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Background Accumulating evidence showed that regulating tumor microenvironment plays a vital role in improving antitumor efficiency. Programmed Death Ligand 1 (PD-L1) is expressed in many cancer cell types, while its binding partner Programmed Death 1 (PD1) is expressed in activated T cells and antigen-presenting cells. Whereas, its dysregulation in the microenvironment is poorly understood. In the present study, we confirmed that evodiamine downregulates MUC1-C, resulting in modulating PD-L1 expression in non-small cell lung cancer (NSCLC). Methods Cell viability was measured by MTT assays. Apoptosis, cell cycle and surface PD-L1 expression on NSCLC cells were analyzed by flow cytometry. The expression of MUC1-C and PD-L1 mRNA was measured by real time RT-PCR methods. Protein expression was examined in evodiamine-treated NSCLC cells using immunoblotting or immunofluorescence assays. The effects of evodiamine treatment on NSCLC sensitivity towards T cells were investigated using human peripheral blood mononuclear cells and Jurkat, apoptosis and IL-2 secretion assays. Female H1975 xenograft nude mice were used to assess the effect of evodiamine on tumorigenesis in vivo. Lewis lung carcinoma model was used to investigate the therapeutic effects of combination evodiamine and anti-PD-1 treatment. Results We showed that evodiamine significantly inhibited growth, induced apoptosis and cell cycle arrest at G2 phase of NSCLC cells. Evodiamine suppressed IFN-γ-induced PD-L1 expression in H1975 and H1650. MUC1-C mRNA and protein expression were decreased by evodiamine in NSCLC cells as well. Evodiamine could downregulate the PD-L1 expression and diminish the apoptosis of T cells. It inhibited MUC1-C expression and potentiated CD8 + T cell effector function. Meanwhile, evodiamine showed good anti-tumor activity in H1975 tumor xenograft , which reduced tumor size. Evodiamine exhibited anti-tumor activity by elevation of CD8 + T cells in vivo in Lewis lung carcinoma model. Combination evodiamine and anti-PD-1 mAb treatment enhanced tumor growth control and survival of mice. Conclusions Evodiamine can suppress NSCLC by elevating of CD8 + T cells and downregulating of the MUC1-C/PD-L1 axis. Our findings uncover a novel mechanism of action of evodiamine and indicate that evodiamine represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat NSCLC cancer patients. MUC1-C overexpression is common in female, non-smoker, patients with advanced-stage adenocarcinoma.

Non‐small cell lung cancer (NSCLC) stands as a predominant cause of cancer‐related mortality worldwide. Brazilin, an active isoflavonoid compound derived from Chinese herbs, has displayed anti‐cancer properties across various cancer cell lines. However, the precise anti‐tumour mechanism of Brazilin in NSCLC remains incompletely understood. In this paper, we demonstrated that Brazilin treatment significantly reduced the proliferation of NSCLC cells and induced apoptosis. Additionally, Brazilin caused G2 cell cycle arrest in NSCLC cells, characterised by decreased expression of Cyclin B1 and increased expression of P21. Brazilin also induced mitochondrial dysfunction and ROS production in NSCLC cells. Mechanistically, Brazilin treatment significantly activated the STING pathway and upregulated the expression of CXCL10, CXCL9, and CCL5 in NSCLC cell lines. Notably, the inhibition of the STING pathway with H‐151 enhances cell viability, suggesting STING is involved in Brazilin‐induced apoptosis. These findings underscore Brazilin as a promising anti‐cancer agent for NSCLC.

Conventional methods in treating non–small cell lung cancer contain surgery, chemotherapy, radiotherapy, and targeted therapy, which have various defects. Recently, with the deeper research on tumor immunity, immunotherapy has made the breakthrough in the treatment of cancers. Especially developments of programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors bring the therapy into a new stage. This review mainly focuses on introducing existing monoclonal antibodies containing nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, along with 3 ordinary biomarkers such as PD-L1 expression, tumor mutation burden, and microsatellite instability. By understanding the resistance mechanism of anti-PD-1/L1 blockade, research is further improving the survival benefit and expanding the benefit population. So, PD-1/PD-L1 inhibitors begin to be combined with various therapeutic strategies clinically. Discussion and comparison of their effectiveness and safety are also comprehensively reviewed. Meanwhile, we explore the potential, the impact, and mechanisms of combining traditional Chinese medicine with immunotherapy.

