Numerous research conducted in recent years has revealed that gut microbial dysbiosis, such as modifications in composition and activity, might influence lung tissue homeostasis through specific pathways, thereby promoting susceptibility to lung diseases. The development and progression of lung cancer, as well as the effectiveness of immunotherapy are closely associated with gut flora and metabolites, which influence immunological and inflammatory responses. During abnormal proliferation, non-small cell lung cancer cells acquire more substances and energy by altering their own metabolic pathways. Glucose and amino acid metabolism reprogramming provide tumor cells with abundant ATP, carbon, and nitrogen sources, respectively, providing optimal conditions for tumor cell proliferation, invasion, and immune escape. This article reviews the relationship of immune response with gut flora and metabolic reprogramming in non-small cell lung cancer, and discusses the potential mechanisms by which gut flora and metabolic reprogramming affect the occurrence, development, and immunotherapy of non-small cell lung cancer, in order to provide new ideas for precision treatment of lung cancer patients.
Humans ; Gastrointestinal Microbiome/immunology* ; Carcinoma, Non-Small-Cell Lung/therapy* ; Lung Neoplasms/therapy* ; Immunotherapy ; Metabolic Reprogramming

The tertiary lymphoid structure (TLS) plays a crucial role in the tumor microenvironment, influencing tumor development and progression. As an emerging biomarker for predicting the prognosis and treatment response in cancer patients, TLS has received increasing attention. However, there is currently a lack of standardized evaluation criteria for TLS, and significant differences exist in TLS across different tumor tissues. This poses challenges for the clinical application of this biomarker in translation. To meet the clinical diagnosis and treatment needs of non-small cell lung cancer (NSCLC), this consensus focuses on the definition, clinical significance, testing components, and assessment methods of TLS in NSCLC. Combining relevant research and Chinese clinical practice, it provides standardized and normalized suggestions for the clinical assessment and application of TLS, so as to improve the understanding of TLS among clinicians and pathologists, and provide a reference basis for the clinical application of the detection of TLS in NSCLC. 
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Humans ; Carcinoma, Non-Small-Cell Lung/immunology* ; Lung Neoplasms/immunology* ; Tertiary Lymphoid Structures/immunology* ; Consensus ; China ; East Asian People

In epidemiological statistics, the incidence rate and mortality rate of malignant lung tumors rank among the top. Non-small cell lung cancer (NSCLC) constitutes an important part of lung cancer and has become a key focus of clinical research and treatment. Among the genomic characteristics of NSCLC, the Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is one of the main tumor drivers, accounting for approximately 25% of all NSCLC cases. The existence of this mutation is closely related to the treatment response and prognosis of patients. Therefore, the treatment strategy for KRAS-mutated NSCLC is an important topic in the field of tumor research. In the current era, immunomodulatory therapy has rapidly gained popularity and developed rapidly in oncology due to its unique mechanism of action and remarkable clinical efficacy. The treatment strategies targeting the KRAS-mutated of NSCLC have gradually become a research hotspot. The advent of immune checkpoint inhibitors (ICIs) has opened up a new therapeutic avenue for patients with such cancers, and clinical studies have shown significant effects in improving survival rates. Nevertheless, there are still many challenges in the application of immunotherapy, such as the complexity of the tumor microenvironment, individual differences among patients, and drug resistance mechanisms. This article reviews the progress of immunotherapy for KRAS-mutated NSCLC, focusing on the specific application of immunotherapy, the exploration of combination therapies, and the results of related clinical trials. At the same time, it discusses the possible future development directions of KRAS-mutated NSCLC treatment, providing a reference for clinical treatment practice.
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Humans ; Carcinoma, Non-Small-Cell Lung/immunology* ; Lung Neoplasms/immunology* ; Proto-Oncogene Proteins p21(ras)/immunology* ; Immunotherapy/methods* ; Mutation ; Animals

Immune checkpoint inhibitors (ICIs) have become the cornerstone of treatment for driver gene-negative advanced non-small cell lung cancer (NSCLC). However, resistance is inevitable, and the underlying mechanisms remain incompletely understood. Histological transformation is a rare but emerging cause of acquired resistance to immunotherapy, with only sporadic case reports documented to date. Here, we report the first case of lung adenocarcinoma that underwent histological transformation to atypical carcinoid following first-line therapy with ICIs combined with chemotherapy, highlighting the critical role of histological lineage switching in mediating NSCLC resistance to ICIs. Notably, the patient harbored a rearranged during transfection (RET) fusion mutation. Subsequent targeted therapy with Selpercatinib after histological transformation demonstrated favorable efficacy, suggesting a potential therapeutic strategy for atypical carcinoid patients with co-occurring rare driver mutations. This case provides a potential therapeutic option for atypical carcinoid patients with rare mutations.
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Humans ; Carcinoid Tumor/drug therapy* ; Carcinoma, Non-Small-Cell Lung/immunology* ; Drug Resistance, Neoplasm ; Immune Checkpoint Inhibitors/therapeutic use* ; Immunotherapy ; Lung Neoplasms/immunology* ; Oncogene Proteins, Fusion/genetics* ; Proto-Oncogene Proteins c-ret/genetics*

Non-small cell lung cancer (NSCLC), as the predominant histological subtype of lung cancer, accounts for approximately 85% of all lung cancer cases. In recent years, immune checkpoint inhibitors (ICIs), represented by programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, have achieved breakthrough advancements in patients with driver gene-negative NSCLC. They have been established as a key component of first-line treatment regimens and have significantly improved clinical outcomes. However, limited clinical evidence has emerged showing the phenomenon of histological transformation from NSCLC to small cell lung cancer (SCLC) in patients experiencing disease progression after ICIs monotherapy or combination therapy. Systematic research data on the clinical characteristics, molecular biological basis, and subsequent treatment strategies for such transformation events are currently lacking. This article reports a case of SCLC transformation occurring in a patient with KRAS-mutated lung adenocarcinoma after 16 months of ICIs combination therapy and provides a systematic review of 22 similar published cases. The study demonstrates that small cell transformation is a critical mechanism of immunotherapy resistance, and transformed patients exhibit poor prognosis. The research emphasizes the importance of dynamic monitoring of neuron-specific enolase (NSE) and standardized repeat biopsies during treatment, providing a basis for clinical practice. This aids in enhancing the recognition and management capabilities for this rare histological transformation, ultimately improving patient outcomes.
Humans ; Immune Checkpoint Inhibitors/therapeutic use* ; Lung Neoplasms/immunology* ; Carcinoma, Non-Small-Cell Lung/immunology* ; Small Cell Lung Carcinoma/genetics* ; Male ; Middle Aged ; Female

Advances in targeted therapy and immunotherapy have significantly improved clinical outcomes for patients with advanced non-small cell lung cancer (NSCLC), reshaping treatment paradigms. However, most patients ultimately face drug resistance, with limited options for subsequent therapies and suboptimal treatment efficacy, presenting a prominent challenge in current clinical practice. Antibody-drug conjugates (ADCs), characterized by high efficacy and favorable safety profiles, have emerged as a promising therapeutic frontier in recent years. This systematic review provides a comprehensive overview of the latest advancements in ADCs-based therapies for lung cancer, alongside discussions of the prevailing challenges in this rapidly evolving domain.
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Humans ; Carcinoma, Non-Small-Cell Lung/immunology* ; Immunoconjugates/therapeutic use* ; Lung Neoplasms/immunology* ; Antineoplastic Agents/therapeutic use* ; Immunotherapy

BACKGROUND: One of the most important treatment modalities for non-small cell lung cancer (NSCLC) is immune checkpoint inhibitor. Nevertheless, a small percentage of patients do not respond well to these therapies, highlighting the significance of identifying important CD8+ T cell subsets for immunotherapy and creating trustworthy biomarkers. The purpose of this study is to assess the potential utility of TIM3+CD8+ T cells as new biomarkers by examining their expressions in various areas of the NSCLC tumor microenvironment. METHODS: Based on biopsy techniques, tumor tissue samples were obtained from patients with NSCLC and categorized into tumor central and non-central regions. Using flow cytometry, the infiltration of TIM3+CD8+ T cells and the surface expression of programmed cell death 1 (PD-1) on these cells were examined, and their correlations with the effectiveness of immunotherapy were assessed. RESULTS: The non-central region of tumor tissues had considerably larger infiltration of TIM3+CD8+ T lymphocytes compared to the non-central region (P<0.0001). This pattern was found in both subgroups with tumor diameters ≥3 cm or <3 cm (P<0.01). In comparison to TIM3-CD8+ T cells, TIM3+CD8+ T cells showed higher levels of PD-1 (P<0.001), with more PD-1+TIM3+CD8+ T cells invading the non-central region (P<0.01). Clinical responders to immunotherapy had considerably lower infiltration levels of TIM3+CD8+ T cells in the tumor non-central region compared to non-responders, with lower levels correlated with better clinical outcomes (P<0.01), while no correlation was identified in the tumor central region (P>0.05). According to reciever operating characteristic (ROC) curve analysis, TIM3+CD8+ T cells in the tumor non-central region had an area under the curve (AUC) of 0.9375 for predicting the effectiveness of immunotherapy, which was considerably higher than that of TIM3+CD8+ T cells in the tumor central region and programmed cell death ligand 1 (PD-L1) [tumor proportion score (TPS)]. CONCLUSIONS In the tumor microenvironment of NSCLC, TIM3+CD8+ T cells show regional distribution patterns. The expression of this cell population in the non-central region of the tumor microenvironment may be a biomarker for predicting the effectiveness of immunotherapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Lung Neoplasms/metabolism* ; Hepatitis A Virus Cellular Receptor 2/immunology* ; Tumor Microenvironment/immunology* ; CD8-Positive T-Lymphocytes/metabolism* ; Male ; Female ; Middle Aged ; Aged ; Adult ; Programmed Cell Death 1 Receptor/metabolism* ; Immunotherapy ; Clinical Relevance

Objective: To investigate the effects of derived neutrophil to lymphocyte ratio (dNLR) and lung immune prognostic index (LIPI) score on the overall survival (OS) of non-surgical elderly non-small cell lung cancer (NSCLC) patients. Methods: Clinical and pathological data of NSCLC patients in Hebei General Hospital from January 2014 to June 2018 were collected retrospectively. The dNLR value was calculated based on the results of blood routine before treatment, and the optimal cut-off value of dNLR was obtained by ROC curve. The patients were divided into low dNLR level group and high dNLR level group based on the optimal dNLR cut-off value. The groups were classified as good, intermediate and poor based on the LIPI score consisting of lactate dehydrogenase (LDH) and dNLR tested before treatment. The Kaplan-Meier method and Log rank test were used for survival analysis, and the Cox risk proportional regression model was used for analysis of prognostic influences. Results: The area under the ROC curve for dNLR predicting prognosis in non-surgical elderly NSCLC patients was 0.591 (95% CI: 0.491, 0.692; P=0.093). The optimal cut-off value for dNLR predicting prognosis in elderly NSCLC patients was 2.515, with a sensitivity of 45.5% and a specificity of 81.8%. The gender, BMI, pathological type and degree of tumor differentiation were associated with dNLR levels (P<0.05). The median survival times were 16 and 10 months for patients in the low dNLR level group (dNLR<2.51) and high dNLR level group (dNLR≥2.51), respectively (P<0.001), and 15, 10 and 6 months for patients with good, intermediate and poor LIPI scores, respectively (P<0.001). The age, gender, smoking, pathological type, tumor differentiation, clinical stage, BMI, dNLR level, LDH level and LIPI scores were all associated with patient prognosis (P<0.05), and age≥76 years, tumor differentiation and clinical stage Ⅲ and Ⅳ were independent factors influencing patient prognosis (P<0.05). Conclusion: No matter what treatment measures are taken, dNLR level and LIPI score are related to patients' prognosis, and non-surgical elderly NSCLC patients with high dNLR level and poor LIPI score before treatment have worse prognoses.
Aged ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Humans ; L-Lactate Dehydrogenase ; Lung Neoplasms/drug therapy* ; Lymphocytes/immunology* ; Neutrophils/immunology* ; Prognosis ; Retrospective Studies

In recent years, the checkpoint inhibitors targeted programmed cell death 1 (PD-1) and its ligand 1 (PD-1 ligand, PD-L1) achieved landmark significance in treating a variety of cancers including non-small cell lung cancer (NSCLC). However, current immunotherapy is not precise enough, only 15%-20% of the unselected patients can benefit from the therapy, and there is a possibility of hyperprogression (HP). Therefore, how to select the dominant population is crucial. Although many studies have emphasized the importance of PD-L1 and tumor mutation burden (TMB) and other indicators to guide immunotherapy, current PD-L1 expression level and mutation load cannot be used as a decisive and excluded predictive marker based on various obstacles. With the deepening of research, we found that there is a close relationship between lung cancer-driver gene mutation and aberrant activation of PD-1/PD-L1 signal pathways, and the correlation between gene mutation and immunotherapy efficacy has broad research value. This article will revolve around the above issues.
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Carcinoma, Non-Small-Cell Lung ; genetics ; immunology ; therapy ; Humans ; Immunotherapy ; methods ; Lung Neoplasms ; genetics ; immunology ; therapy ; Treatment Outcome

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvIII in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis of lung cancer after surgery.
Animals ; Carcinoma, Non-Small-Cell Lung ; immunology ; therapy ; Cell Line, Tumor ; ErbB Receptors ; immunology ; metabolism ; Female ; Humans ; Immunotherapy, Adoptive ; methods ; Lung Neoplasms ; immunology ; therapy ; Mice ; Mice, Inbred NOD ; Receptors, Chimeric Antigen ; immunology ; T-Lymphocytes ; immunology ; Xenograft Model Antitumor Assays