Pan-cancer characterization of cell-free immune-related miRNA identified as a robust biomarker for cancer diagnosis.

Minimally invasive testing is essential for early cancer detection, impacting patient survival rates significantly. Our study aimed to establish a pioneering cell-free immune-related miRNAs (cf-IRmiRNAs) signature for early cancer detection. We analyzed circulating miRNA profiles from 15,832 participants, including individuals with 13 types of cancer and control. The data was randomly divided into training, validation, and test sets (7:2:1), with an additional external test set of 684 participants. In the discovery phase, we identified 100 differentially expressed cf-IRmiRNAs between the malignant and non-malignant, retaining 39 using the least absolute shrinkage and selection operator (LASSO) method. Five machine learning algorithms were adopted to construct cf-IRmiRNAs signature, and the diagnostic classifies based on XGBoost algorithm showed the excellent performance for cancer detection in the validation set (AUC: 0.984, CI: 0.980-0.989), determined through 5-fold cross-validation and grid search. Further evaluation in the test and external test sets confirmed the reliability and efficacy of the classifier (AUC: 0.980 to 1.000). The classifier successfully detected early-stage cancers, particularly lung, prostate, and gastric cancers. It also distinguished between benign and malignant tumors. This study represents the largest and most comprehensive pan-cancer analysis on cf-IRmiRNAs, offering a promising non-invasive diagnostic biomarker for early cancer detection and potential impact on clinical practice.

MOF-on-MOF Heterostructured Electrocatalysts for Efficient Nitrate Reduction to Ammonia.

Electrocatalytic nitrate reduction reaction (NO3-RR) is an important route for sustainable NH3 synthesis and environmental remediation. Metal-organic frameworks (MOFs) are one family of promising NO3-RR electrocatalysts, however, there is plenty of room to improve in their performance, calling for new design principles. Herein, a MOF-on-MOF heterostructured electrocatalyst with interfacial dual active sites and build-in electric field is fabricated for efficient NO3-RR to NH3 production. By growing Co-HHTP (HHTP=2,3,6,7,10,11-hexahydroxytriphenylene) nanorods on Ni-BDC (BDC=1,4-benzenedicarboxylate) nanosheets, experimental and theoretical investigations demonstrate the formation of Ni-O-Co bonds at the interface of MOF-on-MOF heterostructure, leading to dual active sites tailed for NO3-RR. The Ni sites facilitate the adsorption and activation of NO3-, while the Co sites boost the H2O decomposition to supply active hydrogen (Hads) for N-containing intermediates hydrogenation on adjacent Ni sites, cooperatively reducing the energy barriers of NO3-RR process. Together with the accelerated electron transfer enabled by built-in electric field, remarkable NO3-RR performance is achieved with an NH3 yield rate of 11.46 mg h-1 cm-2 and a Faradaic efficiency of 98.4%, outperforming most reported MOF-based electrocatalysts. This work provides new insights into the design of high-performance NO3-RR electrocatalysts.

Nanoporous Heterojunction Photocatalysts with Engineered Interfacial Sites for Efficient Photocatalytic Nitrogen Fixation.

Photocatalytic N2 reduction reaction (PNRR) offers a promising strategy for sustainable production of ammonia (NH3). However, the reported photocatalysts suffer from low efficiency with great room to improve regarding the charge carrier utilization and active site engineering. Herein, a porous and chemically bonded heterojunction photocatalyst is developed for efficient PNRR to NH3 production via hybridization of two semiconducting metal-organic frameworks (MOFs), MIL-125-NH2 (MIL=Material Institute Lavoisier) and Co-HHTP (HHTP=2,3,6,7,10,11-hexahydroxytripehenylene). Experimental and theoretical results demonstrate the formation of Ti-O-Co chemical bonds at the interface, which not only serve as atomic pathway for S-scheme charge transfer, but also provide electron-deficient Co centers for improving N2 chemisorption/activation capability and restricting competitive hydrogen evolution. Moreover, the nanoporous structure allows the transportation of reactants to the interfacial active sites at heterojunction, enabling the efficient utilization of charge carriers. Consequently, the rationally designed MOF-based heterojunction exhibits remarkable PNRR performance with an NH3 production rate of 2.1 mmol g-1 h-1, an apparent quantum yield (AQY) value of 16.2% at 365 nm and a solar-to-chemical conversion (SCC) efficiency of 0.28%, superior to most reported PNRR photocatalysts. Our work provides new insights into the design principles of high-performance photocatalysts.

