The tumor microenvironment (TME) in renal cell carcinoma (RCC) frequently exhibits significant immune cell infiltration. However, tumor cells often manage to evade immune surveillance. This study revealed the mechanism by which circular RNA circGRAMD4 regulates NBR1. CircGRAMD4 is markedly elevated in RCC, and its high levels are correlated with a poor prognosis. Notably, the absence of circGRAMD4 has been demonstrated to result in a significant inhibition of renal cancer cell growth. This inhibition has been attributed to an enhanced anti-tumor immunity mediated by CD8+ T cells. Mechanistically, circGRAMD4 interacts with the RBM4 protein, stabilizing the autophagic cargo receptor NBR1 mRNA. This interaction promotes NBR1 expression, which in turn leads to the degradation of MHC-I molecules through macroautophagy/autophagy pathways. Consequently, this process affects renal cancer cell antigen presentation, induces CD8+ T cell dysfunction, and contributes to tumor immune escape. Moreover, by inhibiting circGRAMD4 and using immune checkpoint blockers (ICB), the immunosuppressive TME is altered to prevent tumor immune evasion, ultimately increasing the effectiveness of ICB treatment. The discovery highlights the significant impact of circGRAMD4 on RCC immune escape and proposes that blocking circGRAMD4 could serve as a promising immunotherapy strategy when combined with ICB to enhance patient outcomes.

The phenotypic transition of pulmonary artery smooth muscle cells (PASMCs) is a central pathological alteration in pulmonary artery remodeling, contributing to pulmonary hypertension. Super-enhancers (SEs), characterized by histone modifications and the binding of coactivators, drive the expression of prominent genes that define cellular identity. However, the specific role of SEs, particularly SE-driven long noncoding RNAs, in hypoxia-induced phenotypic plasticity of PASMCs remains unclear.

In this study, the long noncoding RNA UNC5B antisense RNA 1 (UNC5B-AS1) regulated by SEs was screened in hypoxic PASMCs using RNA sequencing and H3K27ac (histone 3 lysine 27 acetylation) chromatin immunoprecipitation sequencing. Overexpression or knockdown of UNC5B-AS1 in vitro was performed to elucidate its role in pulmonary hypertension pathogenesis. A serotype 5 adenovirus-associated virus carrying a conserved functional fragment of UNC5B-AS1 was used to treat pulmonary hypertension in vivo.

We identified UNC5B-AS1 as an SE-driven long noncoding RNA transcriptionally activated by the transcription factor FOXP3 (forkhead box protein P3), which regulates phenotypic transition in PASMCs. Notably, we demonstrated that UNC5B-AS1 interacts with key glycolytic enzymes in the cytoplasm and likely serves as a molecular scaffold for LRPPRC (leucine-rich PPR motif-containing protein) and oxidative respiratory chain complex IV in mitochondria. Consequently, the deficiency of UNC5B-AS1 in PASMCs promotes the lactylation of promoter regions within inflammatory genes, including those of IL (interleukin)-1β, IL-6, and TNF-α (tumor necrosis factor-α), under hypoxic conditions, ultimately leading to inflammatory phenotypic transition of PASMCs.

Our findings identify SE-driven UNC5B-AS1 as a novel regulatory factor in the hypoxia-induced phenotypic transition of PASMCs and suggest that overexpression of UNC5B-AS1 may represent a promising therapeutic strategy for pulmonary hypertension.

Alternative cleavage and polyadenylation (APA) have gained increasing attention in cancer biology, yet its role in modulating anti-tumor immune response remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (CSTF2), an APA-related gene, as a pivotal suppressor of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDAC). CSTF2 promotes tumor development by inhibiting the infiltration and cytotoxic immune cell recruitment function of TCRαβ+CD4-CD8-NK1.1- innate αβ T (iαβT) cells. Mechanistically, CSTF2 diminishes CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3' untranslated regions of CXCL10 RNA, resulting in shortened PolyA tails and compromised RNA stability. Furthermore, we identify Forsythoside B, a selective inhibitor targeting the RNA recognition motif of CSTF2, can effectively activate anti-tumor immunity and overcome resistance to immune checkpoint blockade (ICB) therapy. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.

In recent years, increasing evidence has shown that metals play important roles in both innate and adaptive immunity. An emerging concept of metalloimmunotherapy has been proposed, which may accelerate the development of immunotherapy for cancers. Here, we discuss how metals affect T cell function through different signaling pathways. Metals impact the fate of T cells, including their activation, proliferation, cytotoxicity, and differentiation. Most importantly, metals also participate in mitochondrial operation by regulating energy production and reactive oxygen species homeostasis in T cells. We also identified the metal-based mutual effects between tumor cells and T cells in the tumor microenvironment. Overall, the antitumor effect of T cells can be improved by targeting metal metabolism and metalloimmunotherapy, which will be a step forward in the treatment of cancers.

Breast cancer is currently the most frequently diagnosed malignancy worldwide, with chemotherapy resistance being a major contributor to breast cancer-related mortality and distant metastasis. The role of lymph nodes as the initial site of immune defense remains controversial, particularly regarding whether complete dissection or preservation is necessary during breast cancer surgery.

We performed single-cell RNA sequencing (scRNA-seq) on cells derived from metastatic tumor draining lymph nodes and tumor tissue of four breast cancer patients exhibiting either sensitivity or resistance to neoadjuvant chemotherapy (NAC).

