Recent studies have revealed a great diversity and complexity in extracellular vesicles and particles (EVPs). The developments in techniques and the growing awareness of the particle heterogeneity have spurred active research on new particle subsets. Latest discoveries highlighted unique features and roles of non-vesicular extracellular nanoparticles (NVEPs) as promising biomarkers and targets for diseases. These nanoparticles are distinct from extracellular vesicles (EVs) in terms of their smaller particle sizes and lack of a bilayer membrane structure and they are enriched with diverse bioactive molecules particularly proteins and RNAs, which are widely reported to be delivered and packaged in exosomes. This review is focused on the two recently identified membraneless NVEPs, exomeres and supermeres, to provide an overview of their biogenesis and contents, particularly those bioactive substances linked to their bio-properties. This review also explains the concepts and characteristics of these nanoparticles, to compare them with other EVPs, especially EVs, as well as to discuss their isolation and identification methods, research interests, potential clinical applications and open questions.

The T790M secondary mutation in EGFR confers therapeutic resistance to EGFR-TKIs, leading to poor outcomes. Non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutation is incurable and there is an urgent need for improved therapeutics. Here we report the identification of a small compound, MG-3C, that kills NSCLC cells with T790M mutation while sparing lung cancer cells without T790M mutation. We found that MG-3C activity targets EGFR-STAT3 signaling pathway in NSCLC through direct inhibition of matrix metalloproteinase 9 (MMP-9), ultimately leading to G2/M phase arrest, growth inhibition and apoptosis. Compared with the reported MMP-9 inhibitor Ilomastat, MG-3C shows high anticancer activity and affinity for targets. MG-3C forms hydrogen bonds with the ASP-113, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -9.04 kcal/mol, while Ilomastat forms hydrogen bonds with the GLN-169, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of -5.98 kcal/mol. The spatial structure composed of ASP-113, ASP-201, and HIS-203 of MMP-9 provides a new coordinate for the design of MMP-9 inhibitors. Most importantly, subcutaneous and oral administration of MG-3C elicit dramatic regression of NSCLC xenograft tumors harboring T790M mutation as well as favorable biosafety profile in vivo, suggesting that MG-3C may be a potential candidate for NSCLC harboring T790M mutation.

Background/Objectives: Laryngeal cancer (LC), predominantly squamous cell carcinoma (SCC), represents a considerable health burden worldwide. Tumour subsite heterogeneity (supraglottic, glottic, subglottic) influences clinical behavior and outcomes. This review synthesizes current knowledge on epidemiology, risk factors, diagnostics, histological variants, biomarkers, treatment modalities, and survival. Results: This narrative review synthesizes current literature on the epidemiology, risk factors, diagnosis, histological variants, biomarkers, and prognosis of LC. The review highlights the critical influence of tumour sites (supraglottic, glottic, subglottic) on metastatic patterns and survival. Key risk factors of LC include tobacco and alcohol use, human papillomavirus (HPV) infection, and occupational exposures. The diagnostic process encompasses clinical examination, endoscopy, biopsy, and imaging. Several biomarkers that aid in diagnosis, treatment plan determination, and prognosis prediction have been established. These biomarkers include long noncoding RNAs, cell cycle regulators, apoptosis regulators, oncogenes, tumour suppressor genes, growth factor pathway components, angiogenic factors, structural proteins, sex hormone receptors, and immunological markers. Current treatment modalities range from organ-preserving surgery and radiotherapy to combined chemoradiotherapy and total laryngectomy. Finally, survival data are presented and stratified by stage and subsite. Conclusions: The review underscores the need for a multidisciplinary approach to LC management, integrating clinical, pathological, and molecular information to optimize patient outcomes.

Glioblastoma (GBM), also known as glioblastoma multiforme, is a rapidly growing and highly invasive malignant tumor. Due to the inability to clearly distinguish between glioblastoma and normal tissue, surgery cannot achieve safe resection, often leading to poor patient prognosis and inevitable tumor recurrence. According to previous studies, GBM invasion is related to intercellular adhesion, matrix degradation, extracellular matrix and its related adhesion molecules, as well as the molecular matrix of protein hydrolases in the microenvironment of GBM cells and stromal cells.

The aim is to enhance our understanding of the molecular mechanisms underlying GBM invasion and to advance research on targeted therapies for inhibiting GBM invasion.

This article describes the protein hydrolases that may affect GBM cell invasion, changes in the cytoskeleton during motility, and the regulatory mechanisms of intracellular signaling pathways in GBM invasion. In addition, we also explored the possibility of targeted therapy against invasion related molecules in GBM.

Autophagy is a crucial cellular process in degrading damaged organelles and maintaining cellular homeostasis. By forming irreversible bonds with specific proteins, covalent inhibitors present a distinct advantage in regulating autophagy and its related pathways. These inhibitors can provide sustained modulation of autophagy at lower doses, improving therapeutic efficacy while minimizing adverse effects. We discuss their mechanisms, including how they affect autophagy-related enzymes and pathways, and their potential applications in the treatment of cancers and other autophagy-related disorders. Studying autophagy-related pathway targets will provide new insights for the development of covalent inhibitors and enhance therapeutic strategies for complex conditions.

