The poor prognosis of lung adenocarcinoma (LUAD) remains unimproved. This study aimed to identify lymph node metastasis (LNM)-related and cellular immunity-related prognostic genes in LUAD and propose novel strategies to improve its prognosis. LUAD-related datasets were obtained from public databases. Prognostic genes and a prognostic model were obtained through various bioinformatics analyzes, and the immunotherapy response in risk groups was assessed. Subsequently, the expression levels of prognostic genes and the intercellular communication relationships were explored at the single-cell level. Moreover, malignant cells were identified, and their differentiation mechanisms were explored via inferCNV analysis. Additionally, FURIN was silenced and overexpressed to investigate its effects on the invasion, metastasis, and lymphangiogenesis of LUAD cells in vitro. RGS20, KYNU, RAET1E, FGF12, GJB2, CACNA2D2, FURIN, and GDF10 were identified as prognostic genes with LNM. In 4 datasets, LUAD patients with the high LNM and immune cell-related risk scores exhibited higher mortality rates compared to those in the low-risk group. Furthermore, individuals in the low-risk group demonstrated a greater propensity to derive advantages from immunotherapeutic interventions. Epithelial cells were identified as key cells, with CACNA2D2 being significantly up-regulated during their late-stage differentiation. Basal cells, the malignant subset within epithelial cells, showed elevated FURIN expression in the pre-differentiation phase, which declined in the middle and late phases. Functionally, FURIN was found to enhance the migratory and proliferative capacities of LUAD cells. Moreover, we demonstrated that FURIN accelerated lymphatic metastasis and lymphangiogenesis in vitro. In this paper, we identified LUAD prognostic genes with LNM and immune cell signatures, emphasized treating LUAD patients according to LNM- and immune cell-related risk scores, and provided novel ideas on how to improve poor prognosis and develop targeted therapy for LUAD.

Background: Following the 2021 first International Consensus on Severe Lung Cancer, global attention to patients with PS 2-4 has grown significantly. Recent advances in novel therapies, interventional techniques, and supportive care, along with emerging real world data, have expanded treatment opportunities for this population. To incorporate these advances, we have updated the consensus. Methods: A multidisciplinary panel comprising experts from oncology, radiation oncology, thoracic surgery, radiology, interventional medicine, respiratory medicine, critical care medicine, and nursing. After being presented with a comprehensive review of the current evidence pertaining to severe lung cancer and thorough discussions, the panel reached a consensus on 11 recommendations, each with over 70% expert agreement. Results: The 11 consensus points focused on definition and causes (n=2), assessment and general strategies (n=4), and specific treatment modalities (n=5) were updated or newly developed. This updated consensus emphasizes dynamic and precise detection, robust life support, flexible application of novel therapies, and MDT guided treatment adjustment based on PS dynamics. Early rehabilitation and comprehensive supportive care are integral to disease management. Conclusions: This consensus updates the definition, diagnostic evaluation, and treatment strategies, providing a practical framework for clinicians based on current evidence and multidisciplinary expert consensus. Prospective trials focusing specifically on patients with severe lung cancer are urgently needed.

Background:Although advancements in cancer therapies have substantially improved the survival of cancer patients, these treatments may also result in acute or chronic lung injury. Cancer treatment-related lung injury (CTLI) presents with a diverse array of clinical manifestations and can involve multiple sites. Due to the lack of specific diagnostic protocols, CTLI can deteriorate rapidly and may be life-threatening if not promptly addressed. Unfortunately, there is no universally accepted consensus document on the diagnosis and management of CTLI. Methods:A multidisciplinary panel comprising experts from respiratory and critical care medicine, oncology, radiation oncology, thoracic surgery, radiology, pathology, infectious diseases, pharmacy, and rehabilitation medicine participated in this consensus development. Through a systematic literature review and detailed panel discussions, the team formulated nine key recommendations. Results:This consensus document addresses the concept, epidemiology, pathogenesis, risk factors, diagnostic approach, evaluation workflow, management strategies, differential diagnosis, type-specific management and clinical staging of CTLI. Emphasis is placed on raising awareness among clinicians and therapeutic practices through comprehensive guidelines. Conclusions:The consensus provides a detailed diagnostic protocol for CTLI and introduces a structured management framework based on grading, typing, and staging. It highlights the critical role of multidisciplinary team (MDT) collaboration and emphasizes the need for individualized, whole-process patient care strategies to optimize clinical outcomes.