Mast cells with low BTG2 expression were identified in the metastatic lymph nodes and in situ tumor of the NAC-resistant group. Mast cells with low BTG2 expression have enhanced migratory capacity and are preferentially recruited to lymph nodes by cytokines such as CCL5, secreted by tumor cells during metastasis. Mechanistically, the mast cells with low BTG2 suppress anti-tumor immunity by inducing Treg cell production through IL-2 secretion, particularly within tumor-draining lymph nodes. Furthermore, the mast cells with low BTG2 promote NAC resistance by inducing fibroblast precursor cells to differentiate into α-SMA-positive fibroblasts via the Tryptase-PAR-2-pERK signaling pathway, leading to excessive collagen fiber production. Finally, we demonstrated that combining radiotherapy upregulating the expression of BTG2 in mast cells with chemotherapy enhances therapeutic efficacy in a murine model.

This study highlights the immunoregulatory role of mast cells in the breast cancer tumor microenvironment and establishes a link between BTG2 expression in mast cells and neoadjuvant chemotherapy response. These findings provide a foundational basis for preserving functional lymph nodes and optimizing combined radiotherapy treatment strategies.

Extracellular vesicles (EVs) are important mediators of intercellular communication and have various roles in physiological and pathological processes. Discovery of regulators of EV biogenesis and release has led to significant improvements in our understanding of EV biology and has highlighted disease-specific pathways. Large scale discovery studies of EV regulators are limited by conventional methods of EV analysis with limited throughput and sensitivity. To address this, this study presents a high-throughput flow cytometry-based platform for the quantification of EVs released from cells. Here, a system was developed using the MDA-MB-231 cell line stably expressing ZsGreen, which passively loads ZsGreen proteins into EVs, and nanoscale flow cytometry. EV detection and quantitation was optimized and validated for a 96-well format. The high-throughput flow cytometry screening platform quantified the effect of 156 kinase inhibitors on EV number and identified AZ191 - a DYRK1b inhibitor - as a potent EV inhibitor. DYRK1b inhibition and knockdown confirmed a significant reduction in total EV number, with small EVs demonstrating the largest reduction. DYRK1b knockdown altered the intracellular distribution of EV marker CD63, suggesting a role for DYRK1b in EV trafficking. In conclusion, our study establishes a platform for high-throughput analysis of EV dynamics and introduces DYRK1b kinase as a novel EV-regulator.

Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive subtype of breast cancer that faces therapeutic challenges due to a shortage of effective targeted therapies. The complex biology of TNBC renders its clinical management fraught with difficulties, especially regarding the immune microenvironment of the tumor. In recent years, long non-coding RNAs (lncRNAs) have been recognized as important gene regulators with key roles in tumor development and microenvironmental regulation. Previous studies have shown that lncRNAs play important roles in the immune microenvironment of TNBC, including the regulation of tumor immune escape and the function of tumor-infiltrating immune cells. However, despite the increasing research on lncRNAs, there are still many unanswered questions, such as their specific mechanism of action and how to effectively utilize them as therapeutic targets. Therefore, the aim of this study was to review the mechanisms of lncRNAs in the TNBC immune microenvironment, explore their regulatory roles in tumor immune escape and immune cell infiltration, and explore their prospects as potential therapeutic targets. By integrating the latest research results, this study aims to provide new ideas and directions for future TNBC treatment.

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death worldwide. The primary therapies for HCC are liver transplantation, hepatic tumor excision, radiofrequency ablation, and molecular-targeted medicines. An unfavorable prognosis marks HCC and has limited pharmacological response in therapeutic studies. The tumor immune microenvironment (TME) imposes significant selection pressure on HCC, resulting in its evolution and recurrence after various treatments. As the principal cellular constituents of tumor-infiltrating lymphocytes (TILs), T cells have shown both anti-tumor and protumor actions in HCC. T cell-mediated immune responses are pivotal in cancer monitoring and elimination. TILs are recognized for their critical involvement in the progression, prognosis, and immunotherapeutic management of HCC. Foxp3 + , CD8 + , CD3 + , and CD4 + T cells are the extensively researched subtypes of TILs. This article examines the functions and processes of several subtypes of TILs in HCC. Emerging T cell-based therapies, including TILs and chimeric antigen receptor (CAR)-T cell therapy, have shown tumor regression in several clinical and preclinical studies. Herein, it also delves into the existing T cell-based immunotherapies in HCC, with emphasis on TILs and CAR-T cells.

More research has been done on the correlation between exercise and cancer, which has revealed several ways that physical activity decreases the risk of developing the disease. The developing function of lncRNAs as an important molecular link between exercise and cancer suppression is the main topic of this review. According to recent research, regular physical exercise also alters the expression levels of several lncRNAs, which are generally elevated in cancer. A complex network of interactions that may provide protective effects against carcinogenesis is suggested by the contribution of these lncRNAs in various cellular processes, such as epigenetic alterations, proliferation, and apoptosis regulation. We offer a comprehensive summary of the existing information regarding specific lncRNAs that are influenced by physical activity and could potentially impact cancer-related processes. We also go over the difficulties in interpreting these alterations, taking into account the fact that several lncRNAs have a dual function in promoting and preventing cancer in various physiological settings. To understand the complex impacts of exercise-induced lncRNA regulation in cancer biology, more study is required. The critique strongly highlights the possibility of lncRNAs serving as both indicators and treatment prospects for cancer-preventive strategies.

