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Background Immune checkpoint inhibitors (ICIs) are regarded as the most promising treatment for advanced-stage non-small cell lung cancer (aNSCLC). Unfortunately, there has been no unified accuracy biomarkers and systematic model specifically identified for prognostic and severe immune-related adverse events (irAEs). Our goal was to discover new biomarkers and develop a publicly accessible method of identifying patients who may maximize benefit from ICIs. Methods This retrospective study enrolled 138 aNSCLC patients receiving ICIs treatment. Progression-free survival (PFS) and severe irAEs were end-points. Data of demographic features, severe irAEs, and peripheral blood inflammatory-nutritional and immune indices before and after 1 or 2 cycles of ICIs were collected. Independent factors were selected by least absolute shrinkage and selection operator (LASSO) combined with multivariate analysis, and incorporated into nomogram construction. Internal validation was performed by applying area under curve (AUC), calibration plots, and decision curve. Results Three nomograms with great predictive accuracy and discriminatory power were constructed in this study. Among them, two nomograms based on combined inflammatory-nutritional biomarkers were constructed for PFS (1 year-PFS and 2 year-PFS) and severe irAEs respectively, and one nomogram was constructed for 1 year-PFS based on immune indices. ESCLL nomogram (based on ECOG PS, preSII, changeCAR, changeLYM and postLDH) was constructed to assess PFS (1-, 2-year-AUC = 0.893 [95% CI 0.837–0.950], 0.828 [95% CI 0.721–0.935]). AdNLA nomogram (based on age, change-dNLR, changeLMR and postALI) was constructed to predict the risk of severe irAEs (AUC = 0.762 [95% CI 0.670–0.854]). NKT-B nomogram (based on change-CD3+CD56+CD16+NKT-like cells and change-B cells) was constructed to assess PFS (1-year-AUC = 0.872 [95% CI 0.764–0.965]). Although immune indices could not be modeled for severe irAEs prediction due to limited data, we were the first to find CD3+CD56+CD16+NKT-like cells were not only correlated with PFS but also associated with severe irAEs, which have not been reported in the study of aNSCLC-ICIs. Furthermore, our study also discovered higher change-CD4+/CD8+ ratio was significantly associated with severe irAEs. Conclusions These three new nomograms proceeded from non-invasive and straightforward peripheral blood data may be useful for decisions-making. CD3+CD56+CD16+NKT-like cells were first discovered to be an important biomarker for treatment and severe irAEs, and play a vital role in distinguishing the therapy response and serious toxicity of ICIs.

Currently, checkpoint inhibitor‐based immunotherapy has emerged as prevailing treatment modality for diverse cancers. However, immunotherapy as a first‐line therapy has not consistently yielded durable responses. Moreover, the risk of immune‐related adverse events increases with combination regimens. Thus, the development of predictive biomarkers is needed to optimize individuals benefit, minimize risk of toxicities, and guide combination approaches. The greatest focus has been on tumor programmed cell death‐ligand 1 (PD‐L1), microsatellite instability (MSI), and tumor mutational burden (TMB). However, there remains a subject of debate due to thresholds variability and significant heterogeneity. Major unmet challenges in immunotherapy are the discovery and validation of predictive biomarkers. Here, we show the status of tumor PD‐L1, MSI, TMB, and emerging data on novel biomarker strategies with oncogenic signaling and epigenetic regulation. Considering the exploration of peripheral and intestinal immunity has served as noninvasive alternative in predicting immunotherapy, this review also summarizes current data in systemic immunity, encompassing solute PD‐L1 and TMB, circulating tumor DNA and infiltrating lymphocytes, routine emerging inflammatory markers and cytokines, as well as gut microbiota. This review provides up‐to‐date information on the evolving field of currently available biomarkers in predicting immunotherapy. Future exploration of novel biomarkers is warranted.

Tertiary lymphoid structures (TLS) represent the ectopic aggregations of immune cells arising during chronic inflammation or tumor progression. In cancer, TLS are often associated with beneficial clinical outcomes in patients undergoing immunotherapy, underscoring their prognostic and predictive significance. Mature TLS, characterized by germinal centers and areas of T-cell and B-cell aggregation, are considered primary locations for activating and maintaining both humoral and cellular anti-tumor immune effects. Despite their recognized importance, the mechanisms driving the formation of mature TLS in cancer and their influence on the immune response within tumors remain insufficiently understood. Therefore, this review aims to comprehensively explore the structural composition, development mechanisms, maturity impact factors, immunological function, and innovative therapeutic strategies of mature TLS within the tumor microenvironment. The research summarized herein offers novel insights and considerations for therapeutic approaches to promote TLS generation and maturation in patients with cancer, representing a promising avenue for future cancer therapies.