Non-small cell lung cancer (NSCLC) is frequently diagnosed at an advanced stage, with 20 % of cases presenting as localized disease, 25 % with regional metastasis, and 55 % with distant metastasis, contributing significantly to increased morbidity and mortality rates. Current treatments, including chemotherapy, immunotherapy, radiotherapy and targeted therapy, have shown therapeutic efficacy but are limited by issues such as lack of specificity, cytotoxicity, and therapeutic resistance. Nanoparticles (NPs) offer promising solutions to these challenges by enhancing drug penetration and retention, improving biocompatibility and stability, and achieving greater precision in targeting cancer cells. This review provides insights into various types of NPs utilized in anti-metastatic drug delivery, emphasizing their ability to enhance the efficacy of existing chemotherapeutics for the prophylaxis of metastatic NSCLC. The usage of NPs as carriers of synthetic and natural compounds aimed at inhibiting cancer cell migration and invasion have also been reviewed. Special attention has been given to biomimetic nanomaterials including extracellular vesicles and engineered exosomes, that are capable of targeting molecular pathways such as EMT, p53 and PI3K/Akt to treat metastatic NSCLC. Additionally, emphasis has been given to clinical trials of these nanoformulations and their efficacy. Although therapeutic outcomes have demonstrated certain improvements, challenges related to toxicity persist, highlighting the need for further optimization of these formulations to enhance safety and efficacy. Finally, we discuss the current limitations and future perspectives for integrating NPs into clinical settings as novel therapeutic agents for lung cancer metastasis.

Covalent drugs have experienced a revival in recent decades due to their advantageous pharmacodynamic profiles and targeting of "undruggable" proteins. However, balancing selectivity, reactivity, and potency is essential for safe and effective drugs. Here, we employ a cell-selective bioorthogonal prodrug design to enhance the selectivity for covalent inhibitors without compromising the reactivity and potency. The upregulation of phosphatase and integrin facilitates the formation of enzyme-instructed supramolecular assemblies (EISA) on the cancer cell membrane. These assemblies localize bioorthogonal reaction handles tetrazine (Tz), which liberate Melphalan from its bioorthogonal prodrug TCO-Mel. The TCO modification disrupts the LAT1-mediated transportation, reducing cellular permeability of TCO-Mel and the corresponding cytotoxicity to normal cells. Although the cell-selective on-membrane assemblies directed prodrug activation restores Melphalan influx to inhibit cancer cell growth. This prodrug activation strategy further demonstrates potent tumor suppression with satisfactory biocompatibility in vivo. Overall, we extend the scope of bioorthogonal prodrug design for covalent drugs via regulating cellular influx of active pharmaceutical ingredients (APIs).

Rationale: Siglec-15 (S15) is a membrane-associated antigen overexpressed across various cancer types, and also induces immunosuppression. We believe this makes S15 a promising target for cellular immunotherapy of solid tumors characterized by an immunosuppressive tumor microenvironment, but this remains underexplored to date. Method: We engineered a bispecific antibody that simultaneously binds S15 on tumor cells and CD3 on T cells in the popular IgG-scFv format; we termed this molecule STAB. Results: In vitro, STAB induced marked proliferation of CD3+ T cells in human PBMCs, and mediated effective killing of Panc-1 pancreatic ductal adenocarcinoma (PDAC) and H460 non-small cell lung cancer (NSCLC) cells in co-culture studies with PBMCs or CD3+ T cells. In NSG mice with human PDAC and NSCLC tumors, STAB effectively suppressed tumor growth and prolonged survival, in sharp contrast to mice receiving either anti-S15 or anti-CD3 mAbs alone. STAB increased activated T cells in both tumor and circulation, as well as reduced the stromal barrier-a key hallmark of PDAC. Conclusion: Our results underscore STAb as a promising therapeutic molecule to be investigated further for PDAC and NSCLC, and potentially other S15-positive solid tumors.

Advanced esophageal squamous cell carcinoma (ESCC) is characterized by molecular heterogeneity and distinct patterns of immune cell infiltration. Regulatory T cells (Tregs), in particular, play a critical role in shaping an immunosuppressive tumor microenvironment (TME), which is associated with poor clinical outcomes.

We developed a prognostic model by integrating GEO-derived bulk RNA sequencing data and single-cell transcriptome. Model predictions were confirmed through RT-qPCR, Western blot, and immunohistochemistry on clinical specimens, while in vitro assays (CCK8, transwell invasion, scratch, colony formation, and immunofluorescence) validated the function of SAP18 in cell proliferation, invasion, and ECM remodeling.