CD8+ T-cell abundance is insufficient to assess antitumor immunity and shows poor performance in predicting breast cancer prognosis and immunotherapy response, presumably owing to the complexity of CD8+ T-cell functionalities. Although single-cell RNA sequencing can dissect the multifaceted functions of CD8+ T cells for better immune assessment, its clinical application is limited. In this study, we developed bulk RNA sequencing-based FuncDimen models from integrative analysis of single-cell RNA sequencing and matched bulk RNA sequencing data to evaluate CD8+ T-cell functionalities across five dimensions: tumor reactivity, cytotoxicity, IFNγ secretion, proliferation, and apoptosis. The FuncDimen models quantifying different functional dimensions of CD8+ T cells were validated in our breast cancer cohort and external databases using immunofluorescence and imaging mass cytometry. We calculated the FuncAggre score by weighted aggregation of all five FuncDimen models to encapsulate the overall antitumor immunity. In our breast cancer cohort and external databases, the FuncAggre score demonstrated superior predictive performance for breast cancer prognosis (time-dependent AUC: 0.56-0.70) and immunotherapy response (AUC: 0.71-0.83) over other immune biomarkers, regardless of the breast cancer molecular subtype. Together, the FuncDimen models offer a refined assessment of antitumor immunity mediated by CD8+ T cells in the clinic, enhancing prognostic prediction and aiding personalized immunotherapy in breast cancer.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Extracellular vesicles (EV) are critical mediators of intercellular communication within the tumor microenvironment, and cancer-cell-secreted EVs often facilitate cancer progression. Here we show that in HBV-associated HCC, tumor-cell-derived EVs contain a TGFβ-inducible long noncoding RNA, termed HDAC2-AS2. EVs enriched with HDAC2-AS2 facilitate cancer progression by suppressing cytotoxicity of intra-tumor CD8+ T cells. Mechanistically, in activated cytotoxic CD8+ T cells, translocation of the transcription factor cyclin-dependent kinase 9 (CDK9), to the cytoplasm is critical for functional integrity. HDAC2-AS2 targets and blocks cytosolic CDK9, and this results in exhaustion of PD-1+CD8+ T cells and suppression of IFN-γ+CD8+ T cell cytotoxicity. Notably, we demonstrate that low CDK9 and high HDAC2-AS2 expressions are associated with poor survival of HCC, which can be rescued by anti-PD-1 therapy. These findings emphasize the significance of tumor-derived EVs in suppressing antitumor CD8+ T cell immunity to promote tumorigenesis, and highlight extracellular HDAC2-AS2 as a promising biomarker and therapeutic target for HCC.

Background/Objectives: Bone metastasis is a common and severe complication of lung adenocarcinoma (LUAD), impacting prognosis and treatment outcomes. Understanding the molecular mechanisms behind LUAD bone metastasis (LUADBM) is essential for developing new therapeutic strategies. The interactions between long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in the competing endogenous RNA (ceRNA) network are crucial in cancer progression and metastasis, but the regulatory mechanisms in LUADBM remain unclear. Methods: Microarray analysis was performed on clinical samples, followed by weighted gene co-expression network analysis (WGCNA) and construction of a ceRNA network. Molecular mechanisms were validated using colony formation assays, transwell migration assays, wound healing assays to assess cell migration, and osteoclastogenesis assays to evaluate osteoclast differentiation. Potential therapeutic drugs and their binding affinities were predicted using the CMap database and Kdeep. The interaction between the small-molecule drug and its target protein was confirmed by surface plasmon resonance (SPR) and drug affinity responsive target stability (DARTS) assays. Mechanistic insights and therapeutic efficacy were further validated using patient-derived organoid (PDO) cultures, drug sensitivity assays, and in vivo drug treatments. Results: Our results identified the XLOC_006941/hsa-miR-543/NPRL3 axis as a key regulatory pathway in LUADBM. We also demonstrated that GATA3-driven Th2 cell infiltration creates an immunosuppressive microenvironment that promotes metastasis. Additionally, we confirmed that the inhibitor E7449 effectively targets NPRL3, and its combination with the IL4R-blocking antibody dupilumab resulted in improved therapeutic outcomes in LUADBM. Conclusions: These findings offer new insights into the molecular mechanisms of LUADBM and highlight potential therapeutic targets, including the XLOC_006941/miR-543/NPRL3 axis and GATA3-driven Th2 cell infiltration. The dual-target therapy combining E7449 with dupilumab shows promise for improving patient outcomes in LUADBM, warranting further clinical evaluation.

Non-coding RNAs have long been recognized for their regulatory roles in various cellular processes, including cancer development and progression. Recent advancements have shed light on a novel aspect of non-coding RNA biology, revealing their ability to encode endogenous peptides also named micropeptides or microprotein through short open reading frames (sORFs). These small proteins play crucial roles in oncogenic processes, acting as either tumour suppressors or tumour promoters, and hold enormous potential as biomarkers for early diagnosis of cancer and as therapeutic targets. This comprehensive review highlights the state of the art on peptides encoded by long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), elucidating their regulatory functions and implications in different cancer types, including breast cancer, hepatocellular carcinoma and colorectal cancer. The review also discusses challenges and future directions in the exploration of these emerging players in cancer biology, emphasizing the importance of further investigation for their clinical translation in diagnosis and therapy.

