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Abstract Objective CircRNAs are involved in cancer progression. However, their role in immune escape in non-small cell lung cancer (NSCLC) remains poorly understood. Methods This study employed RIP-seq for the targeted enrichment of circRNAs, followed by Western blotting and RT-qPCR to confirm their expression. Specific binding was assessed using electrophoretic mobility shift assays. Transwell and wound healing assays were performed to evaluate the invasive and migratory capacities of NSCLC cells. The secretion of TNF-α, IFN-γ, GzmB, and perforin by CD8+ T cells co-cultured with peripheral blood mononuclear cells (PBMCs) was quantitatively measured using enzyme-linked immunosorbent assays. The PD-L1 phenotype and apoptosis levels were determined by flow cytometry, while cell proliferation and apoptosis were evaluated through CCK-8, EdU, and TUNEL assays. The in vivo role of circ₀074158 was investigated using a mouse subcutaneous tumour implantation model. Results QKI6 modulates the level of PD-L1 ubiquitination in NSCLC. Both hsa_(c)irc₀074158 and QKI6 influence the proliferation, invasion, and migration of NSCLC cells. Circ₀074158 regulates PD-L1 ubiquitination by modulating QKI6 expression, thus affecting PD-L1 expression. Furthermore, circ₀074158 activates CD8+ T cells in PBMCs, inhibits immune escape, and promotes tumour cell apoptosis, suppressing tumour growth. Conclusion The circ₀074158/QKI6 axis regulates PD-L1 ubiquitination in NSCLC, limiting tumour cell proliferation and invasion. Our findings reveal a novel function for circ₀074158 in NSCLC, suggesting its potential as a therapeutic target.

Lung cancer still contributes to nearly one‐quarter cancer‐related deaths in the past decades, despite the rapid development of targeted therapy and immunotherapy in non‐small cell lung cancer (NSCLC). The development and availability of comprehensive genomic profiling make the classification of NSCLC more precise and personalized. Most treatment decisions of advanced‐stage NSCLC have been made based on the genetic features and PD‐L1 expression of patients. For the past 2 years, more than 10 therapeutic strategies have been approved as first‐line treatment for certain subgroups of NSCLC. However, some major challenges remain, including drug resistance and low rate of overall survival. Therefore, we discuss and review the therapeutic strategies of NSCLC, and focus on the development of targeted therapy and immunotherapy in advanced‐stage NSCLC. Based on the latest guidelines, we provide an updated summary on the standard treatment for NSCLC. At last, we discussed several potential therapies for NSCLC. The development of new drugs and combination therapies both provide promising therapeutic effects on NSCLC. Based on the development of targeted therapy and immunotherapy, the treatment strategies for NSCLC have been profoundly changed. After evaluation of the incidental finding of nodule, patients are managed to routine follow‐up or diagnosis of NSCLC. Patients with NSCLC should receive molecular testing and PD‐L1 testing to make final treatment decision. For resectable NSCLC with targetable mutations, targeted therapy as adjuvant therapy shows promising effects. Immunotherapy has also been investigated as both neoadjuvant and adjuvant therapy. For unresectable advanced NSCLC with driver gene positive, targeted therapy and immunotherapy play an essential role in anticancer treatment. This review comprehensively presents the current landscape of targeted therapy and immunotherapy in NSCLC.

[This corrects the article DOI: 10.3389/fimmu.2024.1382231.].

Non-small cell lung cancer (NSCLC) accounts for 80% of total lung cancers, which are the main killer of cancer-related death worldwide. Circular RNA (circRNA) has been found to modulate NSCLC development. However, the role of circ₀000376 in NSCLC development has been underreported. The present work showed that circ₀000376 and 3-phos-phoinositide-dependent protein kinase-1 (PDPK1) expression were dramatically increased, but miR-545-3p was decreased in NSCLC tissues and cells. circ₀000376 expression was closely associated with lymph node metastasis, tumor-node-metastasis stage, and tumor size of NSCLC patients. circ₀000376 knockdown repressed NSCLC cell proliferation, migration, invasion, and glutaminolysis but induced cell apoptosis. Additionally, miR-545-3p bound to circ₀000376, and circ₀000376 regulated cell phenotypes by associating with miR-545-3p. MiR-545-3p also participated in NSCLC cell proliferation, migration, invasion, apoptosis, and glutaminolysis by targeting PDPK1. Further, circ₀000376 absence repressed tumor formation in vivo. Collectively, circ₀000376 regulated NSCLC cell tumor properties by the miR-545-3p/PDPK1 axis, suggesting that circ₀000376 could be employed as a therapeutic target for NSCLC.

Propofol, an intravenous anesthetic agent, exerts an anti-tumor peculiarity in multifarious tumors. Circular RNA hsa_(c)irc₀000735 (circ₀000735) is involved in non-small cell lung cancer (NSCLC) progression. The purpose of this study is to investigate whether propofol can curb NSCLC progression via regulating circ₀000735 expression. Cell viability, proliferation, apoptosis, and invasion were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2′-deoxyuridine, flow cytometry, and transwell assays. Evaluation of protein levels was performed using western blotting or immunohistochemistry. Detection of circ₀000735 in tissue samples and cells was carried out using a real-time quantitative polymerase chain reaction. The molecular mechanisms associated with circ₀000735 were predicted by bioinformatics analysis and verified by dual-luciferase reporter assays. The relationship between propofol and circ₀000735 in vivo was verified by xenograft models. The results showed that circ₀000735 was overexpressed in NSCLC samples and cells. Propofol treatment overtly decreased circ₀000735 expression in NSCLC cells and repressed NSCLC cell viability, proliferation, invasion, and facilitated NSCLC cell apoptosis, but these effects mediated by propofol were counteracted by circ₀000735 overexpression. Circ₀000735 functioned as a miR-153-3p sponge and regulated integrin-β1 (ITGB1) expression via adsorbing miR-153-3p. ITGB1 overexpression reversed circ₀000735 silencing-mediated effects on NSCLC cell viability, proliferation, invasion, and apoptosis. In conclusion, propofol restrained NSCLC growth by downregulating circ₀000735, which functioned as a miR-153-3p sponge and regulated ITGB1 expression via adsorbing miR-153-3p. This study provides evidence to support that propofol curbs NSCLC progression by regulating circRNA expression.

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

The approval of osimertinib for adjuvant treatment of stage I–II–III EGFR-mutated NSCLC (early stage) represents a paradigm shift, raising the question of whether other genotype-matched therapeutics approved for advanced-stage NSCLC can also provide clinical benefit in the adjuvant setting. However, there is a paucity of real-world data on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC. We used next-generation sequencing, complemented by immunohistochemistry and fluorescence in situ hybridization, to screen our single-institution cohort of 1961 NSCLC consecutive cases for actionable molecular targets. The prevalence of actionable GAs was comparable in early versus advanced-stage NSCLC, the only exception being KRAS mutations (more frequent in early-stage cases). Consistent with advanced-stage tumors being more aggressive, co-occurrence of TP53 and EGFR GAs as well as copy number gains were less frequent in early-stage tumors. EGFR mutations and high expression of PD-L1 were inversely associated, whereas KRAS mutations and high PD-L1 reactivity showed positive association. Recapitulating advanced-stage tumors, early-stage NSCLC had the highest share of EGFR mutations in lepidic and acinar subtypes. Resected lepidic tumors contained the highest proportion of the KRAS G12C actionable variant. These results, obtained with routine diagnostic technologies in an unselected clinical setting, provide a significant addition of real-world data in early-stage NSCLC.