Nanoarchitectonics of S-Scheme Heterojunction Photocatalysts: A Nanohouse Design Improves Photocatalytic Nitrate Reduction to Ammonia Performance.

Photocatalytic nitrate reduction reaction (NitRR) is a promising route for environment remediation and sustainable ammonia synthesis. To design efficient photocatalysts, the recently emerged nanoarchitectonics approach holds great promise. Here, we report a nanohouse-like S-scheme heterjunction photocatalyst with high photocatalytic NitRR performance. The nano-house has a floor of plate-like metal organic framework-based photocatalyst (NH2-MIL-125), on which another photocatalyst Co(OH)2 nanosheet is grown while ZIF-8 hollow cages are also constructed as the surrounding wall/roof. Experimental and simulation results indicate that the positively charged, highly porous and hydrophobic ZIF-8 wall can modulate the environment in the nanohouse by (i) NO3 - enrichment/NH4 + discharge and (ii) suppression of the competitive hydrogen evolution reaction. In combination with the enhanced electron-hole separation and strong redox capability in the NH2-MIL-125@Co(OH)2 S-scheme heterjunction confined in the nano-house, the designed photocatalyst delivers an ammonia yield of 2454.9 µmol g-1 h-1 and an apparent quantum yield of 8.02 % at 400 nm in pure water. Our work provides new insights into the design principles of advanced photocatalytic NitRR photocatalyst.

Perfect Is Perfect: Nickel Prussian Blue Analogue as A High-Efficiency Electrocatalyst for Hydrogen Peroxide Production.

Prussian blue analogues (PBA) are a large family of functional materials with diverse applications such as in electrochemical fields. However, their use in the emerging two-electron oxygen reduction reaction for clean production of hydrogen peroxide (H2O2) is lagging. Herein, a general solvent exchange induced reconstruction strategy is demonstrated, through which an abnormal NiNi-PBA superstructure is synthesized as a high-performance electrocatalyst for H2O2 generation. The resultant NiNi-PBA superstructure has a stoichiometric composition with saturated lattice water, and a leaf-like morphology composed of interconnected small-size nanosheets with identical orientation and predominate {210} side surface exposure. Our studies show that the Ni-N centers on {210} facets are the active sites, and the saturated lattice H2O favors a six-coordinated environment that results in high selectivity. The "perfect" structure including stoichiometric composition and ideal facet exposure leads to a high selectivity of ~100% and H2O2 yield of 5.7 mol g-1 h-1, superior to the reported MOF-based electrocatalysts and most other electrocatalysts.

High-efficiency Electroreduction of O2 into H2 O2 over ZnCo Bimetallic Triazole Frameworks Promoted by Ligand Activation.

Co-based metal-organic frameworks (MOFs) as electrocatalysts for two-electron oxygen reduction reaction (2e- ORR) are highly promising for H2 O2 production, but suffer from the intrinsic activity-selectivity trade-off. Herein, we report a ZnCo bimetal-triazole framework (ZnCo-MTF) as high-efficiency 2e- ORR electrocatalysts. The experimental and theoretical results demonstrate that the coordination between 1,2,3-triazole and Co increases the antibonding-orbital occupancy on the Co-N bond, promoting the activation of Co center. Besides, the adjacent Zn-Co sites on 1,2,3-triazole enable an asymmetric "side-on" adsorption mode of O2 , favoring the reduction of O2 molecules and desorption of OOH* intermediate. By virtue of the unique ligand effect, the ZnCo-MTF exhibits a 2e- ORR selectivity of ≈100 %, onset potential of 0.614 V and H2 O2 production rate of 5.55 mol gcat -1 h-1 , superior to the state-of-the-art zeolite imidazole frameworks. Our work paves the way for the design of 2e- ORR electrocatalysts with desirable coordination and electronic structure.