Recently, the various regulative functions of long non-coding RNAs (LncRNAs) have been well determined. Recently, the vital role of LncRNAs as gene regulators has been identified in the immune system, especially in the inflammatory response. All cells of the immune system are governed by a complex and ever-changing gene expression program that is regulated through both transcriptional and post-transcriptional processes. LncRNAs regulate gene expression within the cell nucleus by influencing transcription or through post-transcriptional processes that affect the splicing, stability, or translation of messenger RNAs (mRNAs). Recent studies in immunology have revealed substantial alterations in the expression of lncRNAs during the activation of the innate immune system as well as the development, differentiation, and activation of T cells. These lncRNAs regulate key aspects of immune function, including the manufacturing of inflammatory molecules, cellular distinction, and cell movement. They do this by modulating protein-protein interactions or through base pairing with RNA and DNA. Here we review the current understanding of the mechanism of action of lncRNAs as novel immune-related regulators and their impact on physiological and pathological processes related to the immune system, including autoimmune diseases. We also highlight the emerging pattern of gene expression control in important research areas at the intersection between immunology and lncRNA biology.

Previously considered junk or non-functional, long non-coding RNAs (lncRNAs) have emerged over the past few decades as pivotal components in both physiological and pathological processes, including cancer. Neuroblastoma-associated transcript-1 (NBAT-1) was initially discovered a decade ago as a risk-associated tumor suppressor lncRNA in neuroblastoma (NB). Subsequent studies have consistently demonstrated that NBAT-1 serves as a dedicated tumor suppressor in many cancers. NBAT-1 is significantly downregulated in cancer, which is closely linked to higher histological grades, increased metastasis, and poor survival in cancer patients suggesting NBAT-1's potential as a prognostic biomarker. In this review, we delve into the current body of literature, elucidating the tumor-suppressive roles of NBAT-1 and the underlying regulatory mechanisms in the context of human malignancies. Additionally, we shed light on the mechanisms contributing to the diminished expression of NBAT-1 and its potential as both a prognostic biomarker and a promising therapeutic target in cancer.

A new type of nonapoptotic, iron-dependent cell death induced by lipid peroxidation is known as ferroptosis. Numerous pathological processes, including inflammation and cancer, have been demonstrated to be influenced by changes in the ferroptosis-regulating network. Long non-coding RNAs (LncRNAs) are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that lncRNAs can interfere with the progression of ferroptosis by modulating ferroptosis-related genes directly or indirectly. Despite evidence implicating lncRNAs in cancer and inflammation, studies on their mechanisms and therapeutic potential remain scarce. We investigate the mechanisms of lncRNA-mediated regulation of inflammation and cancer immunity, assessing the feasibility and challenges of lncRNAs as therapeutic targets in these conditions.

Despite the progress made in the development of targeted therapies, breast cancer (BC) continues to pose a significant threat to the health of women. Transcriptomics has emerged due to the advancements in high-throughput sequencing technology. This provides crucial information about the role of non-coding RNAs (ncRNAs) in human cells, particularly long ncRNAs (lncRNAs), in disease development and function. When the control of these ncRNAs is disrupted, various illnesses emerge, including cancer. Numerous studies have produced empirical data on the function of lncRNAs in tumorigenesis and disease development. However, the roles and mechanisms of numerous lncRNAs remain unidentified at the molecular level because their regulatory role and the functional implications of abnormalities in cancer biology have yet to be thoroughly defined. The review gives an itemized summary of the most current developments in the role of lncRNA in BC, focusing on three main pathways, PI3K, MAPK, NF-kB, and hypoxia, and their resistance mechanisms.

CFTR, which belongs to the ATP-binding cassette transporter family and whose members are always involved in cancer progression, is implicated in lung adenocarcinoma (LUAD) progression, but the underlying mechanism remains undefined. Therefore, this study intended to investigate how CFTR works exactly on LUAD progression.

Bioinformatics methods were utilized to analyze GATA6 and CFTR expression in LUAD and targeting relationship, followed by a pathway enrichment analysis of CFTR. GATA6 and CFTR expression levels were assessed by qRT-PCR. Cell viability and proliferation were detected through MTT and colony formation assays. An arachidonic acid (AA) assay kit was utilized to measure AA content. mRNA and protein expression levels of genes (cPLA2, COX-2, and CYP1A1) related to the AA metabolism pathway were detected by qRT-PCR and western blot, respectively. Moreover, the Dual-luciferase reporter gene assay and ChIP were used to verify the binding of GATA6 and CFTR promoters.

GATA6 and CFTR were lowly expressed in LUAD, and CFTR was enriched in the AA metabolism pathway. GATA6 activated CFTR transcription. Cellular and rescue experiments revealed that low or high CFTR expression could foster or hamper LUAD cell viability and proliferation, and concomitant treatment of indomethacin, an AA metabolism pathway inhibitor, mitigated stimulation on LUAD progression by low CFTR expression. Silencing of GATA6 reversed the suppressive impact of CFTR overexpression on LUAD progression via modulation of the AA metabolism pathway.

