PpIX in mitochondria via the intrinsic haem biosynthetic pathway. Meanwhile, 3BP remarkably increases the oxygen supply by inhibiting mitochondrial respiration. The accurate co-localization and prompt encounter of PpIX and oxygen produce sufficient ROS to directly disrupt mitochondria, resulting in significantly improved PDT outcomes.

Molecularly Engineered Macrophage-Derived Exosomes with Inflammation Tropism and Intrinsic Heme Biosynthesis for Atherosclerosis Treatment.

Atherosclerosis (AS) is a major contributor to cardiovascular diseases worldwide, and alleviating inflammation is a promising strategy for AS treatment. Here, we report molecularly engineered M2 macrophage-derived exosomes (M2 Exo) with inflammation-tropism and anti-inflammatory capabilities for AS imaging and therapy. M2 Exo are derived from M2 macrophages and further electroporated with FDA-approved hexyl 5-aminolevulinate hydrochloride (HAL). After systematic administration, the engineered M2 Exo exhibit excellent inflammation-tropism and anti-inflammation effects via the surface-bonded chemokine receptors and the anti-inflammatory cytokines released from the anti-inflammatory M2 macrophages. Moreover, the encapsulated HAL can undergo intrinsic biosynthesis and metabolism of heme to generate anti-inflammatory carbon monoxide and bilirubin, which further enhance the anti-inflammation effects and finally alleviate AS. Meanwhile, the intermediate protoporphyrin IX (PpIX) of the heme biosynthesis pathway permits the fluorescence imaging and tracking of AS.

Responsive Exosome Nano-bioconjugates for Synergistic Cancer Therapy.

Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize responsive exosome nano-bioconjugates for cancer therapy. Azide-modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne-modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH-sensitive linkers. After systemic administration, the nano-bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic-imine bonds of the nano-bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished "don't eat me" signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro-tumoral M2 to anti-tumoral M1.

Entrepreneurial failure influences the health of Chinese farmers: Evidence from the data of China labor-force dynamic survey.

High failure rate is a primary characteristic of current farmer entrepreneurial activities in China. We examined the impact of entrepreneurial failure on the health of Chinese farmers based on the data from the China Labor-force Dynamics Survey (CLDS). We found that entrepreneurial failure significantly depresses the health of Chinese farmers. Specifically, the farmers with entrepreneurial failure experience are more likely to have low self-reported levels of psychological and physical health, and the probability of experiencing severe injury and illness is elevated by 4.6 %. Mechanism analysis shows that entrepreneurial failure depresses the health of Chinese farmers through weakening informal social support and increasing the probability of overwork. Furthermore, these effects are more significant in the older generation of farmers who were born before 1980 and the farmers striving to make a living.

Metal-polyphenol "prison" attenuated bacterial outer membrane vesicle for chemodynamics promoted in situ tumor vaccines.

As natural adjuvants, the bacterial outer membrane vesicles (OMV) hold great potential in cancer vaccines. However, the inherent immunotoxicity of OMV and the rarity of tumor-specific antigens seriously hamper the clinical translation of OMV-based cancer vaccines. Herein, metal-phenolic networks (MPNs) are used to attenuate the toxicity of OMV, meanwhile, provide tumor antigens via the chemodynamic effect induced immunogenic cell death (ICD). Specifically, MPNs are assembled on the OMV surface through the coordination reaction between ferric ions and tannic acid. The iron-based "prison" is locally collapsed in the tumor microenvironment (TME) with both low pH and high ATP features, and thus the systemic toxicity of OMV is significantly attenuated. The released ferric ions in TME promote the ICD of cancer cells through Fenton reaction and then the generation of abundant tumor antigens, which can be used to fabricate in-situ vaccines by converging with OMV. Together with the immunomodulatory effect of OMV, potent tumor repression on a bilateral tumor model is achieved with good biosafety.

A combination of multiple LC-MS approaches for the comprehensive characterization of cysteine-linked ADCs.

Antibody-drug conjugates (ADCs) represent the forefront of the next generation of biopharmaceuticals. An ADC typically comprises an antibody covalently linked to a cytotoxic drug via a linker, resulting in a highly heterogeneous product. This study focuses on the analysis of a custom-made cysteine-linked ADC. Initially, we developed a LC-MS-based characterization workflow using brentuximab vedotin (Adcetris®), encompassing native intact MS, analysis of reduced chains and subunits under denaturing condition, peptide mapping and online strong cation exchange chromatography coupled with UV and mass spectrometry detection (SCX-UV-MS) applied for brentuximab vedotin first time reported. Subsequently, we applied this in-depth characterization workflow to a custom-made cysteine-linked ADC. The measured drug-to-antibody ratio(DAR) of this ADC is 6.9, further analysis shown that there is a small amount of unexpected over-conjugation. Over-conjugation sites were successfully identified using multiple UHPLC-MS based characterization techniques. Also, one competitively cysteine-conjugated impurity was observed in native intact MS results, by combing native intact MS, reduced chains, subunit analysis and peptide mapping results, the impurity conjugation sites were also identified. Since this molecule is at early development stage, this provides important information for conjugation process improvement and link-drug material purification. SCX-UV-MS approach can separate the custom-made cysteine-linked ADC carrying different payloads and reduce the complexity of the spectra. The integrated approach underscores the significance of combining the SCX-UV-MS online coupling technique with other characterization methods to elucidate the heterogeneity of cysteine-linked ADCs.

The role of FERMT2 in the tumor microenvironment and immunotherapy in pan-cancer using comprehensive single-cell and bulk sequencing.

FERMT2 has been identified as a participant in integrin-linked kinase signaling pathways, influencing epithelial-mesenchymal transition and thereby affecting tumor initiation, progression, and invasion. While the character of FERMT2 in the tumor microenvironment (TME) as well as its implications for immunotherapy remain unclear. Thus, we conducted a comprehensive analysis to assess the prognostic significance of FERMT2 using Kaplan-Meier analysis. In addition, we employed enrichment analysis to uncover potential underlying molecular mechanisms. Using "Immunedeconv" package, we evaluated the immune characteristics of FERMT2 within TME. Furthermore, we determined the expression levels of FERMT2 in various cell types within TME, based on single-cell sequencing data. To confirm the co-expression of FERMT2 and markers of cancer-associated fibroblasts (CAFs), we performed multiplex immunofluorescence staining on tissue paraffin sections across various cancer types. Our analysis disclosed a significant correlation between elevated FERMT2 expression and unfavorable prognosis in specific cancer types. Furthermore, we identified a strong correlation between FERMT2 expression and diverse immune-related factors, including immune checkpoint molecules, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB). Additionally, there was a significant correlation between FERMT2 expression and immune-related pathways, particularly those associated with activating, migrating, and promoting the growth of fibroblasts in diverse cancer types. Interestingly, we observed consistent co-expression of FERMT2 in both malignant tumor cells and stromal cells, particularly within CAFs. Notably, our findings also indicated that FERMT2, in particular, exhibited elevated expression levels within tumor tissues and co-expressed with α-SMA in CAFs based on the multiplex immunofluorescence staining results.

New evidence on the impact of No-tillage management on agricultural carbon emissions.

Controlling agricultural carbon emissions contributes to achieving peak carbon emissions and carbon neutrality. However, as a conservation management practice of farmland, the impact of No-tillage management (NTM) on agricultural carbon emissions needs to be further discussed. The main purpose of this paper is to assess the direct effect and spatial spillover effect of NTM on agricultural carbon emissions, revealing the regulating mechanism of NTM on agricultural carbon emissions and the combined application of NTM. Results indicate that NTM reduces agricultural carbon emissions, which is significant in the central and western regions, along with the primary grain, corn, and rice production areas, as well as the northern regions of the Huai River. Furthermore, the spatial spillover analysis reveals that the implementation of NTM increases agricultural carbon emissions in neighboring regions, but financial support and cross-regional services can negatively regulate the relationship between NTM and space agricultural carbon emissions. This paper also finds that combining straw-returning technology and NTM reduces agricultural carbon emissions. Building a cross-regional coordination mechanism, an incentive mechanism, and innovating the conservation tillage model is essential for promoting the NTM and achieving agricultural carbon reduction.

Recent Advances for Dynamic-Based Therapy of Atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease, which may lead to high morbidity and mortality. Currently, the clinical treatment strategy for AS is administering drugs and performing surgery. However, advanced therapy strategies are urgently required because of the deficient therapeutic effects of current managements. Increased number of energy conversion-based organic or inorganic materials has been used in cancer and other major disease treatments, bringing hope to patients with the development of nanomedicine and materials. These treatment strategies employ specific nanomaterials with specific own physiochemical properties (external stimuli: light or ultrasound) to promote foam cell apoptosis and cholesterol efflux. Based on the pathological characteristics of vulnerable plaques, energy conversion-based nano-therapy has attracted increasing attention in the field of anti-atherosclerosis. Therefore, this review focuses on recent advances in energy conversion-based treatments. In addition to summarizing the therapeutic effects of various techniques, the regulated pathological processes are highlighted. Finally, the challenges and prospects for further development of dynamic treatment for AS are discussed.

Identification of a pyroptosis-based model for predicting clinical outcomes from immunotherapy in patients with metastatic melanoma.

Immunotherapy has greatly improved outcomes for patients with advanced melanoma, but good predictive biomarkers remain lacking in clinical practice. Although increasing evidence has revealed a vital role of pyroptosis in the tumor microenvironment (TME), it remains unclear for pyroptosis as a predictive biomarker for immunotherapy in melanoma. RNA sequencing data and annotated clinical information of melanoma patients were obtained from four published immunotherapy datasets. LASSO regression analysis was conducted to develop a pyroptosis-based model for quantifying a pyroptosis score in each tumor. Based on four clinical cohorts, we evaluated the predictive capability of the model using multiple immunotherapeutic outcomes, including clinical benefits, overall survival (OS), and progression-free survival (PFS). Furthermore, we depicted the distinctive TME features associated with pyroptosis. Compared with the group with low pyroptosis scores, the group with high pyroptosis scores consistently achieved better durable clinical benefits in four independent cohorts and the meta-cohort. ROC analysis validated that the pyroptosis-based model was a reliable biomarker for predicting clinical benefits from immunotherapy in melanoma. Survival analyses showed that the group with high pyroptosis scores harbored more favorable OS and PFS than those with low pyroptosis scores. Molecular analysis revealed that tumors with high pyroptosis scores displayed a typical immune-inflamed phenotype in TME, including enrichment of immunostimulatory pathways, increased level of tumor-infiltrating lymphocytes, upregulation of immune effectors, and activation of the antitumor immune response. Our findings suggested that the pyroptosis-related model associated with multiple immune-inflamed characteristics might be a reliable tool for predicting clinical benefit and survival outcomes from immunotherapy in melanoma.