Crystal Engineering Enables Cobalt-Based Metal-Organic Frameworks as High-Performance Electrocatalysts for H2O2 Production.

Metal-organic frameworks (MOFs) with highly adjustable structures are an emerging family of electrocatalysts in two-electron oxygen reduction reaction (2e-ORR) for H2O2 production. However, the development of MOF-based 2e-ORR catalysts with high H2O2 selectivity and production rate remains challenging. Herein, an elaborate design with fine control over MOFs at both atomic and nano-scale is demonstrated, enabling the well-known Zn/Co bimetallic zeolite imidazole frameworks (ZnCo-ZIFs) as excellent 2e-ORR electrocatalysts. Experimental results combined with density functional theory simulation have shown that the atomic level control can regulate the role of water molecules participating in the ORR process, and the morphology control over desired facet exposure adjusts the coordination unsaturation degree of active sites. The structural regulation at two length scales leads to synchronous control over both the kinetics and thermodynamics for ORR on bimetallic ZIF catalysts. The optimized ZnCo-ZIF with a Zn/Co molar ratio of 9/1 and predominant {001} facet exposure exhibits a high 2e- selectivity of ∼100% and a H2O2 yield of 4.35 mol gcat-1 h-1. The findings pave a new avenue toward the development of multivariate MOFs as advanced 2e-ORR electrocatalysts.

Identifying the Role of the Cationic Geometric Configuration in Spinel Catalysts for Polysulfide Conversion in Sodium-Sulfur Batteries.

An AB2X4 spinel structure, with tetrahedral A and octahedral B sites, is a paradigmatic class of catalysts with several possible geometric configurations and numerous applications, including polysulfide conversion in metal-sulfur batteries. Nonetheless, the influence of the geometric configuration and composition on the mechanisms of catalysis and the precise manner in which spinel catalysts facilitate the conversion of polysulfides remain unknown. To enable controlled exposure of single active configurations, herein, Cotd2+ and Cooh3+ in Co3O4 catalysts for sodium polysulfide conversion are in large part replaced by Fetd2+ and Feoh3+, respectively, generating FeCo2O4 and CoFe2O4. Through an examination of electrochemical activation energies, the characterization of symmetric cells, and theoretical calculations, we determine that Cooh3+ serves as the active site for the breaking of S-S bonds, while Cotd2+ functions as the active site for the formation of S-Na bonds. The current study underlines the subtle relationship between activity and geometric configurations of spinel catalysts, providing unique insights for the rational development of improved catalysts by optimizing their atomic geometric configuration.

Immuno-oncological role of 20S proteasome alpha-subunit 3 in aggravating the progression of esophageal squamous cell carcinoma.

PSMA3, a member of the proteasome subunit, has been shown to play a major player in protein degradation. Reportedly, PSMA3 functions as a negative regulator in various cancers including colon, pancreatic and gastric cancers. However, the contributions of PSMA3 to the progression of esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remain unclear. Therefore, in this study, we investigated whether PSMA3 is involved in ESCC progression and the potential underlying mechanism. The results revealed that PSMA3 was highly expressed in the ESCC tumor tissues and functioned as a negative indicator according to the data from The Cancer Genome Atlas (TCGA)/Gene Expression Omnibus (GEO) datasets and clinical patients' samples. Pathway enrichment analysis showed that PSMA3 was closely correlated with ESCC cancer stemness and the inflammatory response; however, this correlation was absent after knockdown of PSMA3 in vitro. We further demonstrated that PSMA3 suppressed CD8+ T-cells infiltration depending on the C-C motif chemokine ligand 3 (CCL3)/C-C motif chemokine receptor 5 (CCR5) axis. Collectively, these results demonstrate the role of PSMA3 in ESCC cancer stemness and the negative regulation of CD8 T-cells infiltration mediated by PSMA3. The results of this study may provide a potential target for the immuno-oncology effect of PSMA3 in ESCC therapy.

