Background: An in-depth understanding of immune evasion mechanisms in tumors is crucial to overcome resistance and enable innovative advances in immunotherapy. Circular RNAs (circRNAs) have been implicated in cancer progression. However, much remains unknown regarding whether circRNAs impact immune escape in non-small-cell lung carcinoma (NSCLC). Methods: We performed bioinformatics analysis to profile and identify the circRNAs mediating immune evasion in NSCLC. A luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays and fluorescence in situ hybridization were performed to identify the interactions among circIGF2BP3, miR-328-3p, miR-3173-5p and plakophilin 3 (PKP3). In vitro T cell-mediated killing assays and in vivo syngeneic mouse models were used to investigate the functional roles of circIGF2BP3 and its downstream target PKP3 in antitumor immunity in NSCLC. The molecular mechanism of PKP3-induced PD-L1 upregulation was explored by immunoprecipitation, RIP, and ubiquitination assays. Results: We demonstrated that circIGF2BP3 (hsa_circ_0079587) expression was increased in NSCLC and negatively correlated with CD8⁺ T cell infiltration. Functionally, elevated circIGF2BP3 inactivated cocultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model, and this effect was dependent on CD8⁺ T cells. Mechanistically, METTL3 mediates the N⁶-methyladenosine (m⁶A) modification of circIGF2BP3 and promotes its circularization in a manner dependent on the m⁶A reader protein YTHDC1. circIGF2BP3 competitively upregulates PKP3 expression by sponging miR-328-3p and miR-3173-5p to compromise the cancer immune response. Furthermore, PKP3 engages with the RNA-binding protein FXR1 to stabilize OTUB1 mRNA, and OTUB1 elevates PD-L1 abundance by facilitating its deubiquitination. Tumor PD-L1 deletion completely blocked the impact of the circIGF2BP3/PKP3 axis on the CD8⁺ T cell response. The inhibition of circIGF2BP3/PKP3 enhanced the treatment efficacy of anti-PD-1 therapy in a Lewis lung carcinoma mouse model. Collectively, the PKP3/PD-L1 signature and the infiltrating CD8⁺ T cell status stratified NSCLC patients into different risk groups. Conclusion: Our results reveal the function of circIGF2BP3 in causing immune escape from CD8⁺ T cell-mediated killing through a decrease in PD-L1 ubiquitination and subsequent proteasomal degradation by stabilizing OTUB1 mRNA in a PKP3-dependent manner. This work sheds light on a novel mechanism of PD-L1 regulation in NSCLC and provides a rationale to enhance the efficacy of anti-PD-1 treatment in NSCLC.

Lung cancer is the most commonly diagnosed cancer in China and the second in the United States, approximately 85% of which is non–small cell lung cancer (NSCLC).¹ The precise stratification of patients with NSCLC into groups according to survival outcomes represents a crucial step in treatment. The staging system in the 8th edition of the American Joint Committee on Cancer classifies patients based on tumor, node, and metastasis (TNM) staging.² However, the survival rate within the same stage cohort varies widely.^3-5 It has been found that other independent prognostic factors including age, sex, histology, and treatment choices could significantly contribute to individualized predictions of survival.⁶

Background: Microplastic pollution has become a serious global environmental threat. The abundance of microplastics in the air is an order of magnitude higher than that in other media, which means that all living animals breathing with lungs (including humans) cannot escape the fate of inhaling microplastics. However, there is no direct evidence to demonstrate what type and abundance of microplastics exist in lung tissue. In addition, whether the retention of microplastics and the long-term friction between microplastics and lung tissue are related to some respiratory diseases is largely unknown. Ground glass nodules (GGNs) are areas of lesions of homogeneous density and with hazy increase in density in the lung field that do not obscure the bronchovascular structure, which have been increasingly identified in past decades. Although their etiology is broad, the correlation of microplastics with GGNs remains elusive.Results: In this study, we identified the presence of 65 microfibers, including 24 microplastics (> 20 μm) in 100 human lung tissues with μ-FTIR. The detection rate of microfibers in tumor was 58%, higher than that in normal tissue (46%), and 2/3 of microplastics were found in tumor. Microfibers seemed to be embedded in lung tissues, which was suggested by the in situ observation via LDIR. Additionally, sub-micron-sized plastic particles were also detected in some lung tissues with Raman. The abundance of microfibers in lung tissue gradually accumulated with the increase of age. Moreover, the detection rate in tumor of patients with higher microfiber exposure risk history was significantly higher than those with a relatively lower one, implying microfiber inhalation could be related to the formation of GGN. Further, serious weared surface of microfibers isolated from lung tissue emphasized a possible link of surface roughness to the disease progression.Conclusions: Collectively, the existence of microplastics in human lung tissues was validated, and their correlation with GGN formation was preliminarily explored, which laid a foundation for future research on microplastic exposure in the etiology of lung cancer and other related respiratory diseases.Graphical

Anti-PD-(L)1 treatment is standard for non-small cell lung cancer (NSCLC), but patients show variable responses to the same regimen. The tumor immune microenvironment (TIME) is associated with immunotherapy response, yet the heterogeneous underlying therapeutic outcomes remain underexplored. We applied single-cell RNA and TCR sequencing (scRNA/TCR-seq) to analyze surgical tumor samples from 234 NSCLC patients post-neoadjuvant chemo-immunotherapy. Analyses revealed five distinct TIME subtypes with varying major pathological response (MPR) rates. MPR patients had elevated levels of FGFBP2⁺ NK/NK-like T cells, memory B cells, or effector T cells, while non-MPR patients showed higher CCR8⁺ Tregs. T cell clonal expansion analyses unveiled heterogeneity in non-MPR patients, marked by varying expansions of Tex-relevant cells and CCR8⁺ Tregs. Precursor exhausted T cells (Texp cells) correlated with recurrence-free survival, identifying a patient subgroup with reduced recurrence risk despite lack of MPR. Our study dissects TIME heterogeneity in response to chemoimmunotherapy, offering insights for NSCLC management.