Expression patterns of the 5 Tregs-associated genes in clinical specimens aligned with model predictions, underscoring the model's robustness. The high-risk subgroup was associated with upregulated extracellular matrix (ECM) remodeling, an abundance of immune-suppressive cells, higher TP53 mutation rate, and limited benefit from immunotherapy. In contrast, the low-risk subgroup exhibited anti-tumor immunity. Cell-cell communication analysis also implicated the collagen pathway in Tregs-mediated immune evasion in ESCC. Functional assays indicated that SAP18 in the prognostic model significantly promotes proliferation, invasion, and ECM reconstruction, further highlighting its potential as a therapeutic target.

Our findings elucidate the role of Tregs in the TME, underscoring significant potential of SAP18, which is essential for assessing patient prognosis and may facilitate the development of personalized therapies for ESCC.

Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.

The receptor tyrosine kinase (RTK)/Ras/Raf/MEK/ERK signaling pathway is one of the most tumorigenic pathways in cancer, with its hyperactivation strongly linked to the aggressive nature of glioblastoma (GBM). Although extensive research has focused on developing therapeutics targeting this pathway, clinical success remains elusive due to the emergence of resistance mechanisms.

This review investigates how inhibition of the RTK/Ras/Raf/MEK/ERK pathway alters transcription factors, contributing to acquired resistance mechanisms in GBM. It also highlights the critical role of transcription factor dysregulation in therapeutic resistance.

Findings from key studies on the RTK/Ras/Raf/MEK/ERK pathway in GBM were synthesized to explore the role of transcription factor dysregulation in resistance to targeted therapies, radiation, and chemotherapy. The review highlights that transcription factors undergo significant dysregulation following RTK/Ras/Raf/MEK/ERK pathway inhibition, contributing to therapeutic resistance.

Transcription factors are promising targets for overcoming treatment resistance in GBM, with cotreatment strategies combining RTK/Ras/Raf/MEK/ERK pathway inhibitors and transcription factor-targeted therapies presenting a novel approach. Despite the challenges of targeting complex structures and interactions, advancements in drug development and precision technologies hold great potential. Continued research is essential to refine these strategies and improve outcomes for GBM and other aggressive cancers.

Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality worldwide, with limited options for patients at advanced stages. Immunotherapy, particularly immune cell-based therapies, has gained significant attention as an innovative approach for targeting CRC. This review summarizes the progress in various immune cell therapies, including DC vaccine, CAR/TCR-T cells, CAR-NK cells et al, each engineered to recognize and attack cancer cells expressing specific antigens. CAR-T cell therapy, which has been successful in hematologic cancers, faces challenges in CRC due to the solid tumor microenvironment, which limits cell infiltration and persistence. CAR-NK cells, CAR-M and CAR-γδ T cells, however, offer alternative strategies due to their unique properties, such as the ability to target tumor cells without prior sensitization and a lower risk of inducing severe cytokine release syndrome. Recent advances in lentiviral transduction have enabled effective expression of CARs on NK and γδ T cells, providing promising preclinical results in CRC models. This review explores the mechanisms, tumor targets, preclinical studies, and early-phase clinical trials of these therapies, addressing key challenges such as enhancing specificity to tumor antigens and overcoming the immunosuppressive tumor microenvironment. The potential of combination therapies, including immune checkpoint inhibitors and cytokine therapy, is also discussed some as a means to improve the effectiveness of immune cell-based treatments for CRC. Continued research is essential to translate these promising approaches into clinical settings, offering new hope for CRC patients.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder marked by memory deterioration and cognitive impairment. Bisphenol A (BPA), a common environmental pollutant, has been linked to neurotoxicity and may contribute to AD development. This study aims to uncover potential toxicological targets and molecular mechanisms of BPA-induced AD. BPA's potential neurotoxic effects were predicted using ProTox and ADMETlab. Target prediction for BPA was conducted through the STITCH and Swiss Target Prediction platforms, while AD-related targets were compiled from GeneCards, OMIM, and the Therapeutic Target Database (TTD). Protein-protein interaction (PPI) networks were constructed using STRING and visualized in Cytoscape, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Molecular docking was employed to evaluate the binding interactions between BPA and the identified core targets. Through systematic bioinformatics analyses, 137 candidate targets for BPA-elicited AD were identified. Screening via PPI network analysis highlighted five key targets: STAT3, AKT1, INS, EGFR, and PTEN. GO and KEGG pathway enrichment revealed significant involvement in oxidative stress, neuronal apoptosis, neurodegenerative processes, and pathways such as PI3K/AKT, MAPK, lipid and atherosclerosis, and AD signaling. Molecular docking simulations confirmed strong binding affinities between BPA and these core targets. This study sheds light on the molecular mechanisms underlying BPA's neurotoxic effects in the context of AD and provides a foundation for further research into preventive and therapeutic strategies. The integration of network toxicology and molecular docking offers a robust framework for unraveling toxic pathways of uncharacterized environmental and chemical agents.