The activation of CFTR by GATA6 hampered LUAD progression by modulating the AA metabolism pathway, suggesting that GATA6/CFTR axis might be a therapeutic target for LUAD patients.

Myasthenia gravis (MG) is an acquired autoimmune disease that is mediated by humoral immunity, supplemented by cellular immunity, along with participation of the complement system. The pathogenesis of MG is complex; although autoimmune dysfunction is clearly implicated, the specific mechanism remains unclear. Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules with lengths greater than 200 nucleotides, with increasing evidence of their rich biological functions and high-level structure conservation. LncRNAs can directly interact with proteins and microRNAs to regulate the expression of target genes at the transcription and post-transcription levels. In recent years, emerging studies have suggested that lncRNAs play roles in the differentiation of immune cells, secretion of immune factors, and complement production in the human body. This suggests the involvement of lncRNAs in the occurrence and progression of MG through various mechanisms. In addition, the differentially expressed lncRNAs in peripheral biofluid may be used as a biomarker to diagnose MG and evaluate its prognosis. Moreover, with the development of lncRNA expression regulation technology, it is possible to regulate the differentiation of immune cells and influence the immune response by regulating the expression of lncRNAs, which will provide a potential therapeutic option for MG. Here, we review the research progress on the role of lncRNAs in different pathophysiological events contributing to MG, focusing on specific lncRNAs that may largely contribute to the pathophysiology of MG, which could be used as potential diagnostic biomarkers and therapeutic targets.

Progress in the identification of core multi-protein modules within JAK/STAT pathway has enabled researchers to develop a better understanding of the linchpin role of deregulated signaling cascade in carcinogenesis and metastasis. More excitingly, complex interplay between JAK/STAT pathway and non-coding RNAs has been shown to reprogramme the outcome of signaling cascade and modulate immunological responses within tumor microenvironment. Wealth of information has comprehensively illustrated that most of this complexity regulates the re-shaping of the immunological responses. Increasingly sophisticated mechanistic insights have illuminated fundamental role of STAT-signaling in polarization of macrophages to M2 phenotype that promotes disease aggressiveness. Overall, JAK/STAT signaling drives different stages of cancer ranging from cancer metastasis to the reshaping of the tumor microenvironment. JAK/STAT signaling has also been found to play role in the regulation of infiltration and activity of natural killer cells and CD4/CD8 cells by PD-L1/PD-1 signaling. In this review, we have attempted to set spotlight on regulation of JAK/STAT pathway by microRNAs, long non-coding RNAs and circular RNAs in primary tumors and metastasizing tumors. Therefore, existing knowledge gaps need to be addressed to propel this fledgling field of research to the forefront and bring lncRNAs and circRNAs to the frontline of clinical practice. Leveraging the growing momentum will enable interdisciplinary researchers to gain transition from segmented view to a fairly detailed conceptual continuum.

Cancer remains a major global health concern with high mortality rates mainly due to late diagnosis and poor prognosis. Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression in human cancer, functioning through various mechanisms including as competing endogenous RNAs (ceRNAs) and indirectly regulating miRNA expression. LncRNAs have been found to have both oncogenic and tumor-suppressive roles in cancer, with the former promoting cancer cell proliferation, migration, invasion, and poor prognosis. Recent research has shown that lncRNAs are expressed in various immune cells and are involved in cancer cell immune escape and the modulation of the tumor microenvironment, thus highlighting their potential as targets for cancer immunotherapy. Targeting lncRNAs in cancer or immune cells could enhance the anti-tumor immune response and improve cancer immunotherapy outcomes. However, further research is required to fully understand the functional roles of lncRNAs in cancer and the immune system and their potential as targets for cancer immunotherapy. This review offers a comprehensive examination of the multifaceted roles of lncRNAs in human cancers, with a focus on their potential as targets for cancer immunotherapy. By exploring the intricate mechanisms underlying lncRNA-mediated regulation of cancer cell proliferation, invasion, and immune evasion, we provide insights into the diverse therapeutic applications of these molecules.

This study aimed to investigate the expression and prognostic significance of the MRPL23 protein and mRNA in clear-cell renal cell carcinoma (ccRCC) and adjacent non-tumorous tissues. The goal was to assess the impact of MRPL23 expression on tumor behavior, progression, and patient outcomes.

Using immunohistochemistry (IHC), MRPL23 protein expression was analyzed in 99 cases of ccRCC and 30 adjacent non-tumorous tissues. mRNA levels were assessed using data from The Cancer Genome Atlas (TCGA). Correlations between MRPL23 expression and clinicopathological features were examined, and survival outcomes were evaluated using Kaplan-Meier survival curves and Cox regression analyses.

MRPL23 protein expression was significantly lower in ccRCC tissues compared to normal tissues. In contrast, mRNA levels of MRPL23 were significantly elevated in ccRCC tissues. Expression levels were correlated with clinicopathological features, including gender, tumor grade, pT status, and disease stage, underlining their impact on tumor progression. Elevated MRPL23 protein expression was associated with poorer overall survival (OS) in ccRCC patients and remained an independent prognostic marker for adverse outcomes after adjustment for confounding variables. While high MRPL23 mRNA expression was also linked to worse OS, it did not retain its status as an independent prognostic factor after adjustments.

MRPL23 protein expression is a potential independent prognostic biomarker in ccRCC, emphasizing its utility in predicting patient outcomes and potentially guiding therapeutic decisions. These findings highlight the importance of further research into the role of MRPL23 in ccRCC pathogenesis and its potential as a therapeutic target.

Tumor cells engage with the immune system in a complex manner, utilizing evasion and adaptability mechanisms. The development of cancer and resistance to treatment relies on the ability of immune cells to adjust their phenotype and function in response to cues from the tumor microenvironment, known as immunological cell plasticity. This study delves into the role of long non-coding RNAs (lncRNAs) in enhancing immune cell flexibility in cancer, focusing on their regulatory actions in the tumor microenvironment and potential therapeutic implications. Through a comprehensive review of existing literature, the study analyzes the impact of lncRNAs on macrophages, T-cells, and MDSCs, as well as the influence of cytokines and growth factors like TNF, IL-6, HGF, and TGFβ on immunological cell plasticity and tumor immunoediting. LncRNAs exert a strong influence on immune cell plasticity through mechanisms such as transcriptional regulation, post-transcriptional modifications, and chromatin remodeling. These RNA molecules intricately modulate gene expression networks, acting as scaffolding, decoys, guides, and sponges. Moreover, both direct cell-cell interactions and soluble chemicals in the tumor microenvironment contribute to enhancing immune cell activation and survival. Understanding the influence of lncRNAs on immune cell flexibility sheds light on the biological pathways of immune evasion and cancer progression. Targeting long non-coding RNAs holds promise for amplifying anti-tumor immunity and overcoming drug resistance in cancer treatment. However, further research is necessary to determine the therapeutic potential of manipulating lncRNAs in the tumor microenvironment.

Metabolism reprogramming (MR) is one of the top ten hallmarks of malignant tumors. The aberrant activation of MR has been recognized as a critical contributory factor to the malignant progression of solid tumors. Moreover, various long non-coding RNAs (lncRNAs) are implicated in the aberrant activation of MR in solid tumor cells. Therefore, in this review, we mainly focus on summarizing the functional relevance and molecular mechanistic underpinnings of lncRNAs in modulating MR of solid tumors by targeting glucose metabolism, lipid metabolism, affecting mitochondrial function, and regulating interactions between tumor and non-tumor cells in tumor microenvironment. Besides, we also underscore the potential for constructing lncRNAs-centered tumor metabolic regulation networks and developing novel anti-tumor strategies by targeting lncRNAs and abnormal MR. Ultimately, this review seeks to offer new targets and avenues for the clinical treatment of solid tumors in the future.

This study aims to investigate the mechanism by which PAARH promotes M2 macrophage polarization and immune evasion of liver cancer cells through VEGF, in order to reveal its role in the progression of liver cancer.

The expressions of PAARH, VEGF, and HIF-1α in liver cancer cells were detected using qRT-PCR and Western blot. Flow cytometry was utilized to analyze the polarization status of macrophages and assess the impact on immune evasion-related markers. The relationship between PAARH and VEGF in macrophage polarization was further explored. Additionally, a tumor-bearing mouse model was established to observe tumor growth.

The results show that PAARH is upregulated in liver cancer cells, and silencing PAARH significantly inhibits tumor malignancy progression. Under hypoxic conditions, overexpression of PAARH significantly increases VEGF expression, and PAARH regulates M2 macrophage polarization through VEGF. Overexpression of PAARH significantly promotes M2 macrophage polarization, increases levels of PD-L1 and Th2 immune response markers, and enhances cell proliferation, migration, and invasion; it also suppresses M1 macrophage polarization, decreases levels of PD-L2 and Th1 immune response markers, and inhibits cell apoptosis. Silencing VEGF reverses these effects. Silencing PAARH or overexpressing VEGF weakens the malignant phenotype of the cells and immune evasion. Results from the tumor-bearing mouse model indicate that silencing PAARH significantly reduces tumor size and weight, while overexpressing VEGF significantly increases tumor volume and weight.

PAARH enhances the immune evasion capability of liver cancer cells by upregulating VEGF to promote M2 macrophage polarization, suggesting that PAARH may serve as a new therapeutic target for liver cancer.

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.

Breast cancer (BC) is one of the frequent tumors that seriously endanger the physical and mental well-being in women with strong heterogeneity, and its pathogenesis involves multiple risk factors. Depending on the type of BC, hormonal therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Despite significant progress in understanding BC pathogenesis and therapeutic options, there is still a need to identify new therapeutic targets and develop more effective treatments. According to recent sequencing and profiling studies, non-coding (nc) RNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation, and similarly, the expression of many ncRNAs is altered in breast cancer cell lines and tissues. The ability of single ncRNAs to regulate the expression of multiple downstream gene targets and related pathways provides a theoretical basis for studying them for cancer therapeutic drug development and targeted delivery. Therefore, it is far-reaching to explore the role of ncRNAs in tumor development and their potential as therapeutic targets. Here, our review outlines the potential of two major ncRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) as diagnostic and prognostic biomarkers as well as targets for new therapeutic strategies in breast cancer.

Engineered T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic effects on haematological malignancies. However, CART cells are less effective on solid tumours mainly due to their weak persistence, which might be caused by activation-induced cell death (AICD). To overcome this limitation, CART cell with the antigen, Epidermal growth factor receptor variant III (EGFRvIII), targeting was modified to carry the anti-apoptotic molecule B cell lymphoma 2 (Bcl-2), and the final construct was named as EGFRvIII·CART-Bcl2 cells. Compared with the EGFRvIII·CART cells, EGFRvIII·CART-Bcl2 cells revealed higher capacities of proliferation, anti-apoptosis and tumour cell killing in vitro. Moreover, EGFRvIII·CART-Bcl2 cells had a longer persistence rate and exerted better anti-tumour effects than EGFRvIII·CART cells in cervical carcinoma xenograft model. Taken together, our findings suggest that incorporating anti-apoptotic molecules into CART cells may enhance its therapeutic effects against solid tumours.

In the intricate field of cancer biology, researchers are increasingly intrigued by the emerging role of exosomal long non-coding RNAs (lncRNAs) due to their multifaceted interactions, complex modulation mechanisms, and potential therapeutic applications. These exosomal lncRNAs, carried within extracellular vesicles, play a vital partin tumorigenesis and disease progression by facilitating communication networks between tumor cells and their local microenvironment, making them an ideal candidates for use in a liquid biopsy approach. However, exosomal lncRNAs remain an understudied area, especially in cancer biology. Therefore this review aims to comprehensively explore the dynamic interplay between exosomal lncRNAs and various cellular components, including interactions with tumor-stroma, immune modulation, and drug resistance mechanisms. Understanding the regulatory functions of exosomal lncRNAs in these processes can potentially unveil novel diagnostic markers and therapeutic targets for cancer. Additionally, the emergence of RNA-based therapeutics presents exciting opportunities for targeting exosomal lncRNAs, offering innovative strategies to combat cancer progression and improve treatment outcomes. Thus, this review provides insights into the current understanding of exosomal lncRNAs in cancer biology, highlighting their crucial roles, regulatory mechanisms, and the evolving landscape of therapeutic interventions. Furthermore, we have also discussed the advantage of exosomes as therapeutic carriers of lncRNAs for the development of personalized targeted therapy for cancer patients.

As global population ageing accelerates, cancer emerges as a predominant cause of mortality. Long non-coding RNAs (lncRNAs) play crucial roles in cancer cell growth and death, given their involvement in regulating downstream gene expression levels and numerous cellular processes. Cell death, especially non-apoptotic regulated cell death (RCD), such as ferroptosis, pyroptosis and necroptosis, significantly impacts cancer proliferation, invasion and metastasis. Understanding the interplay between lncRNAs and the diverse forms of cell death in cancer is imperative. Modulating lncRNA expression can regulate cancer onset and progression, offering promising therapeutic avenues. This review discusses the mechanisms by which lncRNAs modulate non-apoptotic RCDs in cancer, highlighting their potential as biomarkers for various cancer types. Elucidating the role of lncRNAs in cell death pathways provides valuable insights for personalised cancer interventions.

TP53, a guardian of the genome, suppresses or enhances tumors through various regulatory pathways. However, the role of p53-related long non-coding RNAs (lncRNAs) in immune regulation of tumor microenvironment and prognosis of gastric cancer (GC) is so far unelucidated. We analyzed the role of TP53-associated lncRNAs (obtained from the TP53LNC-DB database) in immune regulation, immune cell infiltration and RNA modification in gastric cancer. Firstly, using multivariate COX regression analysis, we identified eight lncRNAs related to the prognosis of GC. Furthermore, based on the expression of the lncRNA signature and risk score, the GC patients were divided into high-risk and low-risk groups. We found that M2-macrophages have significantly higher infiltration in the high-risk group. Similarly, significant differences in immune function (APC_co_stimulation, CCR, and checkpoint) and m6A modification (FTO, ZC3H13, YTHDC1, and RBM15), and m5C modification (NOP2 and TET1) between both groups were also observed. These signature lncRNAs were also positively associated with oxidative stress-related genes (MPO, MAPK14, HMOX1, and APP). Additionally, we found that high expression of GAS5 and low expression of MALAT1 in Helicobacter pylori (H-pylori) positive GC patients. Finally, GC patients in the low-risk group showed higher resistance to immunotherapy while patients in the high-risk group were more sensitive to various chemotherapy drugs. Based on these findings, we conclude that p53-associated lncRNAs signature could potentially predict the immune status and overall survival, and may also be used for risk management and planning immunotherapy for gastric cancer patients.

Myasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined.

Using microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter.

Based on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566.

In summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.

RNA therapeutics (RNATx) aim to treat diseases, including cancer, by targeting or employing RNA molecules for therapeutic purposes. Amongst the most promising targets are long non-coding RNAs (lncRNAs), which regulate oncogenic molecular networks in a cell type-restricted manner. lncRNAs are distinct from protein-coding genes in important ways that increase their therapeutic potential yet also present hurdles to conventional clinical development. Advances in genome editing, oligonucleotide chemistry, multi-omics and RNA engineering are paving the way for efficient and cost-effective lncRNA-focused drug discovery pipelines. In this Review, we present the emerging field of lncRNA therapeutics for oncology, with emphasis on the unique strengths and challenges of lncRNAs within the broader RNATx framework. We outline the necessary steps for lncRNA therapeutics to deliver effective, durable, tolerable and personalized treatments for cancer.

Cholangiocarcinoma (CCA) is becoming more common and deadly worldwide. Tumor-infiltrating T cell subtypes make distinct contributions to the immune system; collectively, they constitute a significant portion of the tumor microenvironment (TME) in CCA. By secreting cytokines and other chemicals, regulatory T cells (Tregs) decrease activated T cell responses, acting as immunosuppressors. Reduced CD8+ T cell activation results in stimulating programmed death-1 (PD-1), which undermines the immunological homeostasis of T lymphocytes. On the other hand, cancer cells are eliminated by activated cytotoxic T lymphocyte (CTL) through the perforin-granzyme or Fas-FasL pathways. Th1 and CTL immune cell infiltration into the malignant tumor is also facilitated by γδ T cells. A higher prognosis is typically implied by CD8+ T cell infiltration, and survival is inversely associated with Treg cell density. Immune checkpoint inhibitors, either singly or in combination, provide novel therapeutic strategies for CCA immunotherapy. Furthermore, it is anticipated that immunotherapeutic strategies-such as the identification of new immune targets, combination treatments involving several immune checkpoint inhibitors, and chimeric antigen receptor-T therapies (CAR-T)-will optimize the effectiveness of anti-CCA treatments while reducing adverse effects.

Colon adenocarcinoma (COAD) is one of the most common malignant tumors. The interplay involving ferroptosis between tumor and immune cells plays a crucial in cancer progression. However, the biological basis of this interplay in COAD development remains elusive.

Transcriptome data of COAD samples were obtained from The Cancer Genome Atlas and National Center for Biotechnology Information databases. Using single-sample gene set enrichment analysis, we calculated the ferroptosis score (FS) and immune cell infiltration levels for each sample, leveraging the expression levels of genes related to ferroptosis and various immune cell types. Samples with FSs greater than the 75th percentile were classified into the high-FS subgroup, while those below the 25th percentile were categorized as the low-FS subgroup. Moreover, tumor tissue samples and adjacent normal tissue samples were collected from twenty colon patients. Using real-time quantitative polymerase chain reaction, we validated the expression of certain genes in these samples.

The COAD samples with high FSs experienced favorable survival probability and heightened sensitivity to anticancer drugs, with FSs negatively associated with the pathological stages. Moreover, the up-regulated genes in high-FS subgroup exhibited enrichment in immune-related pathways, suggesting a correlation between immunity and ferroptosis. Importantly, we discovered a key lncRNA-mRNA co-expression network linking tumor cell ferroptosis and immune infiltration (e.g., neutrophil) in the progression and classification of COAD. Further analysis identified several ferroptosis-related lncRNAs (e.g., RP11-399O19.9) within this network, indicating their potential roles in COAD progression and deserving in-depth study.

Our findings provide novel insights into the underlying biological basis, particularly involving lncRNAs, at gene expression level associated with ferroptosis in COAD and cancer therapy. Nevertheless, further analysis and validation are required to expand the findings.

The aim of the present study was to explore the functional mechanism of NF-Kappa B-interacting Long non-protein coding RNA (NKILA) in breast malignant phyllodes tumors (BMPTs). The expression and functional role of NKILA were investigated by performing qRT‒PCR, Transwell assays, and CCK‒8 assays in primary BMPT cells. A Kaplan‒Meier curve was used to assess overall survival (OS) and local recurrence-free survival (LRFS). The location and expression levels of NKILA and P65 were determined by fluorescence in situ hybridization (FISH) and immunofluorescence (IF), respectively. NKILA was downregulated in patients with BMPT, especially in patients with local recurrence. NKILA had an antitumor effect and promoted the chemosensitivity of cells to cisplatin by blocking P65 phosphorylation and nuclear translocation. In conclusion, NKILA may be a potential therapeutic target for BMPT, especially for BMPT patients with local recurrence.

Normal cell and body functions need to be maintained and protected against endogenous and exogenous stress conditions. Different cellular stress response pathways have evolved that are utilized by mammalian cells to recognize, process and overcome numerous stress stimuli in order to maintain homeostasis and to prevent pathophysiological processes. Although these stress response pathways appear to be quite different on a molecular level, they all have in common that they integrate various stress inputs, translate them into an appropriate stress response and eventually resolve the stress by either restoring homeostasis or inducing cell death. It has become increasingly appreciated that non-protein-coding RNA species, such as long noncoding RNAs (lncRNAs), can play critical roles in the mammalian stress response. However, the precise molecular functions and underlying modes of action for many of the stress-related lncRNAs remain poorly understood. In this review, we aim to provide a framework for the categorization of mammalian lncRNAs in stress response and homeostasis based on their experimentally validated modes of action. We describe the molecular functions and physiological roles of selected lncRNAs and develop a concept of how lncRNAs can contribute as versatile players in mammalian stress response and homeostasis. These concepts may be used as a starting point for the identification of novel lncRNAs and lncRNA functions not only in the context of stress, but also in normal physiology and disease.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer-associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF-derived extracellular vesicle (EV)-packaged long non-coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV-packaged lncRNA RP11-161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA-A expression, a key component of antigen presentation. Mechanistically, RP11-161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4-NOT complex, enhancing the degradation of HLA-A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti-tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA-based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF-derived EV-packaged lncRNA RP11-161H23.5/CNOT4/HLA-A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention.