Long non-coding RNAs in ferroptosis, pyroptosis and necroptosis: from functions to clinical implications in cancer therapy.

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.

Extracellular vesicles in the HCC microenvironment: Implications for therapy and biomarkers.

Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer and the third leading cause of cancer mortality globally. Despite surgical resection being the preferred approach for early-stage HCC, most patients are diagnosed at intermediate to advanced stages, limiting treatment options to chemotherapy and immunotherapy, which often yield poor outcomes. Extracellular vesicles (EVs), minute lipid-bilayered particles released by diverse cells under various physiological and pathological conditions, are crucial for mediating communication between cells. Mounting evidence indicates that EVs sourced from different cells can profoundly influence the HCC tumor microenvironment (TME), thereby affecting the progression of HCC. Given their immunogenicity and liver-targeting properties, these EVs not only hold promise for HCC treatment but also provide avenues for advancing early diagnostic methods and assessing prognosis. This review not only describes the function of EVs within the HCC tumor microenvironment but also analyzes their therapeutic advantages and explores their significance in various therapeutic approaches for HCC, including chemotherapy, immunotherapy, combination therapy, and their role as innovative drug delivery carriers. Furthermore, it highlights the potential of EVs as biomarkers for the diagnosis and prognosis of HCC.

Extracellular vesicle-derived biomarkers in prostate cancer care: Opportunities and challenges.

Prostate cancer (PCa) is the second most prevalent cancer in men worldwide, presenting a significant global public health challenge that necessitates early detection and personalized treatment. Recently, non-invasive liquid biopsy methods have emerged as promising tools to provide insights into the genetic landscape of PCa and monitor disease progression, aiding decision-making at all stages. Research efforts have concentrated on identifying liquid biopsy biomarkers to improve PCa diagnosis, prognosis, and treatment prediction. This article reviews recent research advances over the last five years utilizing extracellular vesicles (EVs) as a natural biomarker library for PCa, and discusses the clinical translation of EV biomarkers, including ongoing trials and key implementation challenges. The findings underscore the transformative role of liquid biopsy, particularly EV-based biomarkers, in revolutionizing PCa diagnosis, prediction, and treatment.

Nuclear receptors in ovarian cancer: changing paradigms in cancer therapeutics.

Ovarian cancer (OVC) is one of the most common causes of cancer-related deaths in women worldwide. Despite advancements in detection and therapy, the prognosis of OVC remains poor due to late diagnosis and the lack of effective therapeutic options at advanced stages. Therefore, a better understanding of the biology underlying OVC is essential for the development of effective strategies for early detection and targeted therapies. Nuclear receptors (NRs) are a superfamily of 48 transcription factors that, upon binding to their specific ligand, play a vital role in regulating various cellular processes such as growth, development, metabolism, and homeostasis. Accumulating evidence from several studies has shown that their aberrant expression is associated with multiple human diseases. Numerous NRs have shown significant effects in the development of various cancers, including OVC. This review summarizes the recent findings on the role of NRs in OVC, as well as their potential as prognostic and therapeutic markers. Further, the basic structure and signaling mechanism of NRs have also been discussed briefly. Moreover, this review highlights their cellular and molecular mechanisms in chemoresistance and chemosensitization. Further, the clinical trials targeting NRs for the treatment of OVC have also been discussed.

The role of extracellular vesicles in pyroptosis-mediated infectious and non-infectious diseases.

Pyroptosis, a lytic and pro-inflammatory cell death, is important in various pathophysiological processes. Host- and bacteria-derived extracellular vesicles (EVs), as natural nanocarriers messengers, are versatile mediators of intercellular communication between different types of cells. Recently, emerging research has suggested that EVs exhibit multifaceted roles in disease progression by manipulating pyroptosis. This review focuses on new findings concerning how EVs shape disease progression in infectious and non-infectious diseases by regulating pyroptosis. Understanding the characteristics and activity of EVs-mediated pyroptotic death may conducive to the discovery of novel mechanisms and more efficient therapeutic targets in infectious and non-infectious diseases.

