Cytokines, key contributors to tumorigenesis, are mediators between inflammatory immune or nonimmune and cancer cells. Here, IL-6 production by tumor cells was assessed in a cohort of patients with lung adenocarcinoma treated with conventional therapy. IL-6 levels and neutrophil–lymphocyte ratio (NLR) or systemic immune-inflammation index (SII) markers were evaluated. Changes in pro- and anti-inflammatory cytokines, HMGB1 concentration, and CD4+ and CD8+ T-lymphocyte populations and their subpopulations were investigated. IL-6 expression was detected immunohistochemically in lung adenocarcinoma biopsies. Cytokines were quantified using the cytometric bead array, and TGF-β and HMGB-1 through ELISA. Clinical parameters were collected to assess NLR and SII. CD4+ and CD8+ T-lymphocytes and naïve, memory, and effector subpopulations were quantified by flow cytometry. The data obtained were associated with patients’ median overall survival (OS). IL-6 showed the highest increase, probably because the lung adenocarcinoma cells produced IL-6. Patients with higher OS had lower NLR and SII from the third cycle of chemotherapy. Patients with lower OS had significantly lower percentages of CD8+ T-lymphocyte and its effector subpopulations, with a concomitant increase in the naïve subpopulation. This study suggests that in addition to the known inflammatory markers, IL-6, CD8+ T-lymphocytes and their effector and naïve subpopulations could be useful as predictive markers in lung adenocarcinoma.

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of the dynamic interplay between cancer progression and immune responses. This review explored their influence on key processes of the cancer–immunity cycle, such as immune cell differentiation, antigen presentation, and tumor immunogenicity. By modulating tumor escape from the immune response, therapeutic resistance, and tumor–stroma interactions, lncRNAs actively shape the tumor microenvironment. Due to their growing knowledge in the area of immune suppression, directly intervening in the induction of regulatory T cells (Tregs), M2 macrophages, and regulating immune checkpoint pathways such as PD-L1, CTLA-4, and others, lncRNAs can be considered promising therapeutic targets. Advances in single-cell technologies and immunotherapy have significantly expanded our understanding of lncRNA-driven regulatory networks, paving the way for novel precision medicine approaches. Ultimately, we discussed how targeting lncRNAs could enhance cancer immunotherapy, offering new avenues for biomarker discovery and therapeutic intervention.

Drug-tolerant persistent (DTP) cells have emerged as a reversible, slow-cycling survival state that enables early therapeutic tolerance and underlies the development of stable resistance in all types of cancer. To comprehensively characterize this phenomenon, we conducted a PRISMA-ScR-guided exploratory review across four major databases (PubMed, Scopus, Web of Science, Dimensions), identifying 343 eligible records spanning 2010-2025. In all experimental systems, including 2D cell lines, spheroids, organoids, xenografts, residual disease models, and clinical samples, DTP cells consistently showed survival under high drug concentrations or prolonged exposure, depending on non-genetic adaptive programs, and recovery of proliferative potential and drug sensitivity after treatment cessation. Analysis of the molecular mechanisms revealed a convergence of reversible pathways involving apoptosis escape, quiescence, chromatin remodeling, phenotypic plasticity, metabolic rewiring, downstream survival signaling, and transient programs, such as those of stem cells. These findings support a model in which DTP cells represent an early and plastic node within a broader continuum of resistance, capable of progressing toward genetically fixed resistance through stress-induced mutagenesis. Methodological heterogeneity among studies did not diminish the reproducibility of DTP cells fundamental characteristics but underscored the need for standardized experimental criteria. Notably, the integrated evidence identifies therapeutically exploitable vulnerabilities—epigenetic, metabolic, signaling-based, and plasticity-targeted—that have shown promise in reducing DTP persistence and delaying the development of resistance. This review consolidates current knowledge and provides a mechanistic framework to guide therapeutic strategies that aim to intercept cancer resistance in the earliest and most reversible stages of its development.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance poses a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister (DTP) cells are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study in cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after single exposure to tyrosine kinase inhibitors (TKIs; erlotinib or osimertinib). After establishing DTP cells, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT–qPCR validated the overexpression of lncRNAs and mRNA in the residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms that underlie intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival (OS) of patients with lung cancer.

CD155, also known as the poliovirus receptor (PVR), is a crucial molecule in the development and progression of cancer, as its overexpression favors immune evasion and resistance to immunotherapy. However, little is known about the mechanisms that regulate its overexpression. Proinflammatory factors produced by various cellular components of the tumor microenvironment (TME) have been associated with CD155 expression. We analyzed the effect of interleukin (IL)-6 on CD155 expression in lung adenocarcinoma. We found a positive relationship between mRNA and protein levels. This correlation was also observed in bioinformatics analysis and in biopsies and serum from patients with lung adenocarcinoma. Interestingly, lung adenocarcinoma cell lines expressing suppressor of cytokine signaling 1 (SOCS1) did not show increased CD155 levels upon IL-6 stimulation, and SOCS1 silencing reverted this effect. IL-6 and SOCS1 are critical regulators of CD155 expression in lung adenocarcinoma. Further basic and clinical studies are needed to define the role of these molecules during tumor development and to improve their clinical impact as biomarkers and targets for predicting the efficacy of immunotherapies. This study deepens the understanding of the intricate regulation of the immune checkpoints mediated by soluble factors and allows us to devise new ways to combine conventional treatments with the most innovative anticancer options.

Lung adenocarcinoma is the most prevalent form of lung cancer, and drug resistance is a significant obstacle in its treatment. This study aimed to investigate the overexpression of long non-coding RNAs (lncRNAs) as a mechanism that promotes intrinsic resistance in tumor cells from the onset of treatment. Drug-tolerant persister cells (DTP) are a subset of cancer cells that survive and proliferate after exposure to therapeutic drugs, making them an essential object of study for cancer treatment. The molecular mechanisms underlying DTP cell survival are not fully understood; however, long non-coding RNAs (lncRNAs) have been proposed to play a crucial role. DTP cells from lung adenocarcinoma cell lines were obtained after a single exposure to tyrosine kinase inhibitor TKIs (erlotinib or osimertinib). After establishing DTPs, RNA sequencing was performed to investigate the differential expression of the lncRNAs. Some lncRNAs and one mRNA were found to be overexpressed in DTP cells. The clinical relevance of lncRNAs was evaluated in a cohort of patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). RT-qPCR validated the overexpression of lncRNAs and mRNA in residual DTP cells and LUAD biopsies. Knockdown of these lncRNAs increases the sensitivity of DTP cells to therapeutic drugs. This study provides an opportunity to investigate the involvement of lncRNAs in the genetic and epigenetic mechanisms underlying intrinsic resistance. The identified lncRNAs and CD74 mRNA may serve as potential prognostic markers or therapeutic targets to improve the overall survival of patients with lung cancer.