The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear. Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC). In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor growth derived from lentiviral vector shTMEM160 cells was lower compared with that derived from shNC control cells. Furthermore, the downregulation of TMEM160 significantly restricted tumor growth in immune-competent BALB/c mice. In clinical samples from patients with CRC, we observed a strong positive correlation between TMEM160 expression and PD-L1 expression, as well as a negative correlation with CD8A expression. Importantly, patients with high TMEM160 expression exhibited a worse prognosis compared with those with low or no TMEM160 expression. Our study reveals that TMEM160 inhibits the ubiquitination-dependent degradation of PD-L1 that is mediated by SPOP, thereby stabilizing PD-L1 expression to foster the malignant progress, radioresistance, and immune evasion of CRC cells. These findings suggest that TMEM160 holds potential as a target for the treatment of patients with CRC.

Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%–40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.

Lung adenocarcinoma (LUAD) is the main cause of cancer-related deaths worldwide. Long noncoding RNAs have been reported to play an important role in various cancers due to their special functions. Therefore, identifying the lncRNAs involved in LUAD tumorigenesis and development can help improve therapeutic strategies. The TCGA-LUAD RNA expression profile was downloaded from The Cancer Genome Atlas, and a total of 49 differential lncRNAs, 112 differential miRNAs, and 2,953 differential mRNAs were screened. Through Kaplan-Meier curves, interaction networks, hub RNAs (lncRNAs, miRNAs, and mRNAs) were obtained. These hub genes are mainly involved in cell proliferation, cell cycle, lung development, and tumor-related signaling pathways. Two lncRNAs (SMIM25 and PCAT19) more significantly related to the prognosis of LUAD were screened by univariate Cox analysis, multivariate Cox analysis, and risk model analysis. The qPCR results showed that the expression levels of SMIM25 and PCAT19 were downregulated in clinical tissues, A549 and SPC-A1 cells, which were consistent with the bioinformatics analysis results. Subsequently, the PCAT19/miR-143-3p pairs were screened through the weighted gene co-expression network analysis and miRNA-lncRNA regulatory network. Dual luciferase detection confirmed that miR-143-3p directly targets PCAT19, and qPCR results indicated that the expression of the two is positively correlated. Cell function tests showed that overexpression of PCAT19 could significantly inhibit the proliferation, migration, and invasion of A549 and SPC-A1 cells. In contrast, knockout of PCAT19 can better promote the proliferation and migration of A549 and SPC-A1 cells. The expression of PCAT19 was negatively correlated with tumor grade, histological grade, and tumor mutation load in LUAD. In addition, co-transfection experiments confirmed that the miR-143-3p mimic could partially reverse the effect of PCAT19 knockout on the proliferation of A549 and SPC-A1 cells. In summary, PCAT19 is an independent prognostic factor in patients with LUAD that can regulate the proliferation, migration, and invasion of LUAD cells and may be a potential biomarker for the diagnosis of LUAD. PCAT19/miR-143-3p plays a very important regulatory role in the occurrence and development of LUAD.

Many non-small cell lung cancer (NSCLC) patients initially benefiting from gefitinib are confronted with acquired resistance. MiR-138 was previously stated as a growth inhibitor of several cancer cell lines including NSCLC cells and its expression level was significantly lower in gefitinib-resistant cells. The role of miR-138 in NSCLC cell lines PC9 and A549 was verified using methyl thiazolyl tetrazolium (MTT) assay and colony formation assay. Quantitative real-time PCR (RT-PCR) was employed to assess the level of miR-138 in gefitinib-sensitive PC9 cells and gefitinib-resistant PC9GR cells. Bioinformatic algorithms (TargetScan) and rVISTA 2.0 were used to predict binding sites on miR-138 and its target genes. MiR-138 inhibited cell proliferation of PC9 and A549 cells. In PC9GR cells, miR-138 expression was inhibited. Gefitinib treatment negatively regulated miR-138 in PC9 cells. Transfection of PC9GR cells with miR-138 mimics significantly reduced cell viability. MiR-138 was directly regulated by Homeobox A4 (HOXA4) via an HOXA4-binding site on the promoter region. TargetScan predicted numerous miR-138 target genes and EGFR was found to be the functional downstream effector of miR-138. We demonstrated that miR-138 is regulated by HOXA4 and exerts its functions via inhibiting EGFR expression in NSCLC cells.