In the context of the multitarget paradigm, fixed-dose combination (FDC) drugs, that is, compounds that synergistically target multiple sites when combined, have gained attention for treating complex diseases like cancers and viral infections, as traditional single-drug approaches are often inadequate. This review examines current methods for evaluating and predicting drug synergism in advancing combination drug discovery, highlighting their limitations and providing a unified mathematical framework. Additionally, we present a novel solution to resolve these limitations and improve synergism evaluation, demonstrated through a case study with 20 pairs of FDA-approved chemotherapy drugs for colorectal cancer.

Reactive oxygen species (ROS) constitutes a group of reactive molecules that play a critical role in biological processes. Varying ROS levels have been frequently observed in cancer cells and the tumor microenvironment (TME). The role of ROS displays significant complexity in cancer development and therapy. Elevated ROS levels can induce metabolic reprogramming and promote the proliferation, invasion, and metastasis of cancer cells, resulting in cancer progression. However, excessive ROS accumulation leads to the occurrence of apoptosis, pyroptosis, necroptosis, and ferroptosis in cancer cells, which restrains tumor development. In the TME, ROS frequently promotes angiogenesis and remodels the extracellular matrix (ECM) by enhancing the differentiation of cancer-associated fibroblasts (CAFs), thereby supporting tumor growth. Concurrently, high ROS levels favour immunosuppressive cells, including M2-polarized macrophages, and regulatory T cells (Tregs), while impairing the antitumor capabilities of T cells. In the aspect of cancer therapy, it is overly simplistic to merely combine chemoradiotherapy with antioxidants as a therapeutic strategy. Instead, highlighting targeted therapies that modulate ROS is essential, given their inherent complexity. Fortunately, a variety of innovative treatments have emerged, including nanodrug delivery systems (NDDS), proteolysis-targeting chimeras (PROTAC), and adoptive cell therapy (ADT), which not only exhibit synergistic effects with immune checkpoint therapy (ICT), but also enhance the antitumor capabilities of the TME. In this paper, we elucidate the mechanism of ROS production, enumerate the role of ROS in cancer development and the TME, and discuss advancements in ROS-targeted cancer therapeutics.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is often diagnosed at a late stage, resulting in poor survival rates and limited treatment options. Several factors contribute to the dismal prognosis of PDAC, including the absence of reliable biomarkers and effective therapies, as well as the complex biology of the disease.

KRAS is the most frequently mutated oncogene and its mutational activation drives approximately 25 % of human cancers. Son of Sevenless 1 (SOS1) plays a pivotal role in the KRAS signaling pathway through catalyzing the conversion of inactive GDP-bound KRAS to active GTP-bound KRAS, and is thus considered as a promising target for pan-KRAS inhibition. Currently, four KRASG12C-specific inhibitors, namely sotorasib, adagrasib, fulzerasib and garsorasib, have garnered regulatory approval. However, acquired resistance to KRASG12C inhibition rapidly emerges. In addition, the other prevalent KRAS mutations, including G12D and G12V, are still lacking effective therapeutic drugs. PROTAC-mediated KRAS and SOS1 degradation has been emerged as a promising strategy to overcome these issues, and achieved rapid progress in the recent years. This article provides an overview of the chemical structures, design strategies, structure-activity relationship (SAR) studies as well as in vitro and in vivo activities of the PROTACs degrading KRAS and SOS1, and sheds light on future challenges and opportunities to accelerate the development of new chemotherapies for KRAS-driven cancers.

Morchella spp., also known as delicious morel mushroom, is a general term for the phylum Ascomycota, Pezizomycetes, Pezizales, Morchelllaceae, and Morchella fungi. For thousands of years, Morchella spp. have been considered a precious food supplement and medicinal ingredient. Numerous pharmacologically active chemical components such as polysaccharides, amino acids, sterols, vitamins, and trace elements have been found in Morchella spp. Pharmacological studies have confirmed that bioactive polysaccharides and other important secondary metabolites of the Morchella spp. have various health promoting effects, including antioxidant, immune regulatory, anticancer, antibacterial and other biological characteristics. However, comprehensive evaluations on the preparation and structural characteristics, bioactivities, and toxicology of these functional components (e.g., polysaccharides, sterols, vitamins, trace elements) from various Morchella spp. species are very limited, which may restrict the practical application of Morchella spp. This review summarizes the physicochemical characteristics, pharmacological activities, and possible mechanisms of bioactive components from Morchella spp., and emphasizes the research progress on the extraction, purification, structural characteristics, and pharmacological activity of Morchella polysaccharides (MPs). To provide useful references and promising directions for the comprehensive development and utilization of Morchella spp. in functional foods, and pharmaceuticals. Additionally, the review examines and highlights applications, potential developments, and future research directions. This review helps to fill the knowledge gap between theoretical insights and practical applications, guiding future research and industrial applications of Morchella spp.

The KRASG12C mutation causes the KRAS protein to remain in a constantly activated state, thereby promoting cell proliferation and cancer progression. As researchers have transitioned the KRASG12C mutation from being "undruggable" to "druggable", the development of KRASG12C inhibitors has reached a peak. However, some KRASG12C inhibitors have shown resistance in preclinical studies and clinical trials, resulting in poor clinical outcomes and limiting their application. This review summarizes emerging strategies to overcome resistance, including optimization strategies for KRASG12C mutation site inhibitors (including covalent inhibitors and degraders), as well as potential therapeutic strategies involving combination therapies and multi-target inhibition targeting major resistance mechanisms. Additionally, it discusses the potential issues and challenges that may arise in the development of treatments for KRASG12C mutation resistance. It is hoped that this review can provide insightful perspectives to help overcome KRASG12C inhibitor resistance.

While anthracyclines, commonly used in cancer treatment, are well known to cause cardiotoxicity, no validated biomarkers currently exist that can predict the early development of doxorubicin-induced cardiotoxicity (DIC). Therefore, identifying early biomarkers of DIC is urgently needed. Metabolomics approaches have been used to elucidate this relationship and identified related metabolite markers. However, differences in pre-clinical model systems make it challenging to draw definitive conclusions from the discoveries and translate findings into clinical applications.

Leukemia, a group of blood cancers, presents a significant global health challenge. Despite advancements in conventional therapies like chemotherapy and immunotherapy, the need for more effective and less toxic treatments remains. Nanotechnology offers a promising avenue for targeted drug delivery and immune modulation in the fight against leukemia. Through the utilization of nanomaterials' special qualities, like their small size, large surface area, and capacity to transport a variety of payloads, scientists are creating novel ways to get around the drawbacks of conventional treatments. These strategies include targeted drug delivery, immune cell activation, and overcoming drug resistance. However, challenges remain in translating these promising nanotechnological approaches into clinical applications. Addressing issues such as toxicity, biodistribution, and regulatory hurdles is crucial for the successful development of nanomedicine for leukemia. In conclusion, nanotechnology offers a promising future for the treatment of leukemia. Continued research and development are essential to unlock the full potential of nanomaterials and improve patient outcomes. The potential of nanotechnology-based strategies to improve the effectiveness of leukemia treatments is explored in this review. We go over the function of different nanomaterials in delivering therapeutic agents to leukemia cells, such as liposomes, polymeric nanoparticles, and inorganic anoparticles. We also investigate the engineering of nanomaterials to influence the immune system and promote anti-tumor reactions.

Epigallocatechin gallate (EGCG), a bioactive polyphenol derived from Camellia sinensis, exhibits multimodal anticancer activity through mechanisms such as apoptosis induction, metastasis suppression, and chemoresistance reversal. Despite its therapeutic promise, clinical application is constrained by rapid metabolism, poor bioavailability, and inconsistent biodistribution. Recent advances in nanotechnology have enabled the development of innovative delivery systems including pH-responsive nanoparticles, lipid-polymer hybrids, and ligand-functionalized carriers that enhance EGCG stability, tumor targeting, and bioavailability by 3- to fivefold in preclinical models. These platforms also facilitate synergistic co-delivery with chemotherapeutics like doxorubicin, amplifying cytotoxicity and overcoming multidrug resistance. Mechanistically, EGCG modulates oncogenic pathways via NF-κB suppression, caspase activation, and MMP-9 downregulation, demonstrating efficacy across diverse cancer types. However, translational challenges persist, such as nanoparticle toxicity, variable tumor accumulation, and insufficient penetration in hypoxic microenvironments. Regulatory hurdles, including the lack of harmonized global standards for herbal medicinal products, further complicate clinical adoption. To bridge these gaps, future research must prioritize scalable cGMP-compliant manufacturing, rigorous preclinical toxicity profiling, and robust clinical trials to validate safety and efficacy. Addressing these issues could position nanoengineered EGCG as a paradigm-shifting therapy in precision oncology, aligning with ESCOP's mission to integrate evidence-based phytomedicines into conventional cancer care. This review underscores the necessity of interdisciplinary collaboration to standardize phytopreparations, refine regulatory frameworks, and advance biomarker-driven clinical validation, ultimately unlocking the full potential of EGCG in modern therapeutics.

Macromolecular drugs, such as proteins and nucleic acids, play a pivotal role in treating refractory diseases and hold significant promise in the growing pharmaceutical market. However, without efficient delivery systems, macromolecular drugs are highly susceptible to rapid biodegradation or systemic clearance, underscoring the need for advanced delivery strategies for clinical translation. A major challenge lies in their limited tissue penetration due to large molecular weight and size, which has recently garnered significant attention as it often leads to therapeutic failure or the emergence of resistance. In this review, we first outline the biological barriers limiting macromolecular tissue penetration, then explore the inherent permeation mechanisms of biomacromolecules in biological systems. We then highlight delivery strategies aimed at enhancing the tissue penetration of macromolecular therapeutics, with a particular focus on tissue-adaptive and tissue-remodeling delivery platforms. Finally, we provide a concise perspective on future research directions in deep tissue penetration for biomacromolecules. This review offers a comprehensive summary of recent advancements and presents critical insights into optimizing the therapeutic efficacy of macromolecular drugs.

Uracil incorporation into DNA, as a result of nucleotide pool imbalances or cytosine deamination (e.g., through APOBEC3A/3B), can result in replication stress and is the most common source of mutations in cancer and aging. Despite the critical role of uracil in genome instability, cancer development, and cancer therapy, only now is there emerging data on its impact on fundamental processes such as DNA replication and genome stability. Removal of uracil from DNA by base excision repair (BER) can generate a DNA single-strand break (SSB), which can trigger homologous recombination (HR) repair or replication fork collapse and cell death. Unprocessed uracil can also induce replication stress directly and independently of BER by slowing down replication forks, leading to single-stranded DNA (ssDNA) gaps. In this perspective, we review how genomic uracil induces replication stress, the therapeutic implications of targeting uracil-induced vulnerabilities, and potential strategies to exploit these mechanisms in cancer treatment.

Supramolecular materials represent a powerful class of platforms in cancer diagnosis and therapy, owing to their dynamic architectures, stimuli responsiveness, and high biocompatibility. This review focused on three representative categories-Pillarene-based systems, virus-mimetic nanoparticles (VMNs), and metal-organic frameworks (MOFs)-each offering unique structural and functional properties. Pillarene-based assemblies enable precise host-guest interactions, by being classified into amphiphilic, ionic, and chiral varieties, the robust drug loading and controlled release capabilities of the Pillarene family were emphasized. At the same time, the VMNs, including virus-like particles and virosomes, show power in cancer cell targeting and membrane penetration by emulating natural viral architectures. By discussing the fabrication and application of single-metallic, multi-metallic, and composite MOFs, their potential in multimodal diagnosis and therapy was revealed. In addition, other supramolecular categories, such as cyclodextrin and dendrimers, were introduced as well. We highlighted representative approaches and emerging methods, and comparative perspectives with traditional nanocarriers were included. A critical evaluation of pharmacokinetic behaviors, biosafety concerns, and translational limitations was also proposed, aiming to guide future research in supramolecular cancer nanomedicine. Through an integrative and forward-looking analysis, this review provided a comprehensive framework for understanding and designing supramolecular systems for precision oncology. These emerging nanotechnologies hold promise to reshape cancer medicine by enabling adaptive, targeted, and multifunctional therapeutic strategies.

Reactive oxygen species (ROS), a class of highly reactive molecules, are closely linked to the pathogenesis of various cancers. While ROS primarily originate from normal cellular processes, external stimuli can also contribute to their production. Cancer cells typically exhibit elevated ROS levels due to disrupted redox homeostasis, characterized by an imbalance between antioxidant and oxidant species. ROS play a dual role in cancer biology: at moderate levels, they facilitate tumor progression by regulating oncogenes and tumor suppressor genes, inducing mutations, promoting proliferation, extracellular matrix remodeling, invasion, immune modulation, and angiogenesis. However, excessive ROS levels can cause cellular damage and initiate apoptosis, necroptosis, or ferroptosis.

Mefenamic acid (MA) represents an efficient nonsteroidal anti-inflammatory drug (NSAID) for treatment in many circumstances of painful conditions and inflammation, but its poor water solubility and gastrointestinal side effects often obstruct its clinical application. Consequently, researchers have been conducting studies on the synthesis of prodrugs and heterocyclic compounds as MA derivatives for the improvement of their pharmacological profile. This review discusses an overview of recent developments in the synthesis and biological applications of MA derivatives. It covers several strategies used to modify the chemical structure of MA to pursue pharmacokinetic improvement, solubility, and targeting features, among which are heterocyclic moieties and prodrug design. Following the many synthetically produced derivatives of MA, mainly proposed between classic organic synthesis and more recent methodologies, such as microwave-assisted synthesis and green chemistry protocols, this review will consider how different structural variations are able to influence the assumed pharmacological actions: analgesic, anti-inflammatory, and anticancer. The findings demonstrate significant progress toward the development of safer and more effective NSAID therapies; thus, they support, in a broad and unprecedented way, the potential of MA derivatives and prodrugs in transforming the state of pain management and inflammation treatment.

Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced EGFR-mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies.

Adverse events of anticancer treatment were common and debilitating in cancer patients. Traditional Chinese medicine injection (TCMI) plays an important role in the comprehensive treatment of cancer in China.

The deep-sea ecosystem, one of the most extreme and underexplored environments, harbors a remarkable diversity of microorganisms capable of producing bioactive compounds with immense pharmaceutical potential. Deep-sea microorganisms, inhabiting depths beyond 100 m, have emerged as a particularly promising source of novel bioactive compounds due to their adaptation to extreme conditions such as high pressure, low temperatures, and absence of light. This review highlights recent advancements in the discovery and characterization of 440 novel natural products from deep-sea organisms (100-11,000 m) between 2020 and October 2024. It encompasses a diverse range of deep-sea fungi and actinomycetes, detailing their source organisms, collection depths, and geographic origins. Remarkably, 80 % of these compounds exhibit bioactivity, with nearly half demonstrating potent cytotoxicity at low micromolar concentrations against various human cancer cell lines. Despite the vast majority of deep-sea microbes remaining unexplored, their potential to yield unique natural products is immense. This review succinctly presents these discoveries, emphasizing their potential biological applications and underscoring the deep-sea as a frontier for future pharmaceutical research.

Dual-atom nanozymes (DAzymes), a novel class of nanozymes featuring dual-metal atomic active centers, mimic the multi-metal synergistic mechanisms of natural enzymes to achieve superior catalytic activity compared to conventional single-atom nanozymes. Their unique dual-atom architecture not only effectively mitigates metal atom aggregation but also significantly enhances substrate adsorption capacity and catalytic efficiency through interatomic electronic coupling and spatial synergy. This structural innovation addresses critical limitations of single-atom nanozymes, including low metal loading and homogeneous active sites. This review systematically summarizes recent advancements in DAzymes: First, we elucidate their design principles and structural advantages, with a focus on precise synthesis strategies (e.g., spatial confinement, coordination stabilization) and atomic-level characterization techniques (e.g., synchrotron radiation-based X-ray absorption spectroscopy, spherical aberration-corrected electron microscopy). By unraveling structure-activity relationships, we clarify the multi-dimensional regulatory mechanisms of dual-atom systems-including coordination environments, electronic coupling, and spatial configurations-on redox enzyme-like activities such as peroxidase and superoxide dismutase mimics. Furthermore, we elaborate on their groundbreaking biomedical applications, including antibacterial and antitumor therapies via reactive oxygen species (ROS) regulation, antioxidant damage repair, and biosensing. This review aims to provide theoretical guidance for the rational design of high-performance DAzymes and to advance their translational applications in precision medicine and intelligent biomaterials.

Biological systems do not exist in isolation. Analogous to the intricate design of a spider web, the metabolic adaptations propagated by glioblastoma cells are interlaced, creating a "defense mechanism" that increases the likelihood of mutagenesis and proliferation, while mitigating stress-induced tumor cell death and immune evasion. Previous studies have observed the role of cardiolipin (CL) in the electron transport chain (ETC) function and several other intracellular signaling pathways. Our review provides a synopsis of the existing knowledge about CL in glioblastoma and its complex relationship with metabolic reprogramming at the subcellular level. Through a meticulous examination of CL defects due to its biogenesis and stress-induced modifications, we seek to elucidate the multifaceted connections between aberrant CL variants and the metabolic alterations that underlie glioblastoma progression. A comprehensive grasp of these mechanisms could provide future direction in designing chemotherapeutic agents that selectively target glioblastoma, are less harmful to normal cells, and therefore, may extend patient survival.

Systemic therapies for the treatment of cancer collaborate to reduce cancer progression and have been used for decades. However, despite the clinical benefits, its long-term use is associated with toxicity, promoting important side effects that can compromise the quality of life. Enzyme supplementation has been pointed out as a therapeutic potential in several diseases. Bromelain is an enzyme complex that regulates pathways associated with inflammation. This review aims to evaluate the use of bromelain-containing supplements to improve the side effects of cancer treatment. This systematic review was developed in PubMed, Web of Science, and Cochrane Library, using the terms: Cancer AND Bromelain. 239 studies were retrieved, and only three met our objective. In general, it was possible to observe that supplementation was able to reduce side effects of adjuvant hormone therapy and chemotherapy, such as mucosal dryness, arthralgia, and peripheral neuropathy induced by chemotherapy.