The gradual acquisition of genetic and epigenetic disturbances bestows malignant traits upon hematopoietic stem cells, subverting them into a founder and reservoir cell for de novo acute myeloid leukemia (AML) known as leukemic stem cells (LSC). Beyond its molecular heterogeneity, AML is also characterized by rewiring biological processes to support its onset and maintenance. LSC were observed to inherently and actively trigger mitochondrial turnover through selective autophagic removal such that impairing the process led to cell differentiation at the expense of its stemness. This review provides a current take on autophagy regulation mechanisms according to the current molecular characterization of the process; describes autophagy as a drug resistance mechanism, and a pivotal mechanism whereby LSC harmonize their strong reliance on mitochondrial respiration to obtain energy, and their necessity for lower internal oxidative stress to avoid exhaustion. Therefore, targeting autophagy presents a promising strategy to promote long-term remissions in AML.

Current approaches for prostate cancer (PCa) diagnosis and risk stratification require greater accuracy. Extracellular vesicles and particles (EVPs) containing diverse cargos from parent cells are released into the extracellular microenvironment and play a critical role in intercellular communication. Accumulating evidence demonstrates that EVPs are emerging as a promising focus for the exploration of cancer biomarkers and therapeutic targets. However, the precise categorisation and nomenclature of EVP subpopulations remains challenging due to their compositional complexity, inherent heterogeneity in molecular composition, and structure. The recent identification of two novel non-vesicular extracellular particle subtypes, exomeres and supermeres, has altered our understanding of the distinct subpopulations of EVPs and their roles in biological and physiological processes. Here, we discuss recent advances in the field of EVPs, describe characteristics of EVP subpopulations, focus on the application and potential of EVPs in PCa diagnosis and risk stratification by liquid biopsy, and highlight the major challenges and prospects of EVP research in PCa area.

Synovial sarcoma is a rare type of soft tissue sarcoma that primarily affects adolescents and young adults, featured by aggressive behavior and a high potential for metastasis. Genetically, synovial sarcoma is defined by the fusion oncogene SS18-SSX arising from the translocation of t(X;18)(p11;q11). SS18-SSX fusion gene is the major driver of the oncogenic event in synovial sarcoma. SS18-SSX fusion protein, while not containing any DNA-binding motifs, binds to the SWI/SNF (BAF) complex, a major epigenetic regulator, leading to the disruption of gene expression which results in tumor initiation and progression. Emerging studies on the molecular mechanisms of SS18-SSX associated signaling pathway hold promise for developments in diagnosis and treatments. Advanced diagnostic methods facilitate early and precise detection of the tumor, enabling disease monitoring and prognostic improvements. Treatment of synovial sarcoma typically comprises local surgery, radiotherapy and chemotherapy, while novel managements such as immunotherapy, targeted therapies and epigenetic modifiers are explored. This review focuses on the recent studies of SS18-SSX fusion gene, epigenetic landscape, signaling pathways, diagnostic techniques, and relevant therapeutic advances, aiming to inhibit the oncogenic processes and improve outcomes for patients with synovial sarcoma.

Cancer drug resistance is a major obstacle to the effectiveness of chemoradiotherapy, targeted therapy, and immunotherapy. CRISPR/Cas9 library screening has emerged as a powerful genetic screening tool with significant potential to address this challenge. This review provides an overview of the development, methodologies, and applications of CRISPR/Cas9 library screening in the study of cancer drug resistance. We explore its role in elucidating resistance mechanisms, identifying novel anticancer targets, and optimizing treatment strategies. The use of in vivo single-cell CRISPR screens is also highlighted for their capacity to reveal T-cell regulatory networks in cancer immunotherapy. Challenges in clinical translation are discussed, including off-target effects, complexities in data interpretation, and model selection. Despite these obstacles, continuous technological advancements indicate a promising future for CRISPR/Cas9 library screening in overcoming cancer drug resistance.

Phase separation, a process in which biomolecules segregate into distinct liquid-like compartments within cells, has recently been identified as a crucial regulator of various cellular functions, including the DNA damage response (DDR). Dysregulation of phase separation may contribute to genomic instability, oncogenesis, and tumor progression. However, the specific roles and mechanisms underlying phase separation remain largely elusive. This comprehensive review aims to elucidate the complex relationship between phase separation and the DDR in the context of cancer biology. We focus on the molecular mechanisms underlying phase separation and its role in orchestrating DDR signaling and repair processes. Additionally, we discuss how the dysregulation of phase separation in cancer cells impacts genome stability, tumorigenesis, and therapeutic responses. By leveraging the unique properties of phase separation in the DDR, researchers can potentially advance basic research and develop personalized cancer therapies targeting the dysregulated biomolecular condensates that drive tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) patients have an unfavorable prognosis and disappointing treatment outcomes because of late diagnosis, high chemotherapy resistance, ineffective adjuvant chemotherapy, unavailable molecular targeted therapy, and profound immunosuppressive effects in the tumor microenvironment (TME). There are a variety of critical driver proteins, such as KRAS, TP53, PTEN and SMAD4, putatively involved in PDAC etiology. Current knowledge of their molecular mechanisms is still limited. SMAD4 gene alterations in ~55 % of patients emphasize its key role in PDAC progression, metastasis, resistance and immunity. Despite extensive studies on the TGF-β/SMAD pathway, the impact of SMAD4 mutation/deficiency on PDAC prognosis and treatment, especially its mechanism in drug resistance, has not yet been elucidated. This review summarizes the latest advances in the effect of SMAD4 deficiency on the prognosis and therapeutic resistance of PDAC patients. It might be a predictive and prognostic biomarker or therapeutic target to achieve the desired clinical benefits. Moreover, we discuss potential strategies to implement targeted therapies in terms of SMAD4 genetic status.

Tumor cachexia is a multifactorial syndrome characterized by systemic dysfunction, including anorexia and severe weight loss that is resistant to standard nutritional interventions. It is estimated that approximately 20 % of cancer patients succumb to cachexia in the later stages of their disease. Thus, understanding its pathogenesis is vital for improving therapeutic outcomes. Recent research has focused on the imbalance between energy intake and expenditure in cachexia. Clinically, cachexia presents with anorexia, adipose tissue atrophy, and skeletal muscle wasting, each driven by distinct mechanisms. Anorexia arises primarily from tumor-secreted factors and cancer-induced hormonal disruptions that impair hypothalamic regulation of appetite. Adipose tissue atrophy is largely attributed to enhanced lipolysis, driven by increased activity of enzymes such as adipose triglyceride lipase and hormone-sensitive lipase, coupled with decreased lipoprotein lipase activity. The browning of white adipose tissue, facilitated by uncoupling protein 1, further accelerates fat breakdown by increasing energy expenditure. Skeletal muscle atrophy, a hallmark of cachexia, results from dysregulated protein turnover via the ubiquitin-proteasome and autophagy-lysosomal pathways, as well as mitochondrial dysfunction. Additionally, chemotherapy can exacerbate cachexia. This review examines the molecular mechanisms underlying cancer cachexia and discusses current therapeutic strategies, aiming to inform future research and improve treatment approaches.

Esophageal cancer is a significant contributor to cancer-related mortality, and its poor prognosis is primarily attributed to the aggressive nature of the tumor and challenges in early detection. Currently, there are no ideal drugs developed for treatment, making it crucial to explore potential biomarkers and molecular targets for esophageal cancer. FOXP3, as a transcription factor and major regulator of regulatory T cells, not only plays a role in promoting or inhibiting tumor development in various types of cancer cells including esophageal cancer cells but also influences the function of Treg cells by regulating the expression of multiple genes. This paper provides an in-depth discussion on the functional properties, regulatory mechanisms, key signaling pathways, as well as the role and potential application of FOXP3 in treating esophageal cancer. Furthermore, it comprehensively analyzes the complex role of this transcription factor within the tumor immune microenvironment with an aim to aid in developing new potential targets for esophageal cancer treatment.