Cuproptosis in cancers: Function and implications from bench to bedside.

Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery of a novel type of copper-dependent cell death, known as cuproptosis, has shed light on its role in cancer development. Extensive research is currently underway to unravel the mechanisms underlying cuproptosis and its correlation with various cancer types. In this review, we summarize the findings regarding the roles and mechanisms of cuproptosis in various cancer types, including colorectal cancer, lung cancer, gastric cancer, breast cancer, liver cancer and cutaneous melanoma. Furthermore, the effects of copper-related agents such as copper chelators and copper ionophores on cell proliferation, apoptosis, angiogenesis, tumor immunity, and chemotherapy resistance have been explored in cancer preclinical and clinical trials. These insights provide promising avenues for the development of prospective anticancer drugs aimed at inducing cuproptosis.

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti-PD-1/PD-L1 cancer immunotherapy.

Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), have shown clinical efficacy in clinical tumour immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses to this treatment. An emerging avenue involves triggering non-apoptotic regulated cell death (RCD), a significant mechanism driving cancer cell death in diverse cancer treatments. Recent research demonstrates that combining RCD inducers with ICIs significantly enhances their antitumor efficacy across various cancer types. The use of anti-PD-1/PD-L1 immunotherapy activates CD8+ T cells, prompting the initiation of novel RCD forms, such as ferroptosis, pyroptosis, and necroptosis. However, the functions and mechanisms of non-apoptotic RCD in anti-PD1/PD-L1 therapy remain insufficiently explored. This review summarises the emerging roles of ferroptosis, pyroptosis, and necroptosis in anti-PD1/PD-L1 immunotherapy. It emphasises the synergy between nanomaterials and PD-1/PD-L1 inhibitors to induce non-apoptotic RCD in different cancer types. Furthermore, targeting cell death signalling pathways in combination with anti-PD1/PD-L1 therapies holds promise as a prospective immunotherapy strategy for tumour treatment.

AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies.

Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17ß-hydroxysteroid dehydrogenase (17ß-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17ß-estradiol (a potent estrogen), and 11ß-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Novel AKR1C3 inhibitors, including natural products and analogues of existing drugs designed based on their structures and frameworks, continue to be discovered and developed in laboratories worldwide. The AKR1C3 enzyme has emerged as a key player in carcinoma progression and therapeutic resistance, posing challenges in cancer treatment. This review aims to provide a comprehensive analysis of AKR1C3's role in carcinoma development, its implications in therapeutic resistance, and recent advancements in the development of AKR1C3 inhibitors for tumor therapies.

Perspective view of allogeneic IgG tumor immunotherapy.

Allogeneic tumors are eradicated by host immunity; however, it is unknown how it is initiated until the report in Nature by Yaron Carmi et al. in 2015. Currently, we know that allogeneic tumors are eradicated by allogeneic IgG via dendritic cells. AlloIgG combined with the dendritic cell stimuli tumor necrosis factor alpha and CD40L induced tumor eradication via the reported and our proposed potential signaling pathways. AlloIgG triggers systematic immune responses targeting multiple antigens, which is proposed to overcome current immunotherapy limitations. The promising perspectives of alloIgG immunotherapy would have advanced from mouse models to clinical trials; however, there are only 6 published articles thus far. Therefore, we hope this perspective view will provide an initiative to promote future discussion.

Extracellular vesicle-mediated ferroptosis, pyroptosis, and necroptosis: potential clinical applications in cancer therapy.

