Epigenetic regulation refers to the alteration of gene expression independent of changes in DNA sequence. It involves chemical modifications such as DNA methylation, histone methylation, and histone acetylation, which are regulated by a coordinated interplay of various regulators to ensure precise spatial and temporal regulation of gene expression. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment. In this review, we summarize the essential regulatory mechanisms and dysfunctions of epigenetic regulators involved in DNA methylation, histone methylation, and histone acetylation during tumor development and progression. Moreover, we discuss the current advances and challenges in cancer epigenetic therapy that target these mechanisms in both hematologic malignancies and solid tumors. Finally, we discuss the potential of combining epigenetic drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, as a promising approach for cancer treatment. Overall, we aim to enhance the understanding of epigenetic regulation in cancer therapy and explore targeted therapeutic strategies based on these mechanisms, to ultimately advance cancer therapy and improve patient prognosis.

Glioblastoma multiforme (GBM), a WHO grade IV diffuse glioma, is a highly aggressive brain tumor with a median survival of less than a year. Characterized by robust proliferation and invasion, recent studies spotlight glioma stem cells (GSCs) within GBM tumors, pivotal in tumor development, progression, and treatment resistance. This review aims to shed light on the critical role of GSCs in the initiation and progression of GBM, emphasizing their contribution to tumor development and resistance to existing treatments. Unlike normal stem cells, GSCs play a pivotal role in GBM pathogenesis. The review delves into the unique characteristics of GSCs, marked by heightened metabolic activities and distinct epigenetic and transcriptional programming. Recognizing the significance of GSCs in recent years, the review examines how their presence amplifies the lethal nature of GBM. The review also critically evaluates recent advancements in glioma and GBM diagnostic methods and treatment therapies, which also include targeting GSCs. Providing a concise yet comprehensive overview, the review contributes insights into GBM’s intricate dynamics, offering potential directions for future research and therapeutic strategies.

Rapid growth in nanoparticles (NPs) as delivery systems holds vast promise to promote therapeutic approaches for cancer treatment. Presently, a diverse array of NPs with unique properties have been developed to overcome different challenges and to achieve sophisticated delivery routes for enhancement of a series of therapies. Inspiring advances have been achieved in the field of cancer therapy using NPs. In this review, we aim to summarize the up-to-date progression of NPs for addressing various challenges, and expect to elicit novel and potential opportunities alternatively. We first introduce different sorts of NP technologies, illustrate their mechanisms, and present their applications. Then, the achievements made by NPs to break obstacles in delivering cargoes to specific sites through particular routes are highlighted, including long-circulation, tumor targeting, responsive release, and subcellular localization. We subsequently retrospect recent research of NPs in different cancer treatments from single therapy, like chemotherapy, to combination therapy, like chemoradiotherapy, and to integrative therapy. Finally, the challenges and perspectives of NPs in cancer therapy, and their potential impact on the field of oncology are discussed. We believe this review can offer a deeper understanding of the challenges and opportunities of NPs for cancer therapy.

The tumor microenvironment (TME) is the ecosystem surrounding a tumor, which usually consists of nontumoral cells or components, and molecules they produce and release. The frequent and continuous interplay between tumor cells and the TME strongly affects tumor development, disease progression, metastasis, and responses to therapeutic interventions. As a hub of potential therapeutic targets, the TME has gained appreciable momentum in cancer research. Here we systematically review the progress in targeting the TME as a strategy to develop novel antitumor drugs from the immunological, stromal and extracellular matrix components of the TME, shedding light on its complex synergies with tumor cells. This exploration highlights the transformative potential these elements hold in refining cancer treatment approaches. This thorough examination not only accentuates the TME’s multifaceted nature but also positions it as a formidable avenue for propelling forward the paradigms of cancer therapy. This review aims to foster a deeper understanding of the TME’s role in oncogenesis and its potential exploitation in advancing targeted, efficacious cancer treatments, marking a significant stride in the realm of cancer research.

Janus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure-selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure-based methods for discovering and designing selective JAKi. Other structure-based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.

Synthetic lethality (SL), a genetic concept, has revolutionized the development of antitumor therapies by providing avenues to target previously “undruggable” targets with enhanced specificity for tumor cells over normal tissue. The principles of SL have expanded beyond genetic definitions to encompass biological functions, including genome stability, cell cycle regulation, cell death mechanisms, cellular metabolism, cell-cell interactions, and the tumor microenvironment (TME). Tumor cells with inactivated survival pathways are sensitive to therapeutic inhibition of compensatory mechanisms, while normal cells remain unaffected. Exploiting SL based on functional contexts has the potential to significantly improve cancer patient survival by reducing resistance to targeted therapies and enhancing antitumor efficacy when combined with other treatment modalities. This review explores the underlying mechanisms of synthetic lethality interactions (SLI) characterized by biological functions in individual cancer cells and the TME. We also provide a comprehensive summary of strategies for leveraging the dynamic nature of SLI to overcome therapeutic resistance. Additionally, we discuss various approaches and models for screening and designing potent SL agents tailored to the specific needs of cancer patients, as well as strategies for combining SL drugs in tumor treatment. This review offers valuable insights into harnessing SL as a promising avenue for precision cancer therapy.