Numerous studies have demonstrated the importance of the Epstein-Barr Virus (EBV), which was initially identified in 1964 while studying Burkitt's lymphoma, in the development of a number of cancers, including nasopharyngeal carcinoma, Hodgkin's lymphoma, Burkitt's lymphoma, and EBV-associated gastric carcinoma. Gammaherpesvirus EBV is extremely common; by adulthood, over 90 % of people worldwide have been infected. Usually, the virus causes a permanent latent infection in B cells, epithelial cells, and NK/T cells. It then contributes to oncogenesis by inhibiting apoptosis and promoting unchecked cell proliferation through its latent proteins, which include EBNA-1, LMP1, and LMP2A. Tumor progression further accelerated by EBV's capacity to transition between latent and lytic phases, especially in cases of nasopharyngeal carcinoma. Although our understanding of the molecular underpinnings of EBV has advanced, there are still difficulties in identifying latent infections and creating targeted therapeutics. To tackle EBV-associated malignancies, current research efforts are concentrated on developing vaccines, developing better diagnostic tools, and developing targeted treatments. In order to improve treatment approaches and lower the incidence of EBV-related cancers worldwide, more research into the relationship between EBV and immune evasion and cancer formation is necessary.

Heterogeneous cancers that lack strong driver mutations with high penetrance, such as head and neck squamous cell carcinoma (HNSCC), present unique challenges to understanding their aetiology due to the complex interactions between genetics and environmental factors. The interplay between lifestyle factors (such as poor oral hygiene, smoking, or alcohol consumption), the oral and gut microbiome, and host genetics appears particularly important in the context of HNSCC. The complex interplay between the gut microbiota and cancer treatment outcomes has also received increasing attention in recent years. This review article describes the bidirectional communication between the host and the oral/gut microbiome, focusing on microbiome-derived metabolites and their impact on systemic immune responses and the modulation of the tumour microenvironment. In addition, we review the role of host lifestyle factors in shaping the composition of the oral/gut microbiota and its impact on cancer progression and therapy. Overall, this review highlights the rationality of considering the oral/gut microbiota as a critical determinant of cancer therapy outcomes and points to therapeutic opportunities offered by targeting the oral/gut microbiota in the management of HNSCC.

This review explores the complex relationship between epigenetic mechanisms and Transforming Growth Factor-beta (TGF-β) signalling pathways in the field of cancer research. The study provides an overview of the latest advancements in understanding the crucial functions of epigenetic alterations, such as DNA methylation, histone modifications, and chromatin remodeling, in significantly impacting the TGF-β signalling pathway. The dynamic epigenetic modifications are essential in determining the behaviour of cancer cells, impacting the interactions with the tumor microenvironment, and affecting the overall process of carcinogenesis. Significant attention is given to Breast cancer, Lung cancer, Liver cancer, Prostate cancer, and Pancreatic cancer. Research has revealed intricate regulatory networks in these cancers, involving long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and histone post-translational modifications. These networks are closely connected to TGF-β signalling. Both findings highlight the significant interaction between epigenetic regulation and TGF-β signalling in cancer. They provide valuable insights that can guide the development of new treatment approaches to target both pathways and prevent cancer growth and metastasis.

The emergence of immunotherapies such as immune checkpoint blockade (ICB) has markedly enhanced cancer treatment outcomes for numerous patients. Nevertheless, the effectiveness of immunotherapy demonstrates substantial variation across different cancer types and individual patients. The immunosuppressive characteristics of the tumor microenvironment (TME) play a crucial role in contributing to this variation. Typically, people focus on cells with immunosuppressive functions in the TME, such as tumor-associated macrophages (TAMs), but research on TAMs alone cannot fully explain the complex structure and composition of the TME. Recent studies have reported that tumors can induce erythroid progenitor cells (EPCs) to exert immunosuppressive functions, not only acting within the TME but also secreting artemin in the spleen to promote tumor progression. In this review, we summarize the recent research on EPCs and tumors in recent years. We elucidate the mechanisms by which EPCs exert immunosuppressive functions in tumor-bearing conditions. In this review, we further propose potential therapeutic strategies targeting EPCs and emphasize the importance of in-depth exploration of the mechanisms by which EPCs regulate tumors and the immune system, as well as the significant clinical value of developing corresponding drugs.