Extracellular vesicles (EVs) have gained increasing recognition as significant regulators of intercellular communication in various physiological and pathological processes. These vesicles play a pivotal role in cancer progression by facilitating the transfer of diverse cargoes, including lipids, proteins, and nucleic acids. Regulated cell death (RCD), the orderly and autonomous death of cells, is controlled by a variety of biomacromolecules and, in turn, influences various biological processes and cancer progression. Recent studies have demonstrated that EV cargoes regulate diverse oncogenes and tumor suppressors to mediate different nonapoptotic forms of RCD, notably ferroptosis, pyroptosis, and necroptosis. Nevertheless, comprehensive exploration of EV-mediated nonapoptotic RCD forms in the context of cancer has not been performed. This review summarizes the progress regarding the biological functions and underlying mechanisms of EVs in mediating nonapoptotic RCD by delivery of cargoes to regulate tumor progression. Additionally, the review delves into the potential clinical applications of EV-mediated cell death and its significance in the areas of cancer diagnosis and therapy.

Unleashing the efficacy of immune checkpoint inhibitors for advanced hepatocellular carcinoma: factors, strategies, and ongoing trials.

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing approximately 85% of cases. The diagnosis is often made in the middle and late stages, necessitating systemic treatment as the primary therapeutic option. Despite sorafenib being the established standard of care for advanced HCC in the past decade, the efficacy of systemic therapy remains unsatisfactory, highlighting the need for novel treatment modalities. Recent breakthroughs in immunotherapy have shown promise in HCC treatment, particularly with immune checkpoint inhibitors (ICIs). However, the response rate to ICIs is currently limited to approximately 15%-20% of HCC patients. Recently, ICIs demonstrated greater efficacy in "hot" tumors, highlighting the urgency to devise more effective approaches to transform "cold" tumors into "hot" tumors, thereby enhancing the therapeutic potential of ICIs. This review presented an updated summary of the factors influencing the effectiveness of immunotherapy in HCC treatment, identified potential combination therapies that may improve patient response rates to ICIs, and offered an overview of ongoing clinical trials focusing on ICI-based combination therapy.

The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside.

Extracellular vesicles (EVs) are membrane-encapsulated vesicles released by almost all cell types, which participate in intercellular communication by delivering different types of molecular cargoes, such as non-coding RNAs (ncRNAs). Accumulating evidence suggests that tumor-derived EVs act as a bridge for intercellular crosstalk between tumor cells and surrounding cells, including immune cells. Tumor-derived EVs containing ncRNAs (TEV-ncRNAs) mediate intercellular crosstalk to manipulate immune responses and affect the malignant phenotypes of cancer cells. In this review, we summarize the double-edged roles and the underlying mechanisms of TEV-ncRNAs in regulating innate and adaptive immune cells. We also highlight the advantages of using TEV-ncRNAs in liquid biopsies for cancer diagnosis and prognosis. Moreover, we outline the use of engineered EVs to deliver ncRNAs and other therapeutic agents for cancer therapy.

Dual Effects of miR-181b-2-3p/SOX21 Interaction on Microglia and Neural Stem Cells after Gamma Irradiation.

Ionizing radiation induces brain inflammation and the impairment of neurogenesis by activating microglia and inducing apoptosis in neurogenic zones. However, the causal relationship between microglial activation and the impairment of neurogenesis as well as the relevant molecular mechanisms involved in microRNA (miR) remain unknown. In the present study, we employed immunohistochemistry and real-time RT-PCR to study the microglial activation and miRNA expression in mouse brains. Real-time RT-PCR, western blot, ELISA, cell proliferation and cytotoxicity assay were used in BV2 and mouse neural stem cells (NSCs). In the mouse model, we found the acute activation of microglia at 1 day and an increased number of microglial cells at 1, 7 and 120 days after irradiation at postnatal day 3 (P3), day 10 (P10) and day 21 (P21), respectively. In cell models, the activation of BV2, a type of microglial cell line, was observed after gamma irradiation. Real-time RT-PCR analysis revealed a deceased expression of miR-181b-2-3p and an increased expression of its target SRY-related high-mobility group box transcription factor 21 (SOX21) in a dose- and time-dependent fashion. The results of the luciferase reporter assay confirmed that SOX21 was the target of miR-181b-2-3p. Furthermore, SOX21 knockdown by siRNA inhibited the activation of microglia, thereby suggesting that the direct interaction of 181b-2-3p with SOX21 might be involved in radiation-induced microglial activation and proliferation. Interestingly, the gamma irradiation of NSCs increased miR-181b-2-3p expression but decreased SOX21 mRNA, which was the opposite of irradiation-induced expression in BV2 cells. As irradiation reduced the viability and proliferation of NSCs, whereas the overexpression of SOX21 restored the impaired cell viability and promoted the proliferation of NSCs, the findings suggest that the radiation-induced interaction of miR-181b-2-3p with SOX21 may play dual roles in microglia and NSCs, respectively, leading to the impairment of brain neurogenesis.