Pseudogenes are abundantly present in the human genome and are often thought of as nonfunctional nucleotide sequences, but a growing body of research suggests that pseudogenes can play important biological roles through a variety of pathways, and can be involved in the development of cancer. Lung cancer is one of the most prevalent cancers in the world and it is crucial to find new therapeutic strategies for the treatment of lung cancer. In recent years, studies on the effects of pseudogenes on lung carcinogenesis have increased rapidly. This has pointed to new directions in the diagnosis and treatment of lung cancer. Aim of this paper is to comprehensively discuss the role and influence of pseudogenes in the lung cancer, and the potential of pseudogenes as novel epigenetic targets in lung cancer diagnosis and prognosis and treatment, which is significant for realizing the clinical benefits of pseudogenes.

Head and neck cancer (HNC) is a genetically complex cancer type having treatment difficulties due to affecting multiple organs in complex anatomical sites. Radiotherapy resistance, chemotoxicity, post-surgery disability makes HNC treatment more complicated. Therefore, there is need to developed new treatment approaches. Nanoparticle-based therapies especially cerium oxide nanoparticles with its anti-cancer features, high catalytic activity, anti- or pro-oxidant and radio-protective properties give a boon for HNC treatment. In the current study, two dextran-coated cerium oxide nanoparticles (Dex-CeNPs) namely SD1 and SD2 were synthesized and characterized by using two types of dextran (D1 and D2) having distinct molecular weights and branching characteristics to understand their potential as a new HNC treatment strategy while evaluating the role of dextran type. The effectivity of the SD1 and SD2 on the HNC cell lines (A253, SCC-25, FaDu) were investigated by analyzing their cytotoxicity, genotoxicity, reactive oxygen species (ROS) generation properties. Low IC50 value, high ROS generation and stability profiling of SD2 compared to SD1 indicates the distinct function of dextran type on Dex-CeNPs effectivity on HNC. To better elucidate the effectivity of SD2, flow cytometry analysis and pro-apoptotic (TP53, CASP3, BAX) and anti-apoptotic (Bcl-2) gene expression profiling were investigated in detail. The findings indicate that SD2 exhibits an influence on head and neck cancer cells via the apoptotic pathway. Our research sets the framework for the development of Dex-CeNPs as remarkable nanotherapeutic candidates for treatment of head and neck cancer.

Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.

Distant metastasis is the major cause of gastric cancer mortality, and epidermal growth factor receptor (EGFR) activation plays critical roles in gastric cancer dissemination. However, EGFR targeting therapies in gastric cancer show only marginal effects, and the molecular mechanisms of oncogenic EGFR signaling remain poorly defined. Here, we report Ephrin A1 as a novel ligand of EGFR in gastric cancer. Ephrin A1 facilitates colonization and metastasis of gastric cancer cells in vitro and in vivo via inducing epithelial-mesenchymal transition (EMT). Ephrin A1 directly interacts with EGFR and induces EGFR dimerization, phosphorylation and activation of downstream signaling. Ephrin A1-induced EMT can be rescued by EGFR signaling inhibitors or knockout of EGFR, but not depletion of its classical receptor EphA2. Moreover, Ephrin A1 protein level correlates with EGFR phosphorylation levels in gastric cancer patients. Collectively, our work uncovers Ephrin A1 as a functional ligand of EGFR and highlights the potential role of the Ephrin A1/EGFR/EMT regulatory axis in cancer metastasis.

Although inflammation has been widely associated with cancer development, how it affects the outcomes of immunotherapy and chemotherapy remains incompletely understood. Here, we show that CKLF-like MARVEL transmembrane domain-containing member 4 (CMTM4) is highly expressed in multiple human and murine cancer types including Lewis lung carcinoma, triple-negative mammary cancer and melanoma. In lung carcinoma, loss of CMTM4 significantly reduces tumor growth and impairs NF-κB, mTOR, and PI3K/Akt pathway activation. Furthermore, we demonstrate that CMTM4 can regulate epidermal growth factor (EGF) signaling post-translationally by promoting EGFR recycling and preventing its Rab-dependent degradation. Consequently, CMTM4 knockout sensitizes human lung tumor cells to EGFR inhibitors. In addition, CMTM4 knockout tumors stimulated with EGF show a decreased ability to produce inflammatory cytokines including granulocyte colony-stimulating factor (G-CSF), leading to decreased recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and therefore establishing a less suppressive tumor immune environment in both lung and mammary cancers. We also present evidence indicating that CMTM4-targeting siRNA-loaded liposomes reduce lung tumor growth in vivo and prolong animal survival. Knockout of CMTM4 enhances immune checkpoint blockade or chemotherapy to further reduce lung tumor growth. These data suggest that CMTM4 represents a novel target for the inhibition of tumor inflammation, and improvement of the immune response and tumor drug sensitivity.

