Glioma is a highly aggressive central nervous system tumor with limited treatment options, presenting a significant challenge for effective therapy. Despite advancements, the role of tumor-associated macrophages (TAMs) in glioma remains poorly understood, especially regarding their polarization and its impact on the immune response. This study investigates the effects of Lysosomal-associated protein transmembrane 4 A (LAPTM4A) deficiency on the polarization of TAMs and its role in modulating anti-tumor immunity. Using C57BL/6 male mice, we established an orthotopic glioma model and employed single-cell RNA sequencing, flow cytometry, in vitro co-culture systems, and in vivo anti-PD-1 therapy experiments to explore the functional role of LAPTM4A. We found that LAPTM4A promotes M2 polarization of TAMs, contributing to glioma progression by enhancing cell proliferation and invasion. In contrast, LAPTM4A-deficient glioma models show a shift towards M1 macrophage phenotypes, leading to stronger immune activation and increased sensitivity to anti-PD-1 therapy. These results suggest that targeting LAPTM4A may provide a novel strategy to improve glioma treatment by modulating TAM polarization and enhancing immune responses. This research lays the groundwork for future therapies aimed at reprogramming the tumor microenvironment to combat glioblastoma.

Imatinib treatment is approved for several indications, including chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). Although adverse events are common, hypersensitivity reactions are not. Because there is a clear clinical benefit of imatinib treatment, re-introduction of imatinib after a hypersensitivity reaction should be considered.

A series of aminated quinolinequinones linked to piperazine analogs (QQ1-7) were synthesized and screened against the full panel of National Cancer Institute (NCI) cancer cell lines for their potential as cytotoxic agents. The Developmental Therapeutics Program of the NCI analyzed the NCI-60 screening results and revealed that seven QQs were potent inhibitors of cancer cell growth across several cell lines, advancing them to the five-dose assay. Encouraged by the NCI five-dose assay results, the cytotoxicity of the selected QQs (QQ1 and QQ4) was further studied in three cancer cell lines-HCT-116 (colon cancer), ACHN (renal cancer), MCF7, and T-47D (breast cancer)-as well as in a normal cell line (HUVEC) for a deeper understanding. QQ1 was the hit compound for ACHN cells with an IC50 value of 1.55 μM. QQ1 could inhibit ACHN cell proliferation, induce oxidative stress, and cause cell cycle arrest in ACHN cells. QQ1 did not affect the apoptotic value in ACHN cells. Oral bioavailability was poor for both QQ1 and QQ4 in vivo in rats due to faster intrinsic hepatic clearance in comparison with humans, as evidenced by in vitro metabolic studies with rat and human liver microsomes. Molecular docking simulation with putative target CDC25A revealed the interaction of QQ1 and QQ4 with active site residues responsible for substrate recognition.

Acute myeloid leukemia (AML) is marked by uncontrolled growth of malignant cells in the bone marrow, presenting a major challenge in hematology despite treatment advances. Curcumin, a polyphenol from turmeric, shows promise as an anticancer agent with multiple mechanisms targeting pathways like NF-κB, STAT3, PI3K/AKT, and MAPK. This review highlights curcumin's antileukemic effects, including apoptosis induction, cell proliferation inhibition, and angiogenesis modulation. Although low bioavailability limits its clinical use, nanoformulations such as liposomes and micelles have improved curcumin's stability and uptake. Combining curcumin with standard chemotherapies has shown synergistic effects, enhancing anticancer efficacy. Preclinical studies consistently demonstrate curcumin's antileukemic impact in AML cell lines and animal models, showing reduced tumor load and prolonged survival. Ongoing clinical trials are assessing curcumin's safety and efficacy in AML patients, with early results indicating potential. However, larger randomized trials are needed for confirmation. In conclusion, curcumin's anticancer properties and safety profile make it a valuable candidate for AML treatment. Further research is necessary to refine delivery methods, optimize combination therapies, and substantiate its role through clinical trials.

Tumorigenesis and metastasis of solid tumors are coupled to profound biophysical changes that alter cancer cells' mechanobiology, critically impacting metastatic progression. In particular, cell stiffness determines the ability of cancer cells to invade surrounding tissues, withstand shear fluid stress and evade immune surveillance. Here, we summarize the biological factors, pathological factors, and therapeutic modalities that affect the mechanobiology of cancer cells. We focus on clinically utilized chemotherapeutics and targeted therapies that show direct and indirect modulation of cancer cells' stiffness and discuss how these treatments can be used in combination with other treatment modalities to improve patient outcomes. Finally, we list the outstanding challenges in the field and provide a perspective on expanding the clinical utilization of experimental therapeutics that can act as "mechanotherapeutics" by regulating mechanobiology of cancer cells.

Besides targeting tumor cells via canonical synthetic lethality, poly(ADP-ribose) polymerase inhibitors (PARPis) can remodel tumor immune microenvironment (TIME), which then affects PARPis' anti-tumor capabilities. However, exact function of PARPis on TIME remains insufficiently explored. Here, by leveraging paired samples during neoadjuvant PARPi Niraparib treatment derived from a prospective clinical trial, we discovered that the expression of immune checkpoint ligand B7-H3 was induced by PARPis in cancer-associated fibroblasts (CAFs) of ovarian cancer. Depletion of B7-H3 in CAFs by using host cd276 (coding B7-H3) knockout mice or B7-H3 deficient fibroblast cells both boosted T cell functions and enhanced the anti-tumor capacities of PARPis in immunocompetent mouse models. Besides, increased B7-H3 on CAFs also attenuated the anti-tumor potentials of T cells in co-culture system. Mechanistically, PARPis blocked autophagic flux by inhibiting PIP4K2A expression, a critical regulator of autophagosome and lysosome fusion, and therefore dampening the lysosomal degradation of B7-H3. Importantly, neutralizing B7-H3 antibodies had synergistic effects with PARPis and achieved superior therapeutic efficacy than PARPis plus PD-1 blockade in a syngeneic mouse ovarian cancer model. Collectively, this study revealed an autophagy-mediated pathway by which PARPis contribute to immune evasion via enhanced B7-H3 accumulation on CAFs, highlighting the complexity of the regulation of PARPis on TIME and the potential application of combining PARPis with B7-H3 blockade in the treatment of ovarian cancer.

Thymic epithelial tumors (TETs), categorized predominantly as thymoma (T) or thymic carcinoma (TC), face a challenging prognosis and limited treatment options. Although chemotherapy remains the established treatment for advanced TETs, its responses tend to be short-lived. The emergence of immunotherapy, particularly programmed cell death-1 (PD-1) and programmed death ligand-1 inhibitors (PD-L1), is increasingly being regarded as a promising new treatment option for various malignancies.

As a member of the chaperonin-containing tailless complex polypeptide 1 (TCP1) complex, which plays a pivotal role in ensuring the accurate folding of numerous proteins, chaperonin-containing TCP1 subunit 6A (CCT6A) participates in various physiological and pathological processes. However, its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer (CRC) cells.

Genistein (GEN) shows significant anticancer potential, particularly against prostate cancer. However, its clinical application is limited by poor water solubility, rapid metabolism and excretion, low bioavailability, and lack of targeted delivery to cancer cells, hindering its effectiveness as a chemopreventive or therapeutic agent.