(Nano)platforms in bladder cancer therapy: Challenges and opportunities.

Urological cancers are among the most common malignancies around the world. In particular, bladder cancer severely threatens human health due to its aggressive and heterogeneous nature. Various therapeutic modalities have been considered for the treatment of bladder cancer although its prognosis remains unfavorable. It is perceived that treatment of bladder cancer depends on an interdisciplinary approach combining biology and engineering. The nanotechnological approaches have been introduced in the treatment of various cancers, especially bladder cancer. The current review aims to emphasize and highlight possible applications of nanomedicine in eradication of bladder tumor. Nanoparticles can improve efficacy of drugs in bladder cancer therapy through elevating their bioavailability. The potential of genetic tools such as siRNA and miRNA in gene expression regulation can be boosted using nanostructures by facilitating their internalization and accumulation at tumor sites and cells. Nanoparticles can provide photodynamic and photothermal therapy for ROS overgeneration and hyperthermia, respectively, in the suppression of bladder cancer. Furthermore, remodeling of tumor microenvironment and infiltration of immune cells for the purpose of immunotherapy are achieved through cargo-loaded nanocarriers. Nanocarriers are mainly internalized in bladder tumor cells by endocytosis, and proper design of smart nanoparticles such as pH-, redox-, and light-responsive nanocarriers is of importance for targeted tumor therapy. Bladder cancer biomarkers can be detected using nanoparticles for timely diagnosis of patients. Based on their accumulation at the tumor site, they can be employed for tumor imaging. The clinical translation and challenges are also covered in current review.

Non-Coding RNAs of Extracellular Vesicles: Key Players in Organ-Specific Metastasis and Clinical Implications.

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as "organ-specific metastasis". Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides.

Hypoxia-Induced circRNAs in Human Diseases: From Mechanisms to Potential Applications.

Circular RNAs (circRNAs) are a special class of endogenous RNAs characterized by closed loop structures lacking 5' to 3' polarity and polyadenylated tails. They are widely present in various organisms and are more stable and conserved than linear RNAs. Accumulating evidence indicates that circRNAs play important roles in physiology-related processes. Under pathological conditions, hypoxia usually worsens disease progression by manipulating the microenvironment for inflammation and invasion through various dysregulated biological molecules. Among them, circRNAs, which are involved in many human diseases, including cancer, are associated with the overexpression of hypoxia-inducible factors. However, the precise mechanisms of hypoxic regulation by circRNAs remain largely unknown. This review summarizes emerging evidence regarding the interplay between circRNAs and hypoxia in the pathophysiological changes of diverse human diseases, including cancer. Next, the impact of hypoxia-induced circRNAs on cancer progression, therapeutic resistance, angiogenesis, and energy metabolism will be discussed. Last, but not least, the potential application of circRNAs in the early detection, prognosis, and treatment of various diseases will be highlighted.

Noncoding RNAs of Extracellular Vesicles in Tumor Angiogenesis: From Biological Functions to Clinical Significance.