Lung cancer, a leading cause of cancer-related deaths worldwide, is primarily linked to smoking, tobacco use, air pollution, and exposure to hazardous chemicals. Genetic alterations, particularly in oncogenes like RAS, EGFR, MYC, BRAF, HER, and P13K, can lead to metabolic changes in cancer cells. These cells often rely on glycolysis for energy production, even in the presence of oxygen, a phenomenon known as aerobic glycolysis. This metabolic shift, along with other alterations, contributes to cancer cell growth and survival. To develop effective therapies, it's crucial to understand the genetic and metabolic changes that drive lung cancer. This review aims to identify specific genes associated with these metabolic alterations and screen phytochemicals for their potential to target these genes. By targeting both genetic and metabolic pathways, we hope to develop innovative therapeutic approaches to combat lung cancer.

The epidermal growth factor receptor (EGFR) has been extensively studied for its critical role in the development and progression of various malignancies. In this comprehensive pan-cancer analysis, we investigated the potential of EGFR as a biomarker across multiple tumor types; a comprehensive analysis of EGFR gene mutation and copy number variation was conducted using cBioPortal and other tools. Utilizing multi-omics datasets from The Cancer Genome Atlas (TCGA), we analyzed EGFR's expression patterns, prognostic implications, genetic mutations, and molecular interactions in different cancers. Our findings revealed frequent dysregulation of EGFR in several tumor types, including lung cancers and glioblastoma multiforme. High EGFR expression was consistently associated with poor clinical outcomes, such as reduced overall survival, disease-free survival, and progression-free survival. Genetic alteration analysis indicated a high frequency of EGFR mutations and copy number variations, particularly in glioblastoma multiforme. Additionally, our study suggests a complex relationship between EGFR expression and cancer-associated fibroblast infiltration, which may contribute to an immunosuppressive tumor microenvironment. These findings underscore the clinical relevance of EGFR as a prognostic biomarker and therapeutic target, emphasizing the need for further research and the development of targeted therapies to enhance patient outcomes in cancers with EGFR alterations. The co-expression network of EGFR with genes and proteins involved in cell cycle regulation and mitotic control provided insights into the molecular mechanisms of oncogenesis.

Lung cancer (LC) is the leading cause of cancer-related morbidity and mortality in China, with non-small cell lung cancer (NSCLC) accounting for 85 % of the overall lung cancer cases. AMP-activated protein kinase (AMPK) is a key regulator of energy balance and homeostasis, and its dysregulation is a common feature in various malignancies, particularly in NSCLC with mutations in Liver kinase B1 (LKB1). Studies have shown that the AMPK signalling pathway has a dual role in NSCLC progression, both inhibiting and promoting the progression of malignant tumours. Therefore, drugs targeting the AMPK signalling pathway may hold significant promise for therapeutic application in NSCLC. This review aims to examine the manifestations and mechanisms by which AMPK and its associated signalling molecules influence NSCLC progression and treatment. Firstly, we discuss the critical importance of AMPK within the mutational context of NSCLC. Secondly, we summarise the drugs and related substances that modulate the AMPK signalling pathway in NSCLC and evaluate the evidence from preclinical studies on combination AMPK-targeted therapies to address the issue of drug resistance in NSCLC under current clinical treatments. In summary, this paper highlights the critical importance of developing AMPK-targeted drugs to enhance therapeutic efficacy in NSCLC, as well as the potential for applying these drugs in clinical therapy to overcome drug resistance.

Proteolysis Targeting Chimeras (PROTACs) have revolutionized cancer therapy by offering a selective and innovative approach to degrade key oncogenic proteins associated with various malignancies. These hybrid molecules exploit the ubiquitin-proteasome system, facilitating the degradation of target proteins through an event-driven mechanism, thereby overcoming drug resistance and enhancing selectivity. With diverse targets including androgen receptors, BTK, estrogen receptors, BET proteins, and BRAF, PROTACs offer a versatile strategy for personalized cancer treatment. Advantages of PROTACs over traditional small molecule inhibitors include their ability to operate at lower concentrations, catalyzing the degradation of multiple proteins of interest with reduced cytotoxicity. Notably, PROTACs address challenges associated with traditionally "undruggable" targets, expanding the therapeutic landscape of cancer therapy. Ongoing preclinical and clinical studies highlight the transformative potential of PROTACs, with promising results in prostate, breast, lung, melanoma, and colorectal cancers. Despite their potential, challenges persist in optimizing physicochemical properties and enhancing bioavailability. Further research is needed to refine PROTAC design and address complexities in molecule development. Nevertheless, the development of oral androgen receptor PROTACs represents a significant milestone, demonstrating the feasibility and efficacy of this innovative therapeutic approach. This review provides a comprehensive overview of PROTACs in cancer therapy, emphasizing their mechanism of action, advantages, and challenges. As PROTAC research progresses, continued exploration in both preclinical and clinical settings will be crucial to unlocking their full therapeutic potential and shaping the future of personalized cancer treatment.

Cancer immunotherapy holds significant promise for improving cancer treatment efficacy; however, the low response rate remains a considerable challenge. To overcome this limitation, advanced catalytic materials offer potential in augmenting catalytic immunotherapy by modulating the immunosuppressive tumor microenvironment (TME) through precise biochemical reactions. Achieving optimal targeting precision and therapeutic efficacy necessitates a thorough understanding of the properties and underlying mechanisms of tumor-targeted catalytic materials. This review provides a comprehensive and systematic overview of recent advancements in tumor-targeted catalytic materials and their critical role in enhancing catalytic immunotherapy. It highlights the types of catalytic reactions, the construction strategies of catalytic materials, and their fundamental mechanisms for tumor targeting, including passive, bioactive, stimuli-responsive, and biomimetic targeting approaches. Furthermore, this review outlines various tumor-specific targeting strategies, encompassing tumor tissue, tumor cell, exogenous stimuli-responsive, TME-responsive, and cellular TME targeting strategies. Finally, the discussion addresses the challenges and future perspectives for transitioning catalytic materials into clinical applications, offering insights that pave the way for next-generation cancer therapies and provide substantial benefits to patients in clinical settings.

Glioma is the most common primary intracranial tumors. Although great achievements have been made in the treatment, the efficacy is still unsatisfactory, which imposes a hefty burden on patients and society. Therefore, the exploration of new and effective anti-glioma drugs is urgent.

Human glioma cell lines U251 and LN229 were included in the study. Cell proliferation was detected by cell counting kit-8 (CCK8), plate clone formation assay, EdU incorporation assay and xCELLigence real-time cell analyzer. Cell apoptosis was evaluated by TUNEL assay and flow cytometry. Then, transwell assay was used for assessing the migration. Moreover, tumor xenograft model was established to examine the effect of scutellarin (SCU) and lidocaine on the growth of glioma in vivo. Lastly, western blot was performed to detect the protein level of epidermal growth factor receptor (EGFR).

In present study, we found that SCU and lidocaine suppressed the proliferation and migration, and induced the apoptosis of human glioma cell lines, including U251 and LN229 cells, in a dose-dependent manner in vitro. Moreover, the combination of SCU and lidocaine further restrained the proliferation and migration ability of U251 and LN229 cells, while induced their apoptosis in vitro. Additionally, SCU and lidocaine also inhibited the growth of glioma in vivo, and the effect of the combination was better. Above all, the toxicity of SCU and its combination with lidocaine was low to normal astrocytes and neurons. Mechanistically, the effect of SCU and its combination with lidocaine on glioma cells was partially associated with the repression of EGFR signaling.

Scutellarin and lidocaine exerted a synergistic effect on suppressing the proliferation and migration and inducing the apoptosis of glioma cells, which was partly associated with the repression of EGFR signaling.

Epidermal growth factor receptor (EGFR) is a major oncogenic protein, and thus EGFR-targeting therapies are widely used in patients with various types of cancer, including lung cancer. However, resistance to EGFR inhibitors, such as erlotinib, presents a significant challenge in treating lung cancer. In this study, we established an EGFR-independent, erlotinib-resistant (ER) phenotype in lung cancer A549 cells by exposing them to erlotinib for an extended period. The resulting ER cells exhibited a dramatic increase in erlotinib resistance, a decreased EGFR protein level, and enhanced tumor growth, suggesting a robust mechanism bypassing EGFR inhibition. RNA sequencing identified the transcription factor GRHL2 as a critical player in this resistance. GRHL2 was upregulated in ER cells, and its knockdown and knockout significantly reduced erlotinib resistance. Further analysis revealed that GRHL2 upregulates the receptor tyrosine kinase HER3, and that HER3 knockdown similarly decreases the IC50 for erlotinib. Additionally, ER cells showed increased cell-cell adhesion, linked to upregulated E-cadherin. E-cadherin was found to be vital for erlotinib resistance, largely independent of GRHL2, highlighting multiple parallel pathways sustaining resistance. These findings provide a novel mechanism of drug resistance and suggest that combination therapies targeting both GRHL2-HER3 and E-cadherin-mediated pathways may be necessary to overcome erlotinib resistance in lung cancer.

Epidermal growth factor receptor (EGFR) T790M mutation often occurs during long durational erlotinib treatment of non-small cell lung cancer (NSCLC) patients, leading to drug resistance and disease progression. Identification of new selective EGFR-T790M inhibitors has proven challenging through traditional screening platforms. With great advances in computer algorithms, machine learning improved the screening rates of molecules at full chemical spaces, and these molecules will present higher biological activity and targeting efficiency.

An integrated machine learning approach, integrated by Bayesian inference, was employed to screen a commercial dataset of 70,413 molecules, identifying candidates that selectively and efficiently bind with EGFR harboring T790M mutation. In vitro cellular assays and molecular dynamic simulations was used for validation. EGFR knockout cell line was generated for cross-validation. In vivo xenograft moues model was constructed to investigate the antitumor efficacy of CDDO-Me.

Our virtual screening and subsequent in vitro testing successfully identified CDDO-Me, an oleanolic acid derivative with anti-inflammatory activity, as a potent inhibitor of NSCLC cancer cells harboring the EGFR-T790M mutation. Cellular thermal shift assay and molecular dynamic simulation validated the selective binding of CDDO-Me to T790M-mutant EGFR. Further experimental results revealed that CDDO-Me induced cellular apoptosis and caused cell cycle arrest through inhibiting the PI3K-Akt-mTOR axis by directly targeting EGFR protein, cross-validated by sgEGFR silencing in H1975 cells. Additionally, CDDO-Me could dose-depended suppress the tumor growth in a H1975 xenograft mouse model.

CDDO-Me induced apoptosis and caused cell cycle arrest by inhibiting the PI3K-Akt-mTOR pathway, directly targeting the EGFR protein. In vivo studies in a H1975 xenograft mouse model demonstrated dose-dependent suppression of tumor growth. Our work highlights the application of machine learning-aided drug screening and provides a promising lead compound to conquer the drug resistance of NSCLC.

Oesophaegal cancer patients with a clinical complete response (CR) after neoadjuvant chemoradiotherapy (nCRT) are candidates for an active surveillance strategy. Regrowth rates of 40% after initial clinical CR indicate that identification of a true complete response to nCRT remains challenging. Near-infrared tumour-specific fluorescence endoscopic imaging might help to discriminate patients with a true complete response from patients with residual disease. This study aims to find potential markers to enable molecular imaging in oesophageal cancer and to assess the effect of nCRT on marker expression.

Oesophageal cancer tissue slides of diagnostic biopsies (n = 41) (pre-treatment) and paired surgical specimens (n = 31) (post-treatment) were collected. Tissue slides of patients with adenocarcinoma (n = 29) and squamous cell carcinoma (n = 12)) were included. Immunohistochemistry was performed to assess expression of the tumour markers CEA, EpCAM, VEGF-α, EGFR, and c-MET in the tumour and compared to the expression of these markers in surrounding healthy tissue. A total immunostaining score (TIS, range 0-12), which combines the percentage and intensity of stained cells, was calculated. The TIS of pre-treated biopsies were compared with the TIS of the post-treatment surgical specimens to assess the effect of neoadjuvant therapy on the marker expression.

The median TIS of EpCAM in adenocarcinomas was 10, vs. 0 in healthy mucosa (p < 0.001). The median TIS of EGFR in squamous cell carcinoma was 12, vs. 4 in healthy mucosa (p < 0.001). Neoadjuvant therapy did not affect the expression of the markers.

EpCAM and EGFR appear to be the most suitable targets for tumour-specific NIR fluorescence imaging of oesophageal adenocarcinoma and squamous cell carcinoma, respectively. Unaffected expression of all suitable markers by neoadjuvant therapy implies that the diagnostic biopsy can be used to select a patient-specific target for response evaluation by molecular imaging.

One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.

Recent advances in cancer genome analysis and the practice of precision medicine have made it possible to identify fractions with rare genetic alterations. Among biliary tract cancers, EGFR-amplified cancers are known to be rare fractions across organs and have a poor prognosis. The use of anti-EGFR antibody for EGFR-amplified cancers has been promising; however, the evidence is not yet clear.

In this report, we describe the case of a 48-year-old man diagnosed with advanced gallbladder cancer. The patient was administered gemcitabine plus cisplatin, followed by S-1 monotherapy; however, disease progression was observed after two cycles of each regimen. Comprehensive genomic profiling test revealed EGFR-amplification, and the patient was treated with combination therapy with the anti-EGFR antibody necitumumab, gemcitabine, and cisplatin. After two cycles of treatment, tumor size reduced, and the treatment response was evaluated as partial response. On Day 90, after five cycles of treatment, tumor progression was confirmed. In addition, after disease progression, liquid biopsy revealed acquired pathogenic gene alterations suggesting anti-EGFR antibody resistance.

This report supports the clinical benefit of anti-EGFR antibodies for EGFR-amplified biliary tract cancers and the importance of genomic analysis in personalized therapy and drug resistance research.

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this is mostly due to therapy failure. Limited treatment options and resistance to standard-of-care (SoC) therapies makes PDAC one of the cancer types with poorest prognosis and survival rates [1,2]. Pancreatic tumors are renowned for their poor response to therapeutic interventions including targeted therapies, chemotherapy and radiotherapy. Herein, we review hallmarks of therapy resistance in PDAC and current strategies aiming to tackle escape mechanisms and to re-sensitize cancer cells to therapy. We will further provide insights on recent advances in the field of drug discovery, nanomedicine, and disease models that are setting the ground for future research.

Recent research has highlighted the therapeutic potential of citrus-derived dietary 5,6,7,4'-tetramethoxyflavone (TMF) against HeLa cancer. Our study aims to elucidate its mechanisms of action through proteomics analysis, network pharmacology, and molecular docking. The results suggested that TMF demonstrated efficacy by upregulating CD40, CD40L, Fas, Fas-L, HSP27, HSP60, IGFBP-1, IGFBP-2, IGF-1sR, Livin, p21, p27, sTNFR2, TRAILR2, TRAILAR3, TRAILR4, XIAP, p-Sre, p-Stat1, p-Stat2 p-c-Fos, p-SMAD1, p-SMAD2, p-SMAD4, p-SMAD5, p-IκBα, p-MSK1, p-NFκB, p-TAK1, p-TBK1, p-ZAP70, and p-MSK2, while downregulating p-EGFR, p-ATF2, p-cJUN, p-HSP27, p-JNK, and p-GSK3A. These targets are primarily involved in MAPK, apoptosis, and TNF signaling pathways. Notably, p21, p27, EGFR, SMAD4, JNK, ATF2, and c-JUN merged as pivotal targets contributing to TMF's anti-cancer efficacy against HeLa cells. This study is first to delineate the potential signaling pathways and core targets of TMF in treating of HeLa cancer, paving the way for further exploration of TMF's medical potential.

The concerns on the function of Transmembrane protein 173 (TMEM173)-dependent innate immunity in prevention and management of cancers has recently been increased. The role of TMEM173 in predicting the prognosis and response to treatment in lung adenocarcinoma (LUAD) remain unclear. Our study revealed that TMEM173 expression was significantly differential in various tumors and the related prognosis was heterogeneous. Further investigation discovered that the expression level of TMEM173 in LUAD tissues was significantly decreased and high TMEM173 expression is associated with better overall survival in LUAD patients. TMEM173 was mainly enriched in immune response-regulating signaling pathway, T cell activation and cell cycle G2/M phase. Furthermore, it was found that TMEM173 expression was positively related to markers and infiltration levels of tumor-infiltrating immune cells. TMEM173 could predict response to targeted therapy, chemotherapy and immunotherapy in LUAD patients. In vitro TMEM173 knockdown decreased the percentage of G2 phase cells, contributing to the increased growth of lung cancer cells. These results implied that TMEM173 might be a prognostic biomarker and a potential target of precision therapy for LUAD patients.

Lipid rafts are dynamic microdomains enriched with cholesterol and sphingolipids that play critical roles in cellular processes by organizing and concentrating specific proteins involved in signal transduction. The interplay between lipid rafts, raft-associated caveolae and the human epidermal growth factor receptors has significant implications in cancer biology, particularly in breast and gastric cancer therapy resistance. This review examines the structural and functional characteristics of lipid rafts, their involvement in EGFR and HER2 signaling, and the impact of lipid rafts/CXCL12/CXCR4/HER2 axis on bone metastasis. We also discuss the potential of targeting lipid rafts and caveolin-1 to enhance therapeutic strategies against HER2-positive cancers and the impact of co-localization of trastuzumab or antibody drug conjugates with caveolin-1 on therapy response. Emerging evidence suggests that disrupting lipid raft integrity or silencing caveolin-1, through several strategies including cholesterol-lowering molecules, can influence HER2 availability and internalization, enhancing anti-HER2 targeted therapy and offering a novel approach to counteract drug resistance and improve treatment efficacy.

Lung cancer is the leading cause of cancer-related deaths, in part due to its late diagnosis. Increased epidermal growth factor receptor (EGFR) expression in cancer cells is associated with a poor prognosis, and EGFR tyrosine kinase inhibitors are widely used in cancer treatment. This study aimed to clarify the relationship between EGFR expression on T cells and cancer prognosis in patients with non-small cell lung cancer (NSCLC). Forty patients with NSCLC and 40 healthy volunteers were included in this study. Peripheral CD4+T helper (Th1, Th2, Th9, Th17, Th1Th17, follicular and peripheral Th) and cytotoxic T lymphocyte (CD8+follicular and peripheral T) subsets were identified with flow cytometry according to their chemokine receptors. EGFR expression on T lymphocytes in relation to overall survival (OS) was investigated in patients with NSCLC. The patients [mean age (min-max) = 64.03 (45-83); 20 stage I-III and 20 stage IV] had increased EGFR expression on CD3+T, CD4+Th, Th1, Th2, and Th17 cells compared to the controls (p < 0.05). High EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells was associated with poor OS. Also, PD-1 expression on lymphocytes, CD3+T, and Th cells was increased in patients with NSCLC compared to controls. The high expression of EGFR and PD-1 on Th cells and the reduced percentage of lymphocytes and Th cells, especially in stage IV patients with NSCLC, revealed that increased EGFR activity may trigger apoptosis of Th cells and promote the development of metastases, while high EGFR expression on CD3+T, CD4+Th, Th1, and Th2 cells may be an independent poor prognostic marker in NSCLC.

Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various strategies are employed to address the overactivation of these pathways, among which targeted therapy emerges as a promising approach. Directly targeting specific proteins, leads to encouraging results in cancer treatment. For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation. These inhibitors have shown potent efficacy against Non-Small Cell Lung Cancer. Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins. Additionally, inhibition of proteins like SOS, SH2 domain, and Ras demonstrate promising anti-tumor activity both in vivo and in vitro. Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and Hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL).

We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy.