Ever since RNA sequencing of whole genomes and transcriptomes became available, numerous RNA transcripts without having the classic function of encoding proteins have been discovered. Long non-coding RNAs (lncRNAs) with a length greater than 200 nucleotides were considered as “junk” in the beginning, but it has increasingly become clear that lncRNAs have crucial roles in regulating a variety of cellular mechanisms and are often deregulated in several diseases, such as cancer. Lung cancer is the leading cause of cancer-related deaths and has a survival rate of less than 10%. Immune cells infiltrating the tumor microenvironment (TME) have been shown to have a great effect on tumor development with macrophages being the major cell type within the TME. Macrophages can inherit an inflammatory M1 or an anti-inflammatory M2 phenotype. Tumor-associated macrophages, which are predominantly polarized to M2, favor tumor growth, angiogenesis, and metastasis. In this review, we aimed to describe the complex roles and functions of lncRNAs in macrophages and their influence on lung cancer development and progression through the TME.

The tumor microenvironment (TME) significantly impacts cancer progression, yet traditional animal models do not fully recapitulate the situation in humans. To address this, we developed tumor-derived precision lung slices (TD-PCLS), an ex vivo platform for studying the lung TME and evaluating therapies. TD-PCLS, viable for 8 to 10 days, preserve the heterogeneity and metabolic activity of primary tumors, as confirmed by seahorse analysis. Using multispectral FACS and phenocycler multiplex imaging, we spatially profiled TME components and cancer cell functionality. Additionally, TD-PCLS revealed patient-specific responses to chemo- and immunotherapies. To complement TD-PCLS, we established tumor-cell-seeded PCLS (TCS-PCLS) by introducing tumor and immune cells into healthy lung slices. This model highlighted macrophage-tumor interactions as critical for tumor cell proliferation, migration, and immune modulation. Together, these platforms provide a robust tool for lung cancer research, enabling precision medicine and advancing therapeutic discovery.

Recent evidences suggest that tumor-associated macrophages (TAMs) metabolism plays a crucial role on TAM activation, lung tumor progression and metastasis. However, the molecular pathways underlying this regulation still need to be explored. This study analyzes the role of the long non-coding RNA (lncRNA) ADPGK-AS1 in macrophage activation and metabolic regulation in lung cancer. Through RNAseq analysis in human M1 (anti-tumor) and M2 (pro-tumor) macrophages we were able to identify ADPGK-AS1 as an M2 upregulated lncRNA. In addition, this lncRNA was found to be upregulated in TAMs isolated from human lung tumor tissue. Knock down of ADPGK-AS1 in M2 macrophages led to increased expression of inflammatory M1 marker genes (TNFα, IL-8 and CD80) and downregulation of M2 marker genes (CD206 and TGFβ). Furthermore, to understand the tumor promoting capabilities in vitro, tumor cells were treated with lncRNA-knock-down-conditional medium (KD-CM), where we observed a higher rate of tumor cell apoptosis and decreased tumor cell migration. To decipher the underlying molecular mechanism, RNA sequencing was done to identify downstream targets as well as a mass spectrometry based study to analyze interacting proteins. Interestingly, ADPGK-AS1 seems so interact with a variety of mitochondrial proteins such as their ribosomal proteins as well as with metabolic enzymes. Additionally, overexpression/knock down of ADPGK-AS1 resulted in altered metabolic activity, oxygen consumption and changed activity of the metabolism master regulator protein AMPK. Our findings suggest that ADPGK-AS1 functions as an important regulator in macrophage metabolic reprogramming. Therefore, understanding and targeting ADPGK-AS1 might serve as a future therapeutic approach in lung cancer treatment.