Extracellular vesicles (EVs) act as multifunctional regulators of intercellular communication and are involved in diverse tumor phenotypes, including tumor angiogenesis, which is a highly regulated multi-step process for the formation of new blood vessels that contribute to tumor proliferation. EVs induce malignant transformation of distinct cells by transferring DNAs, proteins, lipids, and RNAs, including noncoding RNAs (ncRNAs). However, the functional relevance of EV-derived ncRNAs in tumor angiogenesis remains to be elucidated. In this review, we summarized current research progress on the biological functions and underlying mechanisms of EV-derived ncRNAs in tumor angiogenesis in various cancers. In addition, we comprehensively discussed the potential applications of EV-derived ncRNAs as cancer biomarkers and novel therapeutic targets to tailor anti-angiogenic therapy.

The potential role of exosomal circRNAs in the tumor microenvironment: insights into cancer diagnosis and therapy.

Exosomes are multifunctional regulators of intercellular communication by carrying various messages under both physiological and pathological status of cancer patients. Accumulating studies have identified the presence of circular RNAs (circRNAs) in exosomes with crucial regulatory roles in diverse pathophysiological processes. Exosomal circRNAs derived from donor cells can modulate crosstalk with recipient cells locally or remotely to enhance cancer development and propagation, and play crucial roles in the tumor microenvironment (TME), leading to significant enhancement of tumor immunity, metabolism, angiogenesis, drug resistance, epithelial mesenchymal transition (EMT), invasion and metastasis. In this review, we describe the advances of exosomal circRNAs and their roles in modulating cancer hallmarks, especially those in the TME. Moreover, clinical application potential of exosomal circRNAs in cancer diagnosis and therapy are highlighted, bridging the gap between basic knowledge and clinical practice.

Targeting hypoxia-inducible factor-1, for cancer treatment: Recent advances in developing small-molecule inhibitors from natural compounds.

Rapid progress in molecular cancer biology coupled with the discovery of novel oncology drugs has opened new horizons for cancer target discovery. As one of the crucial signaling pathways related to tumorigenesis, hypoxia-inducible factor-1 (HIF-1) coordinates the activity of many transcription factors and their downstream molecules that impact tumor growth and metastasis. Accumulating evidence suggests that the transcriptional responses to acute hypoxia are mainly attributable to HIF-1α. Moreover, the overexpression of HIF-1α in several solid cancers has been found to be strongly associated with poor prognosis. Thus, pharmacological targeting of the HIF-1 signaling pathways has been considered as a new strategy for cancer therapy in the recent years. Although over the past decade, tremendous efforts have been made in preclinical studies to develop new HIF-1 inhibitors from natural products (reservoirs of novel therapeutic agents), to date, these efforts have not been successfully translated into clinically available treatments. In this review, we provide new insights into the bio-pharmacological considerations for selecting natural compounds as potential HIF-1 inhibitors to accelerate anti-cancer drug development. In addition, we highlighted the importance of assessing the dependency of cancer on HIF1A to shortlist cancer types as suitable disease models. This may subsequently lead to new paradigms for discovering more HIF-1 inhibitors derived from natural products and facilitate the development of potent therapeutic agents targeting specific cancer types.

Blood-based liquid biopsy: Insights into early detection and clinical management of lung cancer.

Currently, early detection of lung cancer relies on the characterisation of images generated from computed tomography (CT). However, lung tissue biopsy, a highly invasive surgical procedure, is required to confirm CT-derived diagnostic results with very high false-positive rates. Hence, a non-invasive or minimally invasive biomarkers is essential to complement the existing low-dose CT (LDCT) for early detection, improve responses to a certain treatment, predict cancer recurrence, and to evaluate prognosis. In the past decade, liquid biopsies (e.g., blood) have been demonstrated to be highly effective for lung cancer biomarker discovery. In this review, the roles of emerging liquid biopsy-derived biomarkers such as circulating nucleic acids, circulating tumour cells (CTCs), long non-coding RNA (lncRNA), and microRNA (miRNA), as well as exosomes, have been highlighted. The advantages and limitations of these blood-based minimally invasive biomarkers have been discussed. Furthermore, the current progress of the identified biomarkers for clinical management of lung cancer has been summarised. Finally, a potential strategy for the early detection of lung cancer, using a combination of LDCT scans and well-validated biomarkers, has been discussed.