In recent years, the development of targeted therapies for tumors with KRAS mutations has progressed rapidly, rendering the notion of KRAS as "undruggable" outdated. However, targeted therapies for KRAS mutations still face numerous challenges, including resistance, efficacy concerns, toxicity issues, and hurdles in drug development. Exploring alternative treatment modalities is thus essential. Extensive research has demonstrated that KRAS mutations significantly influence the immune microenvironment, presenting both challenges and opportunities for immunotherapy. Interestingly, it has been observed that different KRAS mutations and co-mutation subtypes exhibit significant variations in their immunological microenvironments, which undoubtedly impact immunotherapy choices. Here, we review the history of KRAS-targeted therapy, highlighting existing challenges, and summarize changes in the immune microenvironment of KRAS-mutated cancers and their potential therapeutic targets. We compare differences in the immune microenvironment across various mutation types and co-mutation subtypes, and offer perspectives on future research directions.

Chimeric antigen receptor T (CAR-T) cell therapies have transformed the treatment of relapsed/refractory (R/R) B-cell malignancies and multiple myeloma by redirecting activated T cells to CD19- or BCMA-expressing tumor cells. However, this approach has yet to be approved for acute myeloid leukemia (AML), the most common acute leukemia in adults and the elderly. Simultaneously, CAR-T cell therapies continue to face significant challenges in the treatment of solid tumors. The primary challenge in developing CAR-T cell therapies for AML is the absence of an ideal target antigen that is both effective and safe, as AML cells share most surface antigens with healthy hematopoietic stem and progenitor cells (HSPCs). Simultaneously targeting antigen expression on both AML cells and HSPCs may result in life-threatening on-target/off-tumor toxicities such as prolonged myeloablation. In addition, the immunosuppressive nature of the AML tumor microenvironment has a detrimental effect on the immune response. This review begins with a comprehensive overview of CAR-T cell therapy for cancer, covering the structure of CAR-T cells and the history of their clinical application. It then explores the current landscape of CAR-T cell therapy in both hematologic malignancies and solid tumors. Finally, the review delves into the specific challenges of applying CAR-T cell therapy to AML, highlights ongoing global clinical trials, and outlines potential future directions for developing effective CAR-T cell-based treatments for relapsed/refractory AML.

Telomere biology still remains a topic of interest in life sciences. Analysis of several thousand clinical samples from healthy individuals performed in recent years has shown that the telomere length (TL) in peripheral blood leukocytes correlates with the TL in cells of internal organ and reflects their condition. TL decreases under the influence of damaging factors and can serve as an indicator of health status. The telomere shortening leads to the cell proliferation arrest and is considered as a marker of replicative aging of proliferating cells. A decrease in the TL in peripheral blood leukocytes is viewed as an indicator of organism aging. Recent studies have allowed to formulate the concept on the role of the CST-polymerase α/primase in the C-strand fill in after completion of 3'G overhang synthesis by telomerase during telomere replication. The discovery of the telomeric RNA (TERRA) and its role in the regulation of telomerase activity (TA) and alternative lengthening of telomeres, as well as the possibility of TERRA translation, has provided evidence of the complex epigenetic regulation of the TL maintenance. Analysis of the published data indicates that telomeres are dynamic structures, whose length undergoes significant changes under the influence of damaging factors. TL is determined not only by the chronological age, but also by the exposure to the exogenous and endogenous deleterious factors during the lifetime. A decrease in the TL due to inherited mutations in the genes coding for proteins involved in the telomere structure formation and telomere replication (primarily, proteins of the shelterin and CST complexes and telomerase) has been found in a number of hereditary diseases - telomeropathies. The assessment of TL and TA is of great importance for the diagnostics of telomeropathies and can be useful in the diagnostics of cancer. Analysis of TL can be used for monitoring the health status (e.g., in the case of exposure to ionizing radiation and space flight factors), as well as predicting individual's sensitivity to the action of various damaging agents. The application of modern advancement in genetic technologies in the analysis of TL and TA makes it available for the use in clinical and epidemiological studies, diagnostics of telomeropathies, and monitoring of astronauts' health.

Bladder cancer (BCa) remains a significant clinical challenge because of high recurrence rates and variable response to immunotherapy and chemotherapy. Recent studies have highlighted the role of N6-methyladenosine (m6A) modification in RNA in the regulation of various cellular processes, including tumor progression and drug resistance. The review examines the impact of m6A methylation on BCa pathogenesis, with a particular special focus on the role of m6A pathway factors and m6A-modified RNAs in tumorigenesis, proliferation, invasion, and migration of cancer cells. The mechanisms of m6A-mediated chemotherapy resistance in BCa cells are discussed, including single nucleotide polymorphisms in m6A-associated patterns. Significant advances in the high-throughput analysis of m6A methylation have enabled development of novel m6A-based biomarkers for the risk assessment, early diagnostics, and prediction of relapse and treatment response in BCa. The review outlines the prospects of the m6A-based molecular diagnostics in BCa.

Prostate cancer (PC) is a leading cause of male cancer mortality, with bone metastasis (BM) being a frequent and debilitating complication. Despite therapeutic advancements, the molecular mechanisms underlying BM remain poorly understood. This study aims to bridge this gap by integrating bibliometric analysis with bioinformatics to provide a comprehensive overview of the academic trends and molecular profiles associated with prostate cancer bone metastasis (PCBM).

Colorectal cancer (CRC) is the third highest malignant tumor in the world in terms of incidence rate, accounting for about 10% of all cancer cases and the second leading cause of cancer related deaths. Timely diagnosis and effective treatment are key to significantly improving the survival rate of CRC patients. Various factors including gender, environmental factors, lifestyle choices, and genetic predisposition are all causes of the onset of CRC. Circular RNA(circRNA) mainly exists in cancer cells and tissues, solid tumors, peripheral blood, exosomes, and body fluids (such as serum, plasma, and saliva). Due to their resistance to degradation and presence in body fluids, CircRNA is non-invasive and an ideal candidate for liquid biopsy, thus having high diagnostic potential. Current research has found that circRNA can regulate the proliferation, migration, invasion, and apoptosis of CRC cells.

Neoantigens are tumor-specific antigens presented exclusively by cancer cells. These antigens are recognized as nonself by the host immune system, thereby eliciting an antitumor T-cell response. This response is significantly enhanced through neoantigen-based immunotherapies, such as personalized cancer vaccines. The repertoire of neoantigens is unique to each cancer patient, necessitating neoantigen prediction for designing patient-specific immunotherapies. This review presents the computational methods and data resources used for neoantigen prediction, as well as the prediction-associated challenges. Neoantigen prediction typically uses human leukocyte antigen typing, RNA-seq transcript quantification, somatic variant calling, peptide-major histocompatibility complex (pMHC) presentation prediction, and pMHC recognition prediction as the main computational steps. The immunoinformatics tools used for these steps and for the overall prediction of neoantigens are systematically summarized and detailed in this review.

DNA methylation in breast tumours has been extensively studied and has provided valuable insights into the clinical heterogeneity of breast cancer. In this review, we summarise the current literature that has used DNA methylation markers to subtype breast cancer and predict progression and survival. Widespread methylation differences have been observed across breast cancer subtypes at both the candidate genes and in genome-wide analyses, most notably between oestrogen receptor (ER) positive and ER-negative subtypes and for triple-negative tumours. Studies that attempted to create breast cancer subtypes using methylation data showed limited agreement in their capacity to group breast tumours, possibly due to methodological differences. Although many studies have reported associations of tumour DNA methylation with breast cancer outcomes and used machine learning methods to derive prediction models for survival, the extent to which these would replicate in independent datasets is currently unclear. We conclude that despite the potential of genome-wide methylation markers to unravel the heterogeneity of breast cancer, they currently appear to have limited clinical utility. Larger studies and replication of findings across studies are required to address the limitations of the existing literature.

Drug resistance poses a significant challenge in cancer therapy, contributing to rapid recurrence, disease progression, and high patient mortality. Despite its critical impact, few reliable predictors for cancer drug response or failure have been established for clinical application. Tumor heterogeneity and the tumor microenvironment (TME) are pivotal factors influencing cancer drug efficacy and resistance. Tumor heterogeneity leads to variable therapeutic responses among patients, while dynamic interactions between cancer cells and the TME enhance tumor survival and proliferation, underscoring the urgent need to identify cellular hallmarks for predicting drug response and resistance. Single-cell and spatial omics technologies provide high-resolution insights into gene expression at the individual cell level, capturing intercellular heterogeneity and revealing the underlying pathologies, mechanisms, and cellular interactions. This review delves into the principles, methodologies, and workflows of single-cell and spatial omics in cancer drug research, highlighting key hallmarks involving tumor heterogeneity, TME reprogramming, cell-cell interactions, metabolic modulation, and signaling pathway regulation in drug treatment at single-cell and spatial levels. Furthermore, we synthesize predictive cellular biomarkers for cancer drug response and resistance across 25 cancer types, paving the way for advancements in cancer precision medicine.

Cancer is a leading cause of mortality worldwide, with genetic predispositions playing a key role in disease onset. This review assessed over 80 published genetic studies involving more than 3000 Jordanian cancer patients to explore the hereditary landscape of cancer in Jordan. Breast, colorectal, and lung cancers were the most studied, with BRCA1/2 and TP53 among the most frequently mutated genes. While somatic mutations such as KRAS and EGFR were commonly reported in tumor studies, our primary focus is on germline PSVs that may indicate population-specific genetic risks, including BRCA1 exon 11 mutations in breast cancer and p.Gly12Asp in KRAS for colorectal cancer. Unique or novel PSVs, particularly in BRCA2 and AKT1, were also reported, suggesting potential founder effects or region-specific genetic risks. These findings support integrating multigene panel testing and genetic counseling into national cancer prevention strategies to improve early detection and personalized care in Jordan.

The TIP60 complex is an evolutionarily conserved, multifunctional chromatin remodeling complex involved in critical cellular processes, including DNA repair, transcription regulation, and cell cycle control. Although its molecular organization and functions have been extensively studied, a comparative synthesis of its context-specific roles across evolutionarily distant species and pathological conditions is important to fully grasp its biological and clinical significance. In this review, we provide an integrative overview of the TIP60 complex, emphasizing its composition and conserved functions in Homo sapiens and Drosophila melanogaster, with comparative insights from plant systems. We explore how TIP60 complex dysregulation contributes to the molecular pathology of cancer and neurodevelopmental disorders, highlighting recent mechanistic insights. We also examine the emerging interplay between TIP60 complex subunits and long non-coding RNAs, which are increasingly recognized as pivotal regulators of genome accessibility and transcriptional programs. Finally, in this intriguing scenario, we highlight the non-canonical functions of the TIP60 complex in mitosis and cytokinesis, underscoring its moonlighting roles in maintaining genomic and cellular integrity, beyond its established contribution to epigenetic regulation. By connecting these diverse aspects, our review aims to provide an integrated perspective on the TIP60 complex and its expanding functional landscape in health and disease.

Iron is required for numerous essential processes, including DNA synthesis, DNA repair, and cellular metabolism. Cancer cells frequently demonstrate an enhanced demand for iron when compared to slowly cycling non-cancer cells due to their increased reliance on these processes. Manifestations of this demand include up-regulation of iron import, decrease in iron export, alterations in iron intracellular trafficking, as well as alterations in "iron gene" expression signatures that can predict prognosis. Cells of the tumor microenvironment, including T cells, tumor-associated macrophages, and cancer-associated fibroblasts, crosstalk with tumor cells to further modulate tumor iron status. Dietary iron, particularly heme iron, has been associated with increased cancer risk, although the influence of iron on immune cells of the microenvironment may modulate this risk. Tumor cell reliance on iron creates therapeutic opportunities. For example, the excess iron accumulated by cancer cells renders them susceptible to agents that induce ferroptosis, an iron-dependent form of cell death. In addition, significant progress has been made in the design of agents to target tumor cell iron dependence in other ways, including small molecule iron chelators and agents that target iron uptake, some of which are in current clinical trials. Recent discoveries, such as the key role of iron recycling in KRAS-mutated pancreatic cancer, are expected to further accelerate the transition of such agents to the clinic.

Cancers originating from the same tissue vary significantly in genetic mutations and patient drug response. Furthermore, tumor tissue is composed of diverse cancer cell clones. This phenomenon, known as "cancer cell heterogeneity," occurs among tumors (between patients) and within individual tumors and is an important mechanism driving resistance to cancer therapy. Therefore, an understanding of cancer cell heterogeneity is essential for the development and delivery of more effective personalized treatments. The cancer cell lines typically used in cancer research cannot accurately replicate this heterogeneity. However, patient-derived tumor organoids (PDTOs), three-dimensional cultures of tumor cells, can precisely replicate the histological, molecular, and cellular heterogeneity of the original tumor. PDTOs generated from human cancers are now widely used as innovative tools in cancer research, including in studies of the mechanisms of cancer development and progression and in screening of anti-cancer drug. This review summarizes recent advances in human tumor research that uses PDTOs.

The 2023 update to the FIGO staging system for endometrial cancer has introduced important changes, particularly in classifying early disease, which now more effectively aligns with histological types and molecular profiles to guide treatment strategies. In recent years, molecular classification, including the identification of POLE mutations, mismatch repair deficiency (dMMR), and p53 abnormalities, has become essential in tailoring adjuvant therapies for patients with endometrial cancer. Women with new FIGO stage I non-TP53-mutated tumors, and stage I/II POLE-mutated tumors generally have excellent outcomes, and adjuvant therapy is typically not recommended. In contrast to the established adjuvant treatment of stage IIB disease, controversy surrounds the treatment of stage IIA and IIC patients without POLE mutations. Real-world data suggest that adjuvant radiotherapy or chemotherapy may offer no significant benefit compared to observation in these cases. For stage III POLE-mutated tumors, studies have demonstrated favorable prognoses and high salvage rates upon recurrence, raising important questions about the necessity of adjuvant treatment when complete surgical resection is achieved. For stage III/IV dMMR patients, immune checkpoint inhibitors have demonstrated substantial improvements in both progression-free survival and overall survival when added to chemotherapy, as shown in the RUBY, NRG-GY018, AtTEnd, and ENGOT-en11/GOG-3053/KEYNOTE-B21 trials. These findings have solidified the use of immunotherapy in this molecular subgroup. In the non-specific molecular profile group, hormone receptor status has emerged as a significant prognostic marker. Estrogen receptor-positive tumors in this subgroup have shown favorable responses to progestin therapy, raising the possibility that hormonal therapy could replace chemotherapy in selected patients. Lastly, patients with TP53-mutated tumors, which are associated with poor prognosis, are being evaluated in the RAINBO p53abn-RED trial to assess whether the addition of olaparib to adjuvant chemoradiation can improve outcomes in this high-risk group. In conclusion, integrating molecular subtyping with the 2023 FIGO staging system is reshaping the approach to adjuvant therapy in endometrial cancer, enabling more precise and individualized treatment strategies that improve patient outcomes.

Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by pathogenic variants in DNA mismatch repair (MMR) genes, most commonly MLH1 and MSH2. LS significantly increases the risk of various cancers, including colorectal, endometrial, gastric, and ovarian malignancies. Neuroendocrine neoplasms (NENs) are rare tumors that arise from neuroendocrine cells, predominantly in the gastrointestinal tract, and are frequently associated with hereditary cancer syndromes such as multiple endocrine neoplasia types 1 and 2. While a definitive association between LS and NENs has not been established, isolated cases have been reported. We present the case of a 63-year-old woman with a history of colorectal cancer and a confirmed LS diagnosis, identified through genetic testing that revealed a pathogenic MLH1 variant. Years later, she developed a grade 2 non-functional neuroendocrine tumor (NET), likely of gastrointestinal origin. The patient underwent surgical resection, followed by treatment with somatostatin analogs. Due to this uncommon presentation, we conducted a literature review to explore the potential relationship between LS and NENs. Our analysis identified 13 additional cases of NENs in LS patients, encompassing NETs, neuroendocrine carcinomas (NECs), and mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs). This growing body of evidence suggests that NENs may be part of the LS tumor spectrum. Further research is needed to elucidate the underlying mechanisms and determine whether LS predisposes individuals to NENs. Enhanced surveillance in LS patients could improve early detection of rare malignancies such as NENs, ultimately expanding our understanding of LS-associated cancer risks and guiding more effective clinical management.

Cervical cancer (CC), a common malignant tumor afflicting women, poses serious threats to their health. Therefore, it is critical to develop a thorough understanding of the molecular mechanisms underlying the pathogenesis of CC, and to identify new therapeutic targets and methods for early diagnosis. The multi-omics research in tumors, involving proteomics, transcriptomics, genomics, microbiomics, and metabolomic, offers valuable insights. The multi-omics analysis of biological samples from patients with cervical intraepithelial neoplasia (CIN) and CC can help clarify the pathways involved in the pathogenesis and development of CC. Furthermore, multi-omics studies have identified a number of molecules associated with CC, including actin, lumican, family member with sequence similarity 83 (FAM83A), cadherin EGF-LAG seven-pass G-type receptor 3 (CELSR3), and 5,10-methylenetetrahydrofolate reductase (MTHFR), all of which show potential to be used as new biomarkers. These biomarkers will help make early diagnosis, improve the survival and prognosis of CC patients, and ultimately reduce CC incidence and mortality. This review synthesizes current advances in multi-omics research on cervical cancer.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by multisystem involvement, primarily caused by loss-of-function mutations in the TSC1 or TSC2 genes. TSC is a key integrator of metabolic signaling and cellular stress and has become an important regulator in several kidney diseases. TSC1 and TSC2 can be used not only as genetic markers for disease diagnosis, but also as potential immunotherapeutic targets for kidney disease. Recent studies on the pathogenesis of TSC may provide guidance for developing new treatment strategies for kidney diseases.

Given the prevalence of RAS mutations in various cancers, personalized therapeutic approaches, guided by molecular markers, are essential. Farnesyltransferase inhibitors (FTIs) have emerged as potential therapeutic options; however, they also face obstacles such as toxicity and limited efficacy. Alternative strategies, such as direct inhibitors combined with pathway modulators, RNA interference, and gene-editing technologies, are under clinical investigation. The targeting of RAS, complicated by its structural nuances, particularly in the G domain, has advanced with the identification of druggable pockets such as the SW-II pocket. This breakthrough has led to the development of targeted therapeutics, such as sotorasib and adagrasib, for KRAS G12C-mutated non-small cell lung cancer (NSCLC). However, these advancements face challenges, including adaptive resistance and the necessity for isoform selectivity. New inhibitors, such as LY3537982 or GDC-6036, are promising, but achieving effective and selective RAS inhibition remains a significant challenge. Additionally, clinical trials have highlighted variability in patient responses, attributing limited treatment efficacy to resistance mechanisms, including on-target mutations and off-target pathway activations. Finally, the RAS oncogene, traditionally viewed as predominantly pro-cancerous, plays a complex role in oncogenesis, with recent evidence suggesting context-dependent effects, such as inducing senescence in certain cells. This shift in understanding underscores the therapeutic potential of manipulating the interplay between RAS and TP53 mutations in cancer. In conclusion, the complexity of effectively targeting the RAS-RAF-ERK pathway is exacerbated by the diverse resistance mechanisms. Challenges such as off-target effects and delivery issues remain significant barriers in the introduction of effective therapies based on RAS inhibitors. This overview highlights the evolving nature of targeting RAS in cancer therapy.

The field of hematology has experienced a substantial evolution with the acknowledgment of epigenetic processes as essential factors in the development of hematological malignancies. This review article examines the influence of epigenetic alterations, namely DNA methylation and histone modifications, on the onset and advancement of conditions such as acute myeloid leukemia and myelodysplastic syndromes. We discuss how these epigenetic modifications lead to the deregulation of gene expression, eventually promoting leukemogenesis. The emergence of epigenetic therapies, such as DNA methyltransferase inhibitors (e.g., azacitidine and decitabine), histone deacetylase inhibitors (e.g., vorinostat and romidepsin), and enhancer of zeste homologue 2 inhibitors (e.g., tazmetostat), demonstrates the potential to reverse aberrant epigenetic modifications and restoring normal cellular functions. Moreover, we highlight innovative therapeutic approaches, including combination therapies and CRISPR-based epigenetic editing tools, which are influencing the future of treatment for hematological malignancies. Despite promising results, challenges such as off-target effects, drug resistance, and the need for personalized approaches remain significant barriers to effective treatment. We emphasize that further study is required to improve delivery systems, comprehend resistance mechanisms and develop precision medicine strategies that can tailor therapies to individual patient profiles. By integrating benchside discoveries with clinical applications, this review aims to illuminate the transformative potential of epigenetic therapies in improving patient outcomes in hematology.

Bromodomain and PHD finger-containing protein 1 (BRPF1) is an essential epigenetic regulator and plays a key role in post-translational modification of histones. It is a chromatin reader that recognizes acetylated histones and interacts with the paralogous lysine acetyltransferases KAT6A and KAT6B to promote histone acetylation and related acylations, such as propionylation, at lysine 23 of histone H3, thereby influencing gene expression and regulating developmental programs. BRPF1 contributes to a variety of cellular processes such as cell cycle progression, cell proliferation, cell differentiation, and responses to cellular stresses, including DNA damage. Moreover, BRPF1 is implicated in hematopoiesis, embryonic development, skeletal development, neurodevelopment, neurogenesis, learning, and memory. BRPF1 gene knockout in mice leads to severe bone marrow failure, anemia, and eventual death in a few weeks after birth. This review provides a brief overview of BRPF1 and its contribution to the molecular structure and biological functions of KAT6A and KAT6B complexes. We will explore the emerging evidence linking BRPF1 dysfunction to human diseases, particularly cancer and abnormal neurodevelopment, to highlight promising therapeutic opportunities for treating associated pathology.