Background: There is limited knowledge on the yield of performing capture-based targeted ultradeep sequencing on bronchoalveolar lavage (BAL) specimens from advanced nonsmall cell lung cancer (NSCLC) patients. This study aimed to evaluate gene variations and performance characteristics in BAL and tissue specimens using targeted sequencing. Methods: This cohort study retrospectively enrolled 20 patients with advanced NSCLC. The variant detection percentage, correlation of tumor mutation burden (TMB), and allele frequency heterogeneity (AFH) were compared between paired BAL and tissue samples. A three-tiered system was also applied for the interpretation of gene variants according to the guidelines. Results: No statistical difference was observed in variant detection between BAL and tissue samples (P = .591 for variant tier and P = .409 for variant type). In general, BAL achieved higher detection rates in tier I variants (96.2% vs 84.6%) and gene fusions (75% vs 50%) compared with tissue samples; tissue samples had better variants detection rates for other variants, such as tier II (89.6% vs 76.0%), tier III (87.1% vs 72.6%), single nucleotide variant (SNV, 89.6% vs 76.5%), insertion/deletion/duplication (InDel, 74.6% vs 69.8%) and copy number variation (CNV, 93.8% vs 43.8%). Besides, there were significant correlations of TMB (R2 = 0.96, P < .001) and AFH (R2 = 0.87, P < .001) between BALs and paired tissues. Conclusions: The findings demonstrate that BAL may serve as a supplement in liquid biopsy for mutation detection and for routine utilization in clinical settings.

The emergence of immune checkpoint inhibitors (ICIs) has heralded a transformative era in the therapeutic landscape of non‐small cell lung cancer (NSCLC). While ICIs have demonstrated clinical efficacy in a portion of patients with NSCLC, these treatments concurrently precipitate a spectrum of immune‐related adverse events (irAEs), encompassing mild to severe manifestations, collectively posing a risk of significant organ damage. Consequently, there exists an imperative to augment our comprehension of the pathophysiological underpinnings of irAEs and to formulate more efficacious preventive and ameliorative strategies. In this comprehensive review, we delineate the clinical presentation of organ‐specific irAEs in patients with NSCLC and provide an in‐depth analysis of recent advancements in understanding the mechanisms driving ICI‐induced toxicity. Furthermore, we discuss potential strategies and targets for ameliorating these irAEs. Ultimately, this review aims to furnish valuable insights to guide further research endeavours in the context of irAEs in NSCLC patients. Immunotherapy not only revolutionises lung cancer treatment but also poses serious toxicity risks. Elucidating irAE mechanisms in NSCLC: T/B‐cell dysregulation, cytokine imbalances, autoantibody production, genetic predispositions and gut microbiome alterations. Highlighting precise irAE interventions in NSCLC: corticosteroids, targeted immunosuppressants, monoclonal antibodies targeting lymphocytes, cytokine inhibitors and signalling pathway modulators.

High endothelial venules (HEV) in tertiary lymphoid structures (TLS) are associated with favorable prognoses in malignancies. However, regarding neoadjuvant immunochemotherapy for non-small cell lung cancer (NSCLC), HEV production and its relationship with therapeutic response are poorly elucidated. This study aims to investigate the discrepancy in HEV abundance among NSCLC patients receiving neoadjuvant therapy, as well as the value of the HEV/TLS index as an innovative prognostic marker. Eighty-eight formalin-fixed paraffin-embedded (FFPE) tissues were retrospectively collected from patients with NSCLC and divided into two cohorts: neoadjuvant immunochemotherapy (N = 48) and neoadjuvant chemotherapy (N = 40). We analyzed the differences in HEV abundance score between the cohorts and their relationship with the prognosis. Kaplan-Meier method was used to explore the effect of each indicator on recurrence-free survival (RFS) and overall survival (OS). Receiver operating characteristic (ROC) curves including HEV abundance and HEV/TLS index were plotted to compare the predictive effects of different indicators by area under curve (AUC). HEV were mostly commonly found in the peripheral region (94.2%) within TLS and rarely in the geminal centers compartment (5.8%). The neoadjuvant immunochemotherapy cohort had higher levels of major pathological response (MPR) rate and pathological complete response (pCR) rate than neoadjuvant chemotherapy cohort (MPR: 29.1% vs. 15.0%; pCR: 29.1% vs. 5.0%). Furthermore, neoadjuvant immunochemotherapy exhibited higher HEV abundance score (p < 0.001) and significantly better prognostic RFS (p = 0.0321) and OS (p = 0.0319). Multivariate analysis demonstrated that HEV abundance score remains the most prominent immunological prognostic factor affecting RFS (hazard ratio [HR] = 0.113) and OS (HR = 0.009) after adjusting variables. We found that the predictive accuracy of the combined HEV/TLS index was superior to that of HEV abundance score alone. The HEV/TLS index was more effective than HEV abundance score in predicting patients' prognosis. Therefore, the induction of HEV formation within TLS to increase their abundance may be a potential strategy to enhance the efficacy of neoadjuvant immunochemotherapy in NSCLC.

Immunotherapy has emerged as a transformative treatment for non-small cell lung cancer (NSCLC), yet its clinical benefits remain variable among patients. Early and accurate evaluation of treatment response is critical to guide therapeutic adjustments and improve outcomes. This review synthesizes recent advancements in multimodal imaging techniques-computed tomography (CT), positron emission tomography (PET)/CT, magnetic resonance imaging (MRI), and radiomics-for evaluating and predicting immunotherapy efficacy in NSCLC. We analyze the strengths and limitations of conventional morphological criteria (eg, RECIST, iRECIST) and highlight emerging quantitative biomarkers, including CT texture analysis, metabolic parameters (MTV, TLG), and diffusion-weighted MRI metrics. Notably, radiomics demonstrates promise in decoding tumor heterogeneity, PD-L1 expression, and immune microenvironment features, while immuno-PET probes targeting immune checkpoints offer novel insights into immune activity in vivo. Challenges such as pseudo-progression, nodal immune flare, and discrepancies between imaging responses and pathological responses are critically discussed. By integrating morphological, metabolic, and microenvironmental data, multimodal imaging enhances precision in patient stratification and therapeutic monitoring. Future research should prioritize multicenter, AI-driven radiomics validation and targeted tracer development to optimize NSCLC immunotherapy management. This review provides clinicians and researchers with new directions for utilizing multimodal imaging techniques in developing personalized treatment strategies.

Background Several retinal pathologies exhibit both inflammation and breakdown of the inner blood-retinal barrier (iBRB) resulting in vascular permeability, suggesting that treatments that trigger resolution of inflammation may also promote iBRB restoration. Methods Using the mouse retinal ischemia-reperfusion (IR) injury model, we followed the time course of neurodegeneration, inflammation, and iBRB disruption and repair to examine the relationship between resolution of inflammation and iBRB restoration and to determine if minocycline, a tetracycline derivative shown to reverse microglial activation, can hasten these processes. Results A 90-min ischemic insult followed by reperfusion in the retina induced cell apoptosis and inner retina thinning that progressed for approximately 2 weeks. IR increased vascular permeability within hours, which resolved between 3 and 4 weeks after injury. Increased vascular permeability coincided with alteration and loss of endothelial cell tight junction (TJ) protein content and disorganization of TJ protein complexes. Shunting of blood flow away from leaky vessels and dropout of leaky capillaries were eliminated as possible mechanisms for restoring the iBRB. Repletion of TJ protein contents occurred within 2 days after injury, long before restoration of the iBRB. In contrast, the eventual re-organization of TJ complexes at the cell border coincided with restoration of the barrier. A robust inflammatory response was evident a 1 day after IR and progressed to resolution over the 4-week time course. The inflammatory response included a rapid and transient infiltration of granulocytes and Ly6C + classical inflammatory monocytes, a slow accumulation of Ly6C neg monocyte/macrophages, and activation, proliferation, and mobilization of resident microglia. Extravasation of the majority of CD45 + leukocytes occurred from the superficial plexus. The presence of monocyte/macrophages and increased numbers of microglia were sustained until the iBRB was eventually restored. Intervention with minocycline to reverse microglial activation at 1 week after injury promoted early restoration of the iBRB coinciding with decreased expression of mRNAs for the microglial M1 markers TNF-α, IL-1β, and Ptgs2 (Cox-2) and increased expression of secreted serine protease inhibitor Serpina3n mRNA. Conclusions These results suggest that iBRB restoration occurs as TJ complexes are reorganized and that resolution of inflammation and restoration of the iBRB following retinal IR injury are functionally linked.

Against the backdrop of the profound restructuring in global climate governance, China’s energy management system is undergoing a comprehensive transition from dual energy consumption control to dual carbon emissions control. This policy shift fundamentally alters the underlying logic of energy-focused regulation and inevitably impacts the economy–energy–environment (3E) system. This study innovatively constructs a “Triangular Trinity” theoretical framework integrating internal, intermediate, and external triangular couplings, as well as providing a granular analysis of their transmission relationships and feedback mechanisms. Using Guangdong Province as a case study, this study takes the dual control emissions policy within the external triangle as an entry point to research the restructuring logic of dual carbon emissions control for the coupling coordination mechanisms of the 3E system. The key findings are as follows: (1) Policy efficacy evolution: During 2005–2016, dual energy consumption control significantly improved energy conservation and emissions reduction, elevating Guangdong’s 3E coupling coordination. Post 2017, however, its singular focus on total energy consumption revealed limitations, causing a decline in 3E coordination. Dual carbon emissions control demonstrably enhances 3E systemic synergy. (2) Decoupling dynamics: Dual carbon emissions control accelerates economic–carbon emission decoupling, while slowing economic–energy consumption decoupling. This created an elasticity space of 5.092 million tons of standard coal equivalent (sce) and reduced carbon emissions by 26.43 million tons, enabling high-quality economic development. (3) Mechanism reconstruction: By leveraging external triangular elements (energy-saving technologies and market mechanisms) to act on the energy subsystem, dual carbon emissions control leads to optimal solutions to the “Energy Trilemma”. This drives the systematic restructuring of the sustainability triangle, achieving high-order 3E coupling coordination. The Triangular Trinity framework constructed by us in the paper is an innovative attempt in relation to the theory of energy transition, providing a referenceable methodology for resolving the contradictions of the 3E system. The research results can provide theoretical support and practical reference for the low-carbon energy transition of provinces and cities with similar energy structures.