Asthma, a heterogeneous chronic respiratory disorder affecting millions globally, is driven by complex interactions between genetic susceptibility, environmental triggers, and dysregulated immunity. Emerging evidence positions ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, as a pivotal mechanism. This review introduces the “Ferroptosis-Immune-Metabolic Axis” as an integrative framework for asthma pathogenesis. We detail how environmental insults (e.g., allergens, pollutants) initiate ferroptosis in airway epithelial cells, leading to the release of damage-associated molecular patterns (DAMPs) and lipid peroxidation products (e.g., 4-HNE). These molecules activate and recruit immune cells (M1 macrophages, neutrophils, Th17 cells), which in turn exacerbate oxidative stress and iron dysregulation, creating a self-amplifying cycle. Metabolic reprogramming, including enhanced polyunsaturated fatty acid (PUFA) synthesis and glycolytic flux, provides the essential substrates and energy to sustain this vicious cycle. We dissect endotype-specific manifestations: IL-33-driven epithelial ferroptosis in eosinophilic asthma and ALOX15-mediated lipid peroxidation coupled with hepcidin-induced iron retention in neutrophilic asthma. Therapeutically, we highlight novel strategies such as inhaled GPX4 mRNA nanocarriers and ALOX15 inhibitors, underscoring the potential of targeting this axis for precision medicine in refractory asthma.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, and current therapies often yield limited efficacy. This study investigated the antitumor potential and mechanisms of Pterostilbene (PTE), a natural stilbenoid with superior bioavailability. The antitumor effects of PTE were assessed in A549 and H358 NSCLC cell lines to determine its impact on cell viability, cell cycle, apoptosis, and reactive oxygen species (ROS) generation, using N-acetylcysteine (NAC) to confirm the role of ROS. Key molecular mechanisms were probed via Western blot, siRNA knockdown, and pharmacological inhibition (H-151). The in vivo efficacy of PTE and its effect on the tumor immune microenvironment were evaluated in H358 xenograft and immunocompetent LLC1 murine models. PTE suppressed cell viability in a concentration- and time-dependent manner, inducing G2/M phase arrest and mitochondrial apoptosis driven by ROS. It triggered DNA damage and activated the STING pathway, leading to TBK1/IRF3 phosphorylation and the secretion of T-cell chemoattractants (CXCL10, CXCL9, CCL5). STING inhibition markedly attenuated PTE's effects. , PTE suppressed tumor growth and remodeled the tumor microenvironment by increasing granzyme B , TNF-α , and IFN-γ CD8 T cells while reducing myeloid-derived suppressor cells and regulatory T cells. Our findings elucidate a dual mechanism whereby PTE directly kills NSCLC cells via ROS-mediated apoptosis and simultaneously reinvigorates antitumor immunity through STING pathway activation. This positions PTE as a promising candidate for combination immunotherapy in NSCLC.

Immune checkpoint therapy has emerged as a revolutionary approach in the field of non-small cell lung cancer (NSCLC), offering new hope to patients with various malignancies. Despite its success, a significant proportion of patients exhibit primary or acquired resistance, limiting the efficacy of these treatments. This review provides a comprehensive analysis of recent breakthroughs in immune checkpoint therapy, focusing on the underlying biology of immune checkpoints, current checkpoint inhibitors, and the mechanisms of resistance that challenge treatment effectiveness. In particular, we will explore novel strategies designed to overcome these resistance mechanisms, including combination therapies that enhance anti-tumor immune responses, the use of personalized neoantigen vaccines, and microbiome-modulating therapies. Additionally, we will examine the role of emerging biomarkers, such as TCR clonality and T-cell inflamed gene signatures, in predicting patient responses. By synthesizing these insights, this review aims to highlight innovative approaches that could significantly improve therapeutic outcomes for patients with NSCLC and other malignancies, ultimately advancing the field of cancer immunotherapy.

Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder characterized by persistent airflow limitation and systemic inflammation, with accumulating evidence implicating gut microbiota dysbiosis as a key modulator of disease pathogenesis via the gut-lung axis. This review synthesizes current knowledge on the bidirectional communication between the gut and lungs, highlighting how microbial metabolites—particularly short-chain fatty acids (SCFAs), tryptophan derivatives, and bile acids—regulate pulmonary immunity through G-protein-coupled receptors, histone deacetylase inhibition, and aryl hydrocarbon receptor signaling. Dysbiosis-driven disruptions in these pathways exacerbate neutrophilic inflammation, impair regulatory T-cell function, and sustain TLR4/NF-κB activation, amplifying lung tissue damage and remodeling. Therapeutic strategies targeting the gut-lung axis show promise in restoring microbial homeostasis and mitigating COPD progression. Probiotics (e.g., Lactobacillus and Bifidobacterium ), prebiotics (e.g., inulin), and dietary interventions (e.g., high-fiber diets) enhance SCFA production, strengthen epithelial barriers, and suppress pro-inflammatory cytokines. Advanced approaches, including fecal microbiota transplantation, nanotechnology-enabled metabolite delivery (e.g., dendrimer-complexed indole-3-acetic acid), and traditional Chinese medicine (TCM) formulations (e.g., the postbiotic formulation Qipian), demonstrate efficacy in preclinical and clinical studies by synchronizing gut-lung microbiota and inhibiting inflammatory pathways. Despite these advances, challenges remain in translating findings to clinical practice, including methodological heterogeneity, antibiotic and corticosteroid confounding, and inter-individual microbiota variability. Future research must integrate multi-omics technologies, validate biomarkers (e.g., Bacteroidales/ Lactobacillus ratio, SCFA levels), and develop personalized interventions to bridge the bench-to-bedside gap. Harnessing the gut-lung axis offers transformative potential for COPD management, shifting the paradigm from symptomatic treatment to disease-modifying strategies rooted in microbiome immunology.

Chronic obstructive pulmonary disease (COPD) is a global health crisis driven by oxidative stress and immune dysregulation. Emerging evidence positions ferroptosis—an iron-dependent cell death driven by iron-catalyzed peroxidation of esterified polyunsaturated fatty acids (PUFAs) in membrane phospholipids—as a pivotal mediator of COPD pathogenesis. This review synthesizes cutting-edge insights into how cigarette smoke (CS) induces mitochondrial fission (via dynamin-related protein 1 (DRP1) phosphorylation) to exacerbate ferroptosis, potentially by enhancing lipid droplet (LD)-mitochondria contact sites and promoting lipid peroxidation in airway epithelial cells. This review further elucidates the complex and context-dependent role of nuclear factor erythroid 2-related factor 2 (Nrf2). While Nrf2 signaling is often suppressed globally in COPD lungs, its dysfunction in macrophages may paradoxically promote ferritinophagy-mediated iron retention through nuclear receptor coactivator 4 (NCOA4), overwhelming ferroprotein (FPN)-mediated iron export and unintentionally fueling ferroptosis. Clinically, plasma malondialdehyde (MDA)—a byproduct of lipid peroxidation—serving as a biomarker of oxidative stress severity, with elevated levels correlating with accelerated lung function decline in COPD patients. Therapeutically, promising targeted strategies are highlighted, such as inhaled exosomes loaded with liproxstatin-1, which can selectively inhibit pulmonary ferroptosis without inducing system immunosuppression. By bridging molecular mechanisms to therapeutic innovation, this review outlines a roadmap for precision medicine in COPD, focusing on the ferroptosis-immune axis to disrupt the self-perpetuating cycle of inflammation and tissue damage.

Asthma is a heterogeneous chronic airway disease characterized by complex inflammation. Pyroptosis, a pro-inflammatory form of programmed cell death mediated by gasdermin (GSDM) family proteins, has recently emerged as a critical amplifier of airway inflammation and tissue remodeling in asthma. This review delineates the molecular underpinnings of pyroptosis, focusing on the roles of canonical (e.g., NLRP3-caspase-1) and non-canonical (e.g., caspase-4/5/11) inflammasome pathways, as well as the broader concept of PANoptosis. We elaborate on how the pore-forming activity of GSDMD and other GSDMs facilitates the release of potent pro-inflammatory cytokines (IL-1β, IL-18), driving pathogenic cross talk among structural cells (epithelium), innate immune cells (macrophages, eosinophils, ILC2s), and adaptive immunity. Crucially, we contextualize pyroptosis within distinct asthma endotypes, proposing that allergen-driven, NLRP3-dominated pathways may underpin Th2-high/eosinophilic inflammation, while pollutant/viral-triggered, non-canonical/AIM2 pathways may favor Th2-low/neutrophilic phenotypes. The translational potential of targeting pyroptosis is underscored through a discussion of biomarkers (e.g., GSDMD-N, IL-18) and a comprehensive summary of preclinical and early clinical inhibitors targeting NLRP3, GSDMD, and key cytokines. By synthesizing these multifaceted roles, this review posits that a nuanced understanding of pyroptosis networks holds significant promise for pioneering endotype-specific therapeutic strategies in asthma management.

Pyroptosis, a programmed cell death mechanism mediated by gasdermin proteins such as GSDMD, is typically activated by inflammasomes. While essential for host defense against infections, excessive pyroptosis contributes to chronic inflammation and exacerbates inflammatory diseases. In chronic obstructive pulmonary disease (COPD), dysregulated pyroptosis interacts with immune cells—including neutrophils, macrophages, and T lymphocytes—to perpetuate inflammation, tissue damage, and acute exacerbations. This review explores the molecular mechanisms of pyroptosis, its cell-type-specific roles in COPD pathogenesis, and its implications for therapeutic targeting. By synthesizing evidence from primary research, we highlight how pyroptosis influences immune dysregulation in COPD and propose novel strategies for disease management.