This research extracted and purified polysaccharides from Corydalis yanhusuo residue. The structure of purified polysaccharides of Corydalis yanhusuo (CYP-1) was characterized by methods such as infrared spectroscopy, nuclear magnetic resonance, and monosaccharide composition analysis. In addition, the purified polysaccharides were subjected to preliminary studies in vitro for antioxidant and antitumor activities. The average molecular weight of CYP-1 was 1.427 × 10³ kDa. FT-IR analysis revealed that CYP-1 displayed characteristic absorption bands typical of polysaccharides. Furthermore, NMR spectroscopy suggested that the sugar residue units of CYP-1 consisted of →1)-α-D-Glcp-(4→, →6)-α-D-Galp-(1→, and α-D-Arap-(1→. In vitro bioactivity experiments revealed that CYP-1 exhibits antioxidant activity and effectively inhibits HepG2 cell proliferation with an IC50 value of 1.381 mg/mL, suggesting its potential as a natural antioxidant and antitumor agent.

The Wnt/β-catenin signaling pathway is a highly conserved signaling pathway closely linked to cancer development through various biological processes, including oncogenic transformation, genomic instability, cancer cell proliferation, stemness, metabolism, cell death, immune regulation, and metastasis. Notably, its activation plays a crucial role in drug resistance to chemotherapy, targeted therapy and immunotherapy. Recent advances in drug development have identified several targeted inhibitors acting at key nodal points of this pathway, with some demonstrating synergistic efficacy when combined with immunotherapeutic agents. This review provides a comprehensive analysis of current understanding regarding the Wnt/β-catenin pathway in malignancy, emphasizing its multifaceted roles in tumor initiation, therapeutic resistance, and immune regulation. Additionally, we summarized the clinical performance of combination therapies targeting the Wnt/β-catenin pathway in conjunction with chemotherapy, targeted therapy, and immunotherapy. Although clinical development remains at a relatively early stage, pharmacological modulation of Wnt/β-catenin signaling offers considerable potential as a novel therapeutic paradigm in precision oncology.

Extracellular vesicles (EVs) play a crucial role in intercellular communication. While the effects of EVs released from living or non-dying cancer cells are well characterized, the impact of EVs released from chemotherapy-treated or apoptotic cancer cells is less understood. This study investigated the effects of the chemotherapy agent cisplatin on EV release and miRNA content in apoptotic medulloblastoma cells, as well as their influence on the growth of drug-naïve recipient cancer cells.

The complex dual role of autophagy provides new insights for enhancing tumor treatment efficacy. However, effectively regulating this process is key to enhancing therapeutic efficacy. To address this challenge, this study designed a gambogic acid-iron nanozyme (GAFe) as a novel carrier to enhance the effectiveness of chemotherapy drugs such as doxorubicin (DOX) by inducing excessive autophagy and oxidative stress. The synthesized nanoparticle (GAFe@DOX) is capable of slowly releasing its active components over a prolonged period within tumor tissues. Gambogic acid can induce excessive autophagy, while the multi-enzyme activity of GAFe and the activation of ferroptosis amplify and sustain excessive autophagy, thereby enhancing the chemotherapy effect of DOX. Meanwhile, ferroptosis activated via the GPX4 pathway by GAFe can synergize with excessive autophagy, amplifying oxidative stress and consequently enhancing the overall therapeutic efficacy. Characterization experiments confirmed the successful synthesis of GAFe@DOX and probe assays demonstrated its superior multi-enzyme activity. In vitro cell studies showed that GAFe@DOX effectively kills tumor cells, while in vivo animal experiments revealed its excellent biocompatibility and significant tumor growth inhibition. This study demonstrates a promising strategy to improve tumor therapeutic efficacy by modulating excessive autophagy and oxidative stress. This provides a novel and effective approach to improve the treatment of refractory tumors such as glioblastoma.

Immune checkpoint inhibitors (ICIs) plus chemotherapy have become the first-line standard therapy for non-oncogene addicted advanced non-small cell lung cancer (NSCLC) patients. There is a lack of reliable biomarkers to predict treatment outcomes. This study aimed to identify relevant lipids that can predict treatment outcomes in NSCLC patients receiving first-line ICIs plus chemotherapy via lipidomics.

This study was to screen for circRNAs associated with osimertinib resistance in lung adenocarcinoma (LUAD) and establish a circRNA-miRNA-mRNA ceRNA network.

Bladder cancer (BCa) is approximately the fourth most prevalent diagnosed cancer in men and is three times less common in women. Therefore, identifying biomarkers, developing more effective therapeutic strategies, and understanding the mechanisms underlying BCa tumor growth and progression are urgently required to improve survival rates. Therefore, we aim to investigate the expression of PTEN/Akt in tissue samples of both non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) patients (n = 70) and human BCa cell lines T24 and 5637, along with the potent role of ellagic acid (EA) in the modulation of the PTEN/Akt pathway and the resulting therapeutic potential. Results showed low-intensity nuclear or cytoplasmic PTEN staining or loss of PTEN expression in tumor cells and overexpression of p-Akt (Ser-473) with high intensity in the nucleus or cytoplasm. EA treatment of T24 and 5637 cells reduced cell viability, inflammation (NF-κB, COX-2), invasion (MMP-9), induced the caspase (cas-3 and cas-9) cascade signaling pathway, and induced cell apoptosis along with the suppression of the PI3K/PTEN/Akt signaling pathway after 48h in a dose-dependent manner. Thus, these data suggested that the EA showed a strong potential anti-cancer effect in T24 and 5637 cells. In conclusion, the expression of PTEN/p-Akt and the inverse relation indicated an alteration of the PTEN/Akt pathway, and such cases could benefit from treatment with EA in BCa.

Cholangiocarcinoma (CCA) is a life-threatening malignancy, and there is an urgent need for new biomarkers to improve the prognosis of patients. The expression of ELF3 in CCA tumor and non-tumor tissues was examined in two cohorts. ELF3 expression and the methylation level of its promoter in CCA patients with various clinicopathological features were analyzed using the UALCAN website. Co-expressed genes significantly associated with ELF3 were screened using the LinkedOmics website. A protein-protein interaction (PPI) network for these co-expressed genes was constructed using the STRING website. Core co-expressed genes correlated with ELF3 were identified through random walk with restart (RWR) analysis. GeneMANIA was utilized to analyze the major biological functions within networks of kinases and TFs mediated by ELF3. Potential targeted drugs for CCA treatment were screened using the Connectivity Map (CMAP) database. ELF3 expression in CCA tissue was significantly increased compared with that in normal tissue. Among CCA patients with distinct clinicopathological features, ELF3 expression was notably elevated in tumor tissues compared to normal tissue, while ELF3 promoter's methylation levels in tumor tissue were significantly decreased. In total, 307 co-expressed genes, evidently relevant to ELF3, were identified through LinkedOmics analysis. RWR analysis revealed 61 co-expressed genes closely associated with ELF3. Enrichment analysis indicated that these genes control cell junctions and epithelial cell differentiation. GeneMANIA analysis uncovered that ELF3-involved regulatory networks of kinases and TFs were primarily linked to the regulation of immune cells and cell adhesion. CMAP analysis identified 10 potential small molecules for CCA treatment including 4 existing drugs used for other diseases. ELF3 shows promise as a diagnostic marker for CCA, and the drugs we have identified hold great potential for the treatment of this fatal disease.

This study aimed to screen IL-8/topo I inhibitors from natural products collected in Taibai mountain and explore the underlying mechanisms. A natural product library of Taibai mountain (NPTM) was first constructed containing 186 compounds. Then, 15 and 6 potential inhibitors were screened using pharmacophore modeling for IL-8 and topo I, respectively. Molecular docking indicated that glycycoumarin was IL-8/topo I inhibitor. A 200 ns molecular dynamics simulation reflected high binding stability and favorable hydrogen bond interaction within glycycoumarin-IL-8/topo I complexes. MM/GBSA calculation showed that the binding free energy was - 12.81 kcal/mol and - 31.20 kcal/mol, and Pro 32 and DT 10 contributed most to glycycoumarin and IL-8, topo I, respectively. SMD simulation demonstrated a stable binding under physiological conditions with energy demands to dissociate from IL-8/topo I. Glycycoumarin decreased IL-8 production in the inflammatory cells, and exhibited obvious topo I inhibition, as well as strong cytotoxicity to three cancer cells. A PPI network revealed that glycycoumarin might work through proteoglycans in cancer (hsa05205) and IL-17 signaling pathway (hsa04657). These results improved current understanding of natural IL-8/topo I inhibitors from Taibai mountain. The combination of in silico and bioassay could provide a new strategy for exploring natural lead compounds against inflammation and cancer.

Malignant Pleural Mesothelioma (MPM) is the most prevalent type of Mesothelioma and currently has no effective treatment options. This underscores the urgent need to explore new therapeutic agents and innovative strategies. Phenolic acids are significant natural compounds recognised for their effectiveness in treating various diseases, including cancer. This study evaluates the anti-carcinogenic properties of Cinnamic acid (CINN) and its derivative Caffeic acid (CA) in both MPM and non-cancerous mesothelial cells. Results show that CA exhibited greater efficiency than CINN in reducing cancer cell survival. This enhanced efficacy is primarily attributed to CA's higher selectivity index and its ability to inhibit proliferation at lower concentrations. Consequently, further analysis was conducted using CA. The subsequent findings revealed that CA suppressed proliferative markers, Ki67 and PCNA, inhibited colony formation and wound healing in MM cells. Experiments also exposed that it suppresses the phosphorylation of ERK1/2 and AKT proteins in a concentration-dependent manner, while the phosphorylation of STAT3 remains unaffected. The pattern of protein phosphorylation and expression suppression by CA in 3D cells resembles that in 2D cells, although it occurred at higher concentrations. Additionally, CA significantly enhanced the expression of p53-regulated proteins p21 and p27, resulting in G2/M arrest in both SPC111 and SPC212 cell lines. Moreover, elevated concentrations of CA were associated with an increased number of dead cells, as demonstrated by DAPI/PI and AO/EtBr fluorescence staining. The increased Bax/Bcl-2 protein ratio, and BH3-only proteins (Bik and PUMA) and the cleavage of caspase-3 indicated that CA induces mitochondrial apoptosis. Our research with MM cells and three-dimensional micro-tumours suggests that CA may be a promising alternative for future MM therapies. However, it is vital to conduct high-throughput in vivo studies to elucidate further the potential importance of CA in treating this devastating disease.

A scaffold hybridization approach was utilized to enhance the antitumor and carbonic anhydrase inhibitory activity of our oxindole and coumarin lead compounds (V and X). Two oxindole-coumarin hybrids 6c and 6e showed broad spectrum of anticancer activity with NCI full panel MG-MIDs of 5.01 and 6.31 µM, respectively. They revealed GI50 of a single digit micromolar concentration against 46 and 39 cell lines, respectively. An apoptosis dependent mechanism is suggested for the potent anticancer activity of compounds 6c and 6e via the increase in the BAX/BCL-2 ratio and enhancement of the expression levels of caspase-9 and the tumor suppressor p53. While this structure hybridization resulted in enhanced antitumor activity, it resulted in moderate CA IX and XII inhibitory activity. The potent anticancer compound 6e was among the most active inhibitors of the tumor associated CA IX and CA XII in this study (KI = 1.8 and 2.1 μM, respectively). As a result, even compound 6e's moderate CA IX/XII inhibitory activity may have synergistic effects contributing to its increased tumor growth suppression and proapoptotic activity. Moreover, compound 6e revealed a nonsignificant cytotoxicity toward the normal kidney epithelial Vero cell line and was totally inactive against the cytosolic isoforms CA I and CA II (KI = > 100 μM) which mitigate its side effect as chemotherapeutic agent and enforce its safety profile.