RNF43 and ZNRF3 are recognized as important regulators of Wnt/β-catenin signaling by maintaining Wnt-receptors at minimal essential levels. In various cancer types, particularly gastrointestinal tumors, mutations in these genes lead to abnormal Wnt-dependent activation of β-catenin signaling. However, recent findings implicate RNF43/ZNRF3 also in the regulation of other tumor-related proteins, including EGFR, BRAF, and the BMP-signaling pathway, which may have important implications for tumor biology. Additionally, we describe in detail how phosphorylation and ubiquitination may finetune RNF43 and ZNRF3 activity. We also address the variety of mutations observed in cancers and the mechanism through which they support tumor growth, and challenge the prevailing view that specific missense mutations in the R-spondin and RING domains may possess dominant-negative activity in contributing to tumor formation.

Cancer remains one of the most difficult human diseases to overcome because of its complexity and diversity. Signal transducers and transcriptional activators 3 (STAT3) protein has been found to be overexpressed in a wide range of cancer types. Hyperactivation of STAT3 is particularly associated with low survival in cancer patients. This review summarizes the specific molecular mechanisms of STAT3 in cancer development. STAT3 is activated by extracellular signals in the cytoplasm, interacts with different enzymes in the nucleus, mitochondria or endoplasmic reticulum, and subsequently participates in cancer development. The phosphorylated STAT3 at tyrosine 705 site (YP-STAT3) enters the nucleus and regulates a number of tumor-related biological processes such as angiogenesis, migration invasion, cell proliferation and cancer cell stemness. In contrast, the phosphorylated STAT3 at serine 727 site (SP-STAT3) is found on the mitochondria, affects electron respiration transport chain activity and thereby prevents tumor cell apoptosis. SP-STAT3 also appears on the mitochondria-associated endoplasmic reticulum membrane, influences the flow of Ca, and affects tumor progression. In addition, we summarize the direct and indirect inhibitors of STAT3 which are currently undergoing clinical studies. Some of them such as TTI101 and BBI608 have been approved by the FDA for the treatment of certain cancers. All in all, STAT3 plays an important role in cancer progression and becomes a potential target for cancer treatment.

Mitochondria have a complete and independent genetic system with necessary biological energy for cancer occurrence and persistence. Mitochondrial RNA (mt-RNA) methylation, as a frontier in epigenetics, has linked to cancer progression with growing evidences. This review has comprehensively summarized detailed mechanisms of mt-RNA methylation in regulating cancer proliferation, metastasis, and immune infiltration from the mt-RNA methylation sites, biological significance, and its methyltransferases. The mt-RNA methylation also plays a very significant role via epigenetic crosstalk between nucleus and mitochondria. Importantly, the unique structures and functional characteristics of mt-RNA methyltransferases and the potential targeting treatment drugs for cancer are also analyzed. Revealing human mt-RNA methylation regulatory system and the relationship with cancer will contribute to identifying potential biomarkers and therapeutic targets for precise prevention, detection, intervention and treatment in the future.

The utilization of PARP inhibitors (PARPis) has significantly improved the prognosis for ovarian cancer patients. However, as the use of PARPis increases, the issue of PARPi resistance has become more prominent. Prolonged usage of PARPis can lead to the development of resistance in ovarian cancer, often mediated by mechanisms such as homologous recombination (HR) recovery, ultimately resulting in cancer relapse. Overcoming PARPi resistance in ovarian cancer is a pressing concern, aiming to enhance the clinical benefits of PARPi treatment and delay disease recurrence. Here, we summarize the mechanisms underlying PARPi resistance, methods for analyzing resistance, and strategies for overcoming it. Our goal is to inspire the development of more cost-effective and convenient methods for analyzing resistance mechanisms, as well as safer and more effective strategies to overcome resistance. These advancements can contribute to developing personalized approaches for treating ovarian cancer.

The KH-type splicing regulatory protein (KHSRP), also known as KSRP, is an RNA-binding protein that regulates gene expressions through various mechanisms, including messenger (m)RNA degradation, micro (mi)RNA maturation, and transcriptional activity. KSRP has been implicated in a wide range of physiological and pathological processes, with emerging evidence highlighting its role in modulating diverse aspects of cancer behaviors. In this review, we provide a comprehensive overview of KSRP's clinical relevance and its multifaceted regulatory mechanisms in cancer. Our extensive pan-cancer analysis uncovers associations of KSRP with clinical outcomes and identifies cell cycle progression as a key signaling pathway correlated with KSRP expression. Furthermore, we identify miR-17-5p as critical miRNAs positively correlated with KSRP, and it is associated with poor survival in various cancers. Collectively, this review offers new insights into the potential of KSRP as a target for therapeutic strategies in cancer treatment.

Drug resistance is a significant challenge in oncology and is driven by various mechanisms, among which a crucial role is played by enhanced DNA repair. Thus, targeting DNA damage response (DDR) factors with specific inhibitors is emerging as a promising therapeutic strategy. An important process involved in the modulation of DNA repair pathways, and hence in drug resistance, is post-translational modification (PTM). PTMs such as methylation affect protein function and are critical in cancer biology. Methylation is catalyzed by specific enzymes called protein methyltransferases. In recent years, the SET domain-containing N-lysine methyltransferase SMYD3 has emerged as a significant oncogenic driver. It is overexpressed in several tumor types and plays a signal-dependent role in promoting gastrointestinal cancer formation and development. Recent evidence indicates that SMYD3 is involved in the maintenance of cancer genome integrity and contributes to drug resistance in response to genotoxic stress by regulating DDR mechanisms. Several potential SMYD3 interactors implicated in DNA repair, especially in the homologous recombination and non-homologous end-joining pathways, have been identified by in silico analyses and confirmed by experimental validation, showing that SMYD3 promotes DDR protein interactions and enzymatic activity, thereby sustaining cancer cell survival. Targeting SMYD3, in combination with standard or targeted therapy, shows promise in overcoming drug resistance in colorectal, gastric, pancreatic, breast, endometrial, and lung cancer models, supporting the integration of SMYD3 inhibition into cancer treatment regimens. In this review, we describe the role played by SMYD3 in drug resistance and analyze its potential as a molecular target to sensitize cancer cells to treatment.

Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.

Cytokines are the crucial signaling proteins that mediate the crosstalks between the cells of tumor microenvironment (TME). Interferon-1 (IFN-1) are the important cytokines that are widely known for their tumor suppressive roles comprising of cancer cell intrinsic and extrinsic mechanisms. Despite having known antitumor effects, IFN-1 are also reported to have tumor promoting functions under varying circumstances. This dichotomy in the functions of IFN-1 is largely attributed to the acute and chronic activation of IFN-1 signaling in TME. The chronic activation of IFN-1 signaling in tumor cells results in altered stimulation of downstream pathways that result in the expression of tumor promoting proteins, while the acute IFN-1 signaling activation maintains its tumor inhibiting functions. In the present review, we have discussed the anti- and pro-tumor actions of IFN-1 signaling under acute and chronic IFN-1 signaling activation. We have also discussed the downstream changes in signaling components that result in tumor supportive functions of a constitutive IFN-1 signaling. We have further discussed the possible strategies to overcome the detrimental effects of chronic IFN-1 pathway activation and to successfully employ IFN-1 for their beneficial anti-tumor effects.

Chordomas are rare malignant tumors that pose significant challenges in terms of effective treatment options. Surgical resection remains the only established approach that has proven useful in the treatment of chordoma. However, recent evidence has shed light on the role of brachyury, also known as the T-gene and TBXT, as both a diagnostic marker and a potential therapeutic target in chordoma. Considering these developments, this review aims to provide a comprehensive summary of the current knowledge and understanding of brachyury in chordomas.