Background Cardiac issues following radiotherapy are increasingly prevalent among patients with thoracic cancer and coronary disease. However, the mechanisms underlying radiotherapy-induced plaque instability and changes in plaque characteristics on imaging remain unclear. This study used single-cell RNA sequencing to identify key features of vulnerable plaques following radiotherapy.Methods We applied dual-mode synchronized optical coherence tomography-intravascular ultrasound imaging in a rabbit model to reveal the characteristics of vulnerable plaques at various time points postradiotherapy. We then conducted single-cell RNA sequencing on atherosclerotic lesions from ApoE-/- (apolipoprotein E-/-) mice across 3 stages: nonirradiated, early irradiation, and advanced irradiation. Bioinformatics was used to analyze cell populations, trajectories, and interaction differences among the groups. This was followed by pathological staining, flow cytometry, gene knockout, and antibody depletion.Results In vivo optical coherence tomography-intravascular ultrasound imaging at the initial stage accurately evaluated radiation exposure's effect on the stability of rabbit carotid plaques. High-throughput single-cell transcriptomics mapped the radiotherapy-induced immune system remodeling in atherosclerotic lesions, and identified a granzyme K+ CD8+ (cluster of differentiation 8+) T-cell subpopulation. The infiltrating cells highly expressed the cytotoxic molecule GZMB (granzyme B) in the plaques. The absence of CD8+ T cells or GZMB ameliorated radiotherapy-exacerbated atherosclerotic lesions. This demonstrates the pathogenic function of GZMK+ (granzyme K+) CD8+ cytotoxic T cells in promoting radiotherapy-induced atherosclerotic lesion progression.Conclusions We identified characteristic arterial imaging changes resulting from radiation injury, accurately and dynamically assessing the effects of radiation exposure on plaque stability. Radiation exposure affected plaque stability by modulating GZMK+ CD8+ T-cell activation and GZMB function, suggesting GZMB as a mediator of radio-cardiovascular injury and a potential therapeutic target.

Background:Uncommon epidermal growth factor receptor (EGFR) gene mutant locally advanced non-small cell lung cancer (NSCLC) has been poorly documented in the literature. Our study aimed to investigate the clinical features and outcomes associated with these mutations. Methods:A multi-center retrospective study was conducted to review 511 patients with EGFR mutant unresectable stage III lung adenocarcinoma, treated between 2012 and 2018 across 12 Chinese institutions. The patients were categorized into three groups based on their primary treatment: chemoradiotherapy (CRT), EGFR-TKIs (tyrosine kinase inhibitors), and radiotherapy (RT) combined with EGFR-TKIs. Results:Among the 511 patients, 49 (9.6%) had uncommon EGFR mutations. Of these, 37 had detailed systemic treatment information. The uncommon mutations included exon 18 G719X (22.4%), exon 20 insertion (18.4%), exon 20 S768I (8.2%), T790M (8.2%), and exon 21 L861Q (4.1%). Compound mutations were identified in 34.7% of patients. There was a significant difference in progression-free survival (PFS) for uncommon and common mutation group (median 11.9 vs. 17.5 months, P=0.005). However, no significant difference was observed in overall survival (OS, P=0.14). The median PFS for the uncommon mutation group was 11.9 months for CRT (n=12, 32.4%), 5.0 months for EGFR-TKIs (n=16, 43.2%), and 14.8 months for RT combined with TKIs (n=9, 23.4%) (P=0.02). The median OS for the same groups were 43.6 months, 30.9 months, and not reached, respectively (P=0.18). Compared to EGFR-TKIs, both CRT and RT combined with TKIs significantly improved PFS (P=0.02, 0.04, respectively), and showed a trend toward superior OS compared to EGFR-TKIs (P=0.49, 0.06, respectively). Conclusions:This study was the first to systematically summarize the clinical features and outcomes of unresectable locally advanced lung adenocarcinoma, with uncommon EGFR mutations. RT combined with sensitivity EGFR-TKIs may be a promising treatment option, while CRT remains the primary treatment choice.

Consolidation durvalumab following no progression on concurrent chemoradiotherapy (cCRT) is standard of care for unresectable stage III non-small-cell lung cancer (NSCLC). However, in clinical practice many patients receive sequential CRT (sCRT). The PACIFIC-5 trial aimed to evaluate the efficacy and safety of consolidation durvalumab for unresectable stage III NSCLC following no progression on cCRT or sCRT. This randomised, double-blind, placebo-controlled, phase III trial enrolled patients aged ≥ 18 years with unresectable stage III NSCLC, regardless of PD-L1 expression or sensitising EGFR or ALK aberrations, without disease progression after cCRT or sCRT. Patients were randomised (2:1) to durvalumab 1500 mg or placebo intravenously every 4 weeks (stratified by tumour PD-L1 expression and prior treatment) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival (PFS) by blinded independent central review in the modified intention-to-treat population (mITT). Secondary endpoints included overall survival (OS) in the mITT and safety. The safety analysis set include patients who received at least one dose of study treatment. Of 407 patients randomised to receive durvalumab (n = 272) or placebo (n = 135), 405 received at least one dose of durvalumab (n = 271) or placebo (n = 134). The mITT comprised 381 patients randomised to durvalumab (n = 252) or placebo (n = 129). Durvalumab showed statistically significant improvement in PFS versus placebo in the mITT (median [95

BACKGROUND AND AIMS:Methylmalonic acid (MMA) is involved in myocardial mitochondrial damage and energy metabolism disorders. We sought to investigate the association of MMA with subclinical myocardial injury and its incremental value in predicting cardiovascular mortality risk based on conventional risk factors and cardiac biomarkers. METHODS:This study included 11,373 participants aged ≥18 years without prevalent cardiovascular disease (CVD). The cross-sectional associations of MMA with subclinical elevation of cardiac biomarkers (high-sensitivity cardiac troponin [hs-cTn] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]), and their prospective associations with long-term mortality, were assessed. The predictive performance for 10-year cardiovascular mortality was estimated. RESULTS:The association between MMA and elevated cardiac biomarkers was significant with a dose-response pattern. Compared with participants in the lowest quartile of MMA, the multivariable-adjusted rate ratios (95% CIs) in the highest quartile for elevated hs-cTnT and NT-proBNP were 2.35 (1.64-3.37) and 1.35 (1.12-1.62), respectively (each p trend <0.001). Strikingly, the cardiovascular mortality risk associated with elevated hs-cTnT or NT-proBNP was at least two-fold higher in adults with elevated MMA levels than in those with lower MMA levels. The adjusted hazard ratios (95% CIs) of elevated hs-cTnT for cardiovascular mortality were 1.58 (1.00-2.50) among individuals with MMA ≤125 nmol/L and 2.45 (1.94-3.11) among participants with MMA >125nmol/L. CONCLUSION:MMA accumulation is independently associated with subclinical myocardial injury before cardiovascular events occur. These findings support the additional value of mitochondria-related indicators to guide cardiac biomarker-based screening of populations at high risk for cardiovascular events.

Objective:This study aimed to evaluate whether integrating the TeamSTEPPS model with PEARLS structured debriefing improves teamwork competencies and clinical decision-making among radiotherapy residents, compared to traditional simulation teaching, and to assess its broader applicability in medical education. Methods:From June to December 2023, 36 standardized training residents from the Radiotherapy Department of Harbin Medical University Cancer Hospital were selected and randomly assigned to an experimental group and a control group, each with 18 participants, using a random number table The experimental group underwent scenario-based simulation teaching incorporating the TeamSTEPPS model and PEARLS structured debriefing, while the control group received traditional simulation teaching. Post-intervention, a unified quantitative assessment evaluated theoretical knowledge, skill performance, and simulation performance in both groups. Additionally, satisfaction levels were assessed via questionnaire. Results:The experimental group exhibited significantly higher scores in theoretical knowledge (88.55±6.52) and skill performance (87.68±18.42) compared to the control group (71.63±5.69 and 58.96±11.47, respectively; P<0.05). The experimental group exhibited statistically significant improvements in teamwork competencies, including communication (23.22±2.21 vs 21.43±3.77, P<0.05), leadership (23.40±2.22 vs 22.19±3.51, P<0.05), situational awareness (18.95±1.61 vs 17.62±2.64, P<0.05), and mutual support (27.93±2.92 vs 25.69±5.76, P<0.05). The experimental group's higher satisfaction (94.44% vs 77.78%, P<0.05) underscores the potential of this integrated approach to address systemic challenges in clinical education, such as fragmented teamwork training and insufficient reflective practice. These findings suggest that combining TeamSTEPPS with PEARLS could serve as a replicable framework for multidisciplinary medical training programs aiming to enhance both technical proficiency and collaborative care. Conclusion:The innovative combined teaching method applied in this study to scenario-based simulation teaching in radiation oncology can significantly enhance residents' theoretical knowledge, skill performance, and team collaboration abilities.This methodology exhibits notable advantages in clinical teaching within the radiotherapy department and with potential applicability to multidisciplinary medical education and standardized residency programs.

Background: owing to the intricate nature, variability, and persistent oxygen-deficient environment associated with esophageal cancer (EC) tissues, radiotherapy (RT) sometimes doesn't work as well because some cancer cells can resist the radiation to a certain extent. This can lead to the cancer coming back in the same spot or even making the treatment ineffective. The integration of RT with oxygenation strategies is a common approach in cancer treatment. The advent of oxygen-enhancing sonodynamic therapy (SDT), leveraging the cytotoxic effects of reactive oxygen species (ROS), has garnered significant attention as an innovative approach to inducing cell death. Methods: this study utilized nanobubbles (NBs) containing the acoustic sensitizer indocyanine green (ICG) to create a nanoplatform (ICG@O2 NBs) that incorporates oxygen-enhanced SDT and RT. Besides, NBs are paired with low-frequency ultrasound (LFUS), known as ultrasound-targeted nano-bubble destruction (UTND), for precise drug release and improved safety. Results: experimental findings, including JC-1/DCFH-DA assays, demonstrate that ICG@O2 NBs effectively enhance the performance of both RT and SDT. RNA sequencing (RNA-seq) demonstrated differential expression of mRNA and LncRNA prior to and after co-treatment. KEGG and GO pathway analysis were then conducted for enriching and recognizing target genes and pathways correlated with the sensitivity of RT, which were revealed to be remarkably clustered in RT-associated pathways. Conclusion: in vitro and in vivo investigations have indicated significant efficacy of synergistic treatments, highlighting the potential of combining NBs with SDT and RT for managing EC.

BACKGROUND AND AIMS:Viral myocarditis is an inflammatory pathology of the myocardium that involves innate immune responses, especially those involving neutrophils. However, strategies targeting neutrophils to alleviate inflammation have not achieved complete success. Alpha lipoic acid (ALA), a natural organosulfur compound, has the capacity to modulate immune cell behavior. This study aimed to investigate whether ALAs can regulate innate immunity to provide protection against coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS:Abdominal administration of ALA improved cardiac dysfunction and reduced mortality in a CVB3-induced mouse model of myocarditis (VM). ALA treatment induced neutrophils and inhibited Ly6Chi pro-inflammatory macrophages, favoring a reparatory environment in the myocardium. However, depleting neutrophils with anti-Ly6G antibodies increased Ly6Chi pro-inflammatory macrophage recruitment in blood and heart in ALA-treated VM mice. Further flow cytometry analysis indicated that ALA promoted Ym-1 expression of neutrophils. Blocking Ym-1 significantly reversed ALA-mediated cardiac reparative macrophages infiltration and cardiac function improvement post-VM. Recombinant Ym-1 drives macrophages toward a reparative phenotype and attenuates CVB3-induced viral myocarditis. Mechanistically, ALA reprogrammed neutrophil metabolic patterns, leading to increased production of the metabolite acetyl-CoA, thereby increasing the transcription of Ym-1 by promoting STAT6 acetylation. CONCLUSIONS:ALA protects against VM by activating metabolic reprogramming/STAT6 acetylation/Ym-1 axis in neutrophils. These results highlight the heterogeneity of neutrophils and suggest that ALA might represent a feasible strategy to improve the prognosis of VM patients.

Cold stimulation has been shown to regulate glucose,lipid,and amino acid metabolism,while also increasing heat production and energy expenditure in the body.Disordered energy metabolism is a key factor in the onset and progression of chronic metabolic conditiones such as diabetes,obesity,and cardiovascular disease.Recent research has unveiled the myriad pathways through which cold stimulation affects human energy metabolism.This article provides an overview of how cold stimulation affects energy metabolism across the three major metabolic pathways.Furthermore,it explores the implications and potential therapeutic applications of cold stimulation in the prevention and treatment of various metabolic diseases.

Cancer treatment has long been a topic of interest and the use of small molecule targeted drugs has highlighted the potential of nanomaterials as carriers for reducing drug side effects. In this study, we investigated the decoration of various transition metals on B12N12 nanocages as parameters for nitrosourea drug delivery carriers using density functional theory (DFT) and time-dependent DFT (TDDFT) calculations. We examined the electronic properties, topological analysis, electrostatics, and van der Waals (vdW) potential analysis. Our findings revealed a gradual weakening of the interaction between transition metals in same period and B12N12 nanocages, which could affect the adsorption energy of the Nu drug. Quantum theory of atoms in molecules (QTAIM), non-covalent interactions (NCI) and vdW potential analysis unveil that there are weak non-covalent interactions between metals and O atom and the interaction between Nu and B12N12 nanocages plays significant role in drug adsorption. Compared to the free drug, the adsorption of drugs on nano-cages could reduce the HOMO-LUMO energy gap and chemical hardness of the complexes, facilitating electron transfer and indicating activity at the target site. The charge-transfer between drug and B12N12 nanocages can effectively change the adsorption character of drug. Computed results shown that compared with other carriers, BN_Ni and BN_Pt exhibit better performances, which possess moderate recovery times at body temperature. This research evaluates the drug delivery capabilities of transition metal-decorated B12N12 nanocages for nitrosourea (Nu) in gas and aqueous environments, providing a rational perspective for designing novel nitrosourea drug carriers.

Lymphatic dysfunction is a pivotal pathological mechanism underlying the development of early atherosclerotic plaques. Potential targets of lymphatic function must be identified to realize the early prevention and treatment of atherosclerosis (AS). The immunity-related GTPase Irgm1 is involved in orchestrating cellular autophagy and apoptosis. However, the effect of Irgm1 on early AS progression, particularly through alterations in lymphatic function, remains unclear. In this study, we confirmed the protective effect of lymphangiogenesis on early-AS in vivo. Subsequently, an in vivo model of early AS mice with Irgm1 knockdown shows that Irgm1 reduces early atherosclerotic plaque burden by promoting lymphangiogenesis. Given that lymphatic endothelial cell (LEC) autophagy significantly contributes to lymphangiogenesis, Irgm1 may enhance lymphatic circulation by promoting LEC autophagy. Moreover, Irgm1 orchestrates autophagy in LECs by inhibiting mTOR and facilitating nuclear translocation of Tfeb. Collectively, these processes lead to lymphangiogenesis. Thus, this study establishes a link between Irgm1 and early AS, thus revealing a novel mechanism by which Irgm1 exerts an early protective influence on AS within the context of lymphatic circulation. The insights gained from this study have the potential to revolutionize the approach and management of AS onset.

As the major malignant tumors in the chest, non-small cell lung cancer (NSCLC) and esophageal cancer (EC) bring huge health burden to human beings worldwide. Currently, surgery is still the mainstay for comprehensive treatment for NSCLC and EC, but the prognosis is still poor as the results of cancer recurrence and distant metastasis. Neoadjuvant therapy refers to a single or combined treatment before surgery, aiming to improve the therapeutic effects of the traditional therapies. Unfortunately, the clinical outcomes and effects of neoadjuvant therapy are still controversial due to its apparent advantages and disadvantages, and different patients may respond differentially to the same scheme of neoadjuvant therapy, which makes it urgent and necessary to develop personalized scheme of neoadjuvant therapy for different individuals. Therefore, this review summarizes the novel schemes and strategies of neoadjuvant therapy, which may help to significantly improve of life quality of patients suffering from chestrelated malignancies.

Doxorubicin (DOX) is an effective anticancer agent, but its clinical utility is constrained by dose-dependent cardiotoxicity, partly due to cardiomyocyte ferroptosis. However, the progress of developing cardioprotective medications to counteract ferroptosis has encountered obstacles. Protosappanin A (PrA), an anti-inflammatory compound derived from hematoxylin, shows potential against DOX-induced cardiomyopathy (DIC). Here, it is reported that PrA alleviates myocardial damage and dysfunction by reducing DOX-induced ferroptosis and maintaining mitochondrial homeostasis. Subsequently, the molecular target of PrA through proteome microarray, molecular docking, and dynamics simulation is identified. Mechanistically, PrA physically binds with ferroptosis-related proteins acyl-CoA synthetase long-chain family member 4 (ACSL4) and ferritin heavy chain 1 (FTH1), ultimately inhibiting ACSL4 phosphorylation and subsequent phospholipid peroxidation, while also preventing FTH1 autophagic degradation and subsequent release of ferrous ions (Fe 2+ ) release. Given the critical role of ferroptosis in the pathogenesis of ischemia-reperfusion (IR) injury, this further investigation posits that PrA can confer a protective effect against IR-induced cardiac damage by inhibiting ferroptosis. Overall, a novel pharmacological inhibitor is unveiled that targets ferroptosis and uncover a dual-regulated mechanism for cardiomyocyte ferroptosis in DIC, highlighting additional therapeutic options for chemodrug-induced cardiotoxicity and ferroptosis-triggered disorders.

Tricetin (TRI) has been reported to have anti-inflammatory and antioxidant effects; however, its therapeutic potential and molecular mechanisms in atherosclerosis remain unclear. In this study, we aimed to investigate the effects of TRI on atherosclerosis. Our findings revealed that TRI inhibits macrophage ferroptosis by activating the NRF2 pathway. In vivo, ApoE-/- mice fed a high-fat diet and injected with TRI showed improved atherosclerosis progression through reduced oxidative stress and suppression of macrophage ferroptosis. In vitro experiments demonstrated that TRI administration increases GPX4 and xCT levels, attenuates oxidative stress, improves mitochondrial function, and inhibits lipid peroxidation, thereby suppressing ox-LDL-induced macrophage ferroptosis. Furthermore, TRI enhanced the nuclear translocation of NRF2. Notably, the protective effects of TRI on antioxidant capacity and ferroptosis were reversed in macrophages treated with ML385 (a specific NRF2 inhibitor). NRF2 knockdown in ApoE-/- mice using AAV-sh-NRF2 significantly reversed TRI-mediated inhibition of atherosclerosis progression and exacerbated macrophage ferroptosis in the plaque. Conclusively, this study identifies TRI as a potential therapeutic agent for atherosclerosis by inhibiting macrophage ferroptosis and oxidative stress through activation of the NRF2 pathway, offering a novel strategy to combat disease progression.

Protein phosphatases have demonstrated considerable promise in the realm of early tumor diagnosis across various malignancies. These enzymes play a critical role in modulating the PI3K-Akt signaling pathway, which is integral to cellular processes such as proliferation, survival, and migration. When the activity of protein phosphatases becomes abnormal, it can disrupt these essential signaling pathways, potentially leading to the initiation and progression of tumors. Consequently, monitoring for abnormal expression and activity levels of protein phosphatases could serve as a vital biomarker for early cancer detection. By identifying these alterations, clinicians may be better equipped to diagnose tumors at an earlier stage, significantly improving patient outcomes.In summary, our study highlights the multifaceted and significant role of PTEN in various forms of cancer, including esophageal squamous cell carcinoma (ESCA). Further analysis showed that the expression levels of protein phosphatase and PTEN protein were significantly associated with the early diagnosis of tumors, especially in the early stage of tumors, and their detection sensitivity and specificity were high. Therefore, by detecting the expression of protein phosphatase and PTEN protein, the early diagnosis of tumor can be achieved, and the therapeutic effect and prognosis of patients can be improved.

Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes. This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999–2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015. During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p < 0.001). Notably, the sex-specific difference in associations between MMA and mortality was significant only in adults with diagnosed diabetes (p for interaction = 0.028), not in adults with no diabetes and prediabetes. Adjusted HRs (95

Background and aims: The outcomes of current treatment for non-small cell lung cancer (NSCLC) are unsatisfactory and development of new and more efficacious therapeutic strategies are required. The Notch pathway, which is necessary for cell survival to avert apoptosis, induces the resistance of cancer cells to antitumour drugs. Notch pathway activation is controlled by the cleavage of Notch proteins/receptors mediated by A disintegrin and metalloproteinase 17 (ADAM17); therefore, ADAM17 is a reliable intervention target for anti-tumour therapy to overcome the drug resistance of cancer cells. This work aims to develop and elucidate the activation of Compound 2b , a novel-structured small-molecule inhibitor of ADAM17, which was designed and developed and its therapeutic efficacy in NSCLC was assessed via multi-assays. Methods and results: A lead compound for a potential inhibitor of ADAM17 was explored via pharmacophore modelling, molecular docking, and biochemical screening. It was augmented by substituting two important chemical groups [R1 and R2 of the quinoxaline-2,3-diamine (its chemical skeleton)]; subsequently, serial homologs of the lead compound were used to obtain anoptimized compound ( 2b ) with high inhibitory activity compared with leading compound against ADAM17 to inhibit the cleavage of Notch proteins and the accumulation of the Notch intracellular domain in the nuclei of NSCLC cells. The inhibitory activity of compound 2b was demonstrated by quantitative polymerase chain reaction and Western blotting. The specificity of compound 2b on ADAM17 was confirmed via point-mutation. Compound 2b enhanced the activation of antitumor drugs on NSCLC cells, in cell lines and nude mice models, by targeting the ADAM17/Notch pathway. Conclusion: Compound 2b may be a promising strategy for NSCLC treatment.

Radiation therapy is one of the main treatment methods for patients with thoracic malignant tumors, which can effectively improve the survival rate of the patients. However, radiation therapy can also cause damage to normal tissues while treating tumors, leading to radiation-induced lung injury such as radiation pneumonia and pulmonary fibrosis. Radiation-induced lung injury is a complex pathophysiological process involving many factors, and its prevention and treatment is one of the difficult problems in the field of radiation medicine. Therefore, the search for sensitive predictors of radiation-induced lung injury can guide clinical radiotherapy and reduce the incidence of radiation-induced lung injury. With the in-depth study of intestinal flora, it can drive immune cells or metabolites to reach lung tissue through the circulatory system to play a role, and participate in the occurrence, development and treatment of lung diseases. At present, there are few studies on intestinal flora and radiation-induced lung injury. Therefore, this paper will comprehensively elaborate the interaction between intestinal flora and radiation-induced lung injury, so as to provide a new direction and strategy for studying the protective effect of intestinal flora on radiation-induced lung injury.
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Background: Although the role of tumor microenvironment in lung adenocarcinoma (LUAD) has been explored in a number of studies, the value of TME-related signatures in immunotherapy has not been comprehensively characterized. Materials and Methods: Consensus clustering was conducted to characterize TME-based molecular subtypes using transcription data of LUAD samples. The biological pathways and immune microenvironment were assessed by CIBERSORT, ESTIMATE, and gene set enrichment analysis. A TME-related risk model was established through the algorithms of least absolute shrinkage and selection operator (Lasso) and stepwise Akaike information criterion (stepAIC). Results: Four TME-based molecular subtypes including C1, C2, C3, and C4 were identified, and they showed distinct overall survival, genomic characteristics, DNA methylation pattern, immune microenvironment, and biological pathways. C1 had the worst prognosis and high tumor proliferation rate. C3 and C4 had higher enrichment of anti-tumor signatures compared to C1 and C2. C4 had evidently low enrichment of epithelial–mesenchymal transition (EMT) signature and tumor proliferation rate. C3 was predicted to be more sensitive to immunotherapy compared with other subtypes. C1 is more sensitive to chemotherapy drugs, including Docetaxel, Vinorelbine and Cisplatin, while C3 is more sensitive to Paclitaxel. A five-gene risk model was constructed, which showed a favorable performance in three independent datasets. Low-risk group showed a longer overall survival, more infiltrated immune cells, and higher response to immunotherapy than high-risk group. Conclusion: This study comprehensively characterized the molecular features of LUAD patients based on TME-related signatures, demonstrating the potential of TME-based signatures in exploring the mechanisms of LUAD development. The TME-related risk model was of clinical value to predict LUAD prognosis and guide immunotherapy.