Humanized mouse models with endogenously developed human natural killer cells for in vivo immunogenicity testing of HLA class I-edited iPSC-derived cells.

Human induced pluripotent stem cells (hiPSCs) genetically depleted of human leucocyte antigen (HLA) class I expression can bypass T cell alloimmunity and thus serve as a one-for-all source for cell therapies. However, these same therapies may elicit rejection by natural killer (NK) cells, since HLA class I molecules serve as inhibitory ligands of NK cells. Here, we focused on testing the capacity of endogenously developed human NK cells in humanized mice (hu-mice) using MTSRG and NSG-SGM3 strains to assay the tolerance of HLA-edited iPSC-derived cells. High NK cell reconstitution was achieved with the engraftment of cord blood-derived human hematopoietic stem cells (hHSCs) followed by the administration of human interleukin-15 (hIL-15) and IL-15 receptor alpha (hIL-15Rα). Such "hu-NK mice" rejected HLA class I-null hiPSC-derived hematopoietic progenitor cells (HPCs), megakaryocytes and T cells, but not HLA-A/B-knockout, HLA-C expressing HPCs. To our knowledge, this study is the first to recapitulate the potent endogenous NK cell response to non-tumor HLA class I-downregulated cells in vivo. Our hu-NK mouse models are suitable for the non-clinical evaluation of HLA-edited cells and will contribute to the development of universal off-the-shelf regenerative medicine.

Costimulatory molecule expression profile as a biomarker to predict prognosis and chemotherapy response for patients with small cell lung cancer.

Owing to the paucity of specimens, progress in identifying prognostic and therapeutic biomarkers for small cell lung cancer (SCLC) has been stagnant for decades. Considering that the costimulatory molecules are essential elements in modulating immune responses and determining therapeutic response, we systematically revealed the expression landscape and identified a costimulatory molecule-based signature (CMS) to predict prognosis and chemotherapy response for SCLCs for the first time. We found T cell activation was restrained in SCLCs, and costimulatory molecules exhibited widespread abnormal genetic alterations and expression. Using a LASSO Cox regression model, the CMS was built with a training cohort of 77 cases, which successfully divided patients into high- or low-risk groups with significantly different prognosis and chemotherapy benefit (both P < 0.001). The CMS was well validated in an independent cohort containing 131 samples with qPCR data. ROC and C-index analysis confirmed the superior predictive performance of the CMS in comparison with other clinicopathological parameters from different cohorts. Importantly, the CMS was confirmed as a significantly independent prognosticator for clinical outcomes and chemotherapy response in SCLCs through multivariate Cox analysis. Further analysis revealed that low-risk patients were characteristic by an activated immune phenotype with distinct expression of immune checkpoints. In summary, we firstly uncovered the expression heterogeneity of costimulatory molecules in SCLC and successfully constructed a novel predictive CMS. The identified signature contributed to more accurate patient stratification and provided robust prognostic value in estimating survival and the clinical response to chemotherapy, allowing optimization of treatment and prognosis management for patients with SCLC.

Spatial Specific Janus S-Scheme Photocatalyst with Enhanced H2 O2 Production Performance.

Photocatalytic oxygen reduction reaction (ORR) for H2 O2 production in the absence of sacrificing agents is a green approach and of great significance, where the design of photocatalysts with high performance is the central task. Herein, a spatial specific S-scheme heterojunction design by introducing a novel semiconducting pair with a S-scheme mechanism in a purpose-designed Janus core-shell-structured hollow morphology is reported. In this design, TiO2 nanocrystals are grown inside the inner wall of resorcinol-formaldehyde (RF) resin hollow nanocakes with a reverse bumpy ball morphology (TiO2 @RF). The S-scheme heterojunction preserves the high redox ability of the TiO2 and RF pair, the spatial specific Janus design enhances the charge separation, promotes active site exposure, and reduces the H2 O2 decomposition to a large extent. The TiO2 @RF photocatalyst shows a high H2 O2 yield of 66.6 mM g-1  h-1 and solar-to-chemical conversion efficiency of 1.11%, superior to another Janus structure (RF@TiO2 ) with the same heterojunction but a reversed Janus spatial arrangement, and most reported photocatalysts under similar reaction conditions. The work has paved the way toward the design of next-generation photocatalysts for green synthesis of H2 O2 production.

A Pacman-Like Titanium-Doped Cobalt Sulfide Hollow Superstructure for Electrocatalytic Oxygen Evolution.

Transition-metal sulfides (TMSs) are attractive oxygen evolution reaction (OER) electrocatalysts. Developing new strategies to improve their electrochemical performance of TMSs is of great significance. Herein, a unique pacman-like titanium-doped cobalt sulfide hollow superstructure (Ti-CoSx HSS) is fabricated as an OER electrocatalyst. Using a prearranged metal-organic framework (MOF)-on-MOF heterostructure as a precursor treated by one-pot sulfidation, a sequential structural conversion process leads to the formation of Ti-CoSx HSS, which is assembled by interconnected Ti-doped CoSx nanocages around a cake-like cavity. Benefiting from the architecture and compositional advantages, Ti-CoSx HSS exhibits excellent OER performance with an overpotential of 249 mV at 10 mA cm-2 and Tafel slope of 45.5 mV dec-1 due to increased active site exposure, enhanced electron and mass transfer. This strategy enabled by MOF-on-MOF paves the way toward innovative MOF derivatives for various applications.

A novel immune checkpoints-based signature to predict prognosis and response to immunotherapy in lung adenocarcinoma.

BACKGROUND: Except for B7-CD28 family members, more novel immune checkpoints are being discovered. They are closely associated with tumor immune microenvironment and regulate the function of many immune cells. Various cancer therapeutic studies targeting these novel immune checkpoints are currently in full swing. However, studies concerning novel immune checkpoints phenotypes and clinical significance in lung adenocarcinoma (LUAD) are still limited. METHODS: We enrolled 1883 LUAD cases from nine different cohorts. The samples from The Cancer Genome Atlas (TCGA) were used as a training set, whereas seven microarray data cohorts and an independent cohort with 102 qPCR data were used for validation. The immune profiles and potential mechanism of the system were also explored. RESULTS: After univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a novel immune checkpoints-based system (LTA, CD160, and CD40LG) were identified from the training set, which significantly stratified patients into high- and low-risk groups with different survivals. Furthermore, this system has been well validated in different clinical subgroups and multiple validation cohorts. It also acted as an independent prognostic factor for patients with LAUD in different cohorts. Further exploration suggested that high-risk patients exhibited distinctive immune cells infiltration and suffered an immunosuppressive state. Additionally, this system is closely linked to various classical immunotherapy biomarkers. CONCLUSION: we constructed a novel immune checkpoints-based system for LUAD, which predicts prognosis and immunotherapeutic implications. We believe that these findings will not only aid in clinical management but will also shed some light on screening appropriate patients for immunotherapy.

Metformin Enhances the Antitumor Activity of CD8+ T Lymphocytes via the AMPK-miR-107-Eomes-PD-1 Pathway.

Metformin has been studied for its anticancer effects by regulating T cell functions. However, the mechanisms through which metformin stimulates the differentiation of memory T cells remain unclear. We found that the frequencies of memory stem and central memory T cells increased for both in peripheral and tumor-infiltrating CD8+ T cells in metformin-treated lung cancer patients compared with those not taking the medication. An in vitro assay showed that metformin promoted the formation of memory CD8+ T cells and enhanced their antiapoptotic abilities. In addition, AMP-activated protein kinase (AMPK) activation decreased microRNA-107 expression, thus enhancing Eomesodermin expression, which suppressed the transcription of PDCD1 in metformin-treated CD8+ T cells. In the CAR-T cell therapy model, metformin also exhibited cytotoxicity-promoting effects that led to decreased tumor growth. Metformin could reprogram the differentiation of CD8+ T cells, which may benefit the clinical therapy of cancer patients by facilitating long-lasting cytotoxic functions.

ZnO nanoparticles embedded in hollow carbon fiber membrane for electrochemical H2O2 production by two-electron water oxidation reaction.

Electrochemical two-electron water oxidation reaction (2e-WOR) provides a promising alternative route for hydrogen peroxide (H2O2) production, where the design of earth abundant and environmentally friendly electrocatalysts with both high selectivity and production rate is crucial. Here we report the synthesis of ZnO nanoparticles embedded in hollow carbon fiber membrane as efficient 2e-WOR electrocatalyst by a metal-organic framework engaged electrospinning-pyrolysis method. The resultant ZnO@carbon composite fiber exhibits a foam-like hierarchical structure composed of interconnected hollow carbon nanocubes encapsulated with oxygen vacancy rich ZnO nanocrystals. Owing to the improved selectivity of ZnO, excellent conductivity of carbon fiber, promoted active site exposure and mass transfer of hollow structure, the free-standing membrane electrode shows superior 2e-WOR performances with high selectivity (83.8% at 2.8 V vs. RHE), H2O2 generation rate (19.7 µmol cm-2 min-1) and robust stability.

Morphological Anisotropy in Metal-Organic Framework Micro/Nanostructures.

Anisotropy plays a unique role in the structural regulation of metal-organic frameworks (MOFs) and their composites, especially at the micro- and nanoscale. However, there is a lack of a understanding of MOF micro/nanoparticles (MNPs) from the perspective of morphological anisotropy. In this Minireview, recent advances in anisotropic MOF MNPs are summarized, with a focus on how morphological anisotropy leads to innovative structures and modulates properties. First, anisotropic pristine MOF MNPs with diverse morphologies are introduced and classified by their morphology-dependent and morphology-independent anisotropy. Secondly, the anisotropy-enabled site-selective higher-order construction of MOF-based materials is highlighted. Finally, challenges and prospects for anisotropic MOFs are discussed, aiming to provide inspiration for further developments in this interesting research field.

Spin Effect to Promote Reaction Kinetics and Overall Performance of Lithium-Sulfur Batteries under External Magnetic Field.

Lithium-sulfur batteries (LSBs) are still limited by the shuttle of lithium polysulfides (LiPS) and the slow Li-S reaction. Herein, we demonstrate that when using cobalt sulfide as a catalytic additive, an external magnetic field generated by a permanent magnet can significantly improve the LiPS adsorption ability and the Li-S reaction kinetics. More specifically, the results show both experimentally and theoretically how an electron spin polarization of Co ions reduces electron repulsion and enhances the degree of orbital hybridization, thus resulting in LSBs with unprecedented performance and stability. Under an external magnetic field, LSBs with 0.0084 % per cycle decay rate at 2 C during 8150 cycles are produced. Overall, this work not only demonstrates an effective strategy to promote LiPS adsorption and electrochemical conversion in LSBs at no additional energy cost but also enriches the application of the spin effect in the electrocatalysis fields.

Regulatory T cells promote glioma cell stemness through TGF-ß-NF-κB-IL6-STAT3 signaling.

Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-ß secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-ß acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB-IL6-STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-ß were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy-with or without immune checkpoint inhibitors (anti-PDs)-is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. METHODS: We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts-including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients' responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. RESULTS: We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75-9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. CONCLUSIONS: Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.