Hepatocellular carcinoma (HCC) poses a significant global public health challenge, with conventional therapies often limited by severe adverse reactions. This study utilized network pharmacology and molecular docking to identify anti-HCC compounds from Ganoderma applanatum triterpenoids (GAT). Sixty compounds were screened using Swiss ADME, with potential targets predicted subsequently. Intersection analysis with HCC-associated targets identified 339 overlapping targets. Subsequent protein-protein interaction (PPI) network analysis identified nine core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that GAT inhibits HCC progression by modulating cancer-associated signaling pathways such as PI3K-Akt, MAPK, Ras, and Rap1 signaling. A compound-target network identified core compounds. Molecular docking demonstrated strong binding affinities between four compounds (applanaic acid C, methyl gibbosate A, bovistol, lucidone A) and three targets (AKT1, MAPK1, SRC). Toxicity predictions indicated low acute oral toxicity for applanaic acid C (LD50 > 300 mg/kg) and lucidone A (LD50 > 5000 mg/kg). Moreover, immunotoxicity risks were noted, which require key attention during subsequent drug development. This study systematically elucidates the multi-target and multi-pathway anti-HCC mechanisms of GAT providing a foundation for developing natural product-derived therapeutics. Further experimental validation of the efficacy and safety profiles is warranted for these potential lead compounds.

Glioblastoma (GBM) is one of the most aggressive and treatment-refractory brain tumors. Temozolomide (TMZ) remains the standard chemotherapeutic agent but is frequently compromised by DNA-repair mechanisms, whereas tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis only in a subset of tumors due to strong intrinsic resistance. Here, we identify the Mu-2-related death-inducing gene (MUDENG/MuD) as the µ-subunit of adaptor protein complex 5 (AP5M1). TurboID-based proximity labeling revealed reproducible interactions with AP5B1 and AP5M1 subunits, as well as additional associations with AP1-3 complexes and nuclear proteins involved in cell-cycle regulation. These findings establish MuD as a multifunctional component of the AP5 complex that modulates cell-fate signaling in a context-dependent manner. Using MuD-mutant GBM cell lines, we demonstrate that MuD suppresses TRAIL-induced apoptosis by interfering with extrinsic and intrinsic pathways downstream of Bid, whereas it promotes TMZ-induced cytotoxicity through p53-dependent cell-cycle control and DNA-damage responses. Gene set enrichment analysis (GSEA) and functional profiling further revealed distinct MuD-associated interactomes linked to receptor endocytosis and genotoxic-stress pathways. Together, these results uncover opposing roles of MuD in TRAIL- and TMZ-mediated cell death, with MuD suppressing apoptotic signaling in response to TRAIL while modulating p53-dependent genotoxic stress responses that influence TMZ-induced cytotoxicity in glioblastoma.

While anti-programmed death-1 (anti-PD-1) therapy has revolutionized lung cancer treatment, its efficacy remains limited by an immunosuppressive tumor microenvironment (TME). We therefore investigated whether combining anti-PD-1 inhibitor with catgut embedding at the Zusanli acupoint (CIAA) could enhance anti-tumor immunity by reprogramming the TME in a lung cancer mouse model. Combining in vivo tumor monitoring, multi-parametric immune profiling (flow cytometry, IHC, ELISA), and multi-omics analyses (transcriptomics and metabolomics), we found that the combination therapy was associated with enhanced tumor growth inhibition. This effect correlated with a comprehensive TME transformation: conversion to an immunologically active state with increased effector immune cell infiltration (CD8⁺ T, CD4⁺ T, B cells, macrophages) and decreased regulatory T cells, coupled with suppression of pro-tumorigenic factors (VEGF, IL-6). Integrated omics analysis suggests that the combined treatment may modulate tumor-stroma interaction pathways (e.g., PI3K-Akt, focal adhesion) and rewire immunometabolic networks (e.g., tryptophan metabolism). Our study provides hypothesis-generating correlative data positioning CIAA as a potential adjunct capable of remodeling the TME to potentiate anti-PD-1 therapy in lung cancer.

A growing number of malignancies have shown favorable responses to immune checkpoint inhibitors (ICI), most commonly anti-PD-(L)1 antibodies. However, prostate cancer has been associated with mostly unfavorable responses to ICI. This review discusses various trials related to PD-(L)1 inhibitors in prostate cancer.

The aim of the present study was to investigate the prevalence of oral manifestations among patients undergoing chemotherapy.

Photodynamic therapy (PDT)-induced immunogenic cell death (ICD) has emerged as a promising strategy to stimulate robust antitumor immunity. However, the effectiveness of PDT-induced ICD on noncovalent photosensitizers remains suboptimal, as their oxidative capacity is influenced by limited cellular accumulation and suboptimal proximity to target tissue. In this work, we report a covalent ICD inducer, MBTP-Py, which incorporates a carbonylvinylpyridinium warhead into an aggregation-induced emission (AIE)-based photosensitizer. MBTP-Py covalently binds to amino and thiol groups on intracellular proteins with minimal cytotoxicity, thereby enhancing ROS oxidative capacity through improved cellular retention and proximity to target tissues. Upon light activation, MBTP-Py induces both ferroptosis and pyroptosis, thereby releasing damage-related molecular patterns and initiating ICD. Tumor cells treated with MBTP-Py, when used as a vaccine in animal models, significantly enhanced antitumor immune responses. Overall, this research integrates principles of covalent drugs to design a covalent ICD inducer, which promotes the development of tumor vaccines.

Melanoma, an aggressive cancer with a poor prognosis, is difficult for early diagnosis, and there are limited drug treatments. Biologically active molecules, especially polyphenols and flavonoids, have a great therapeutic potential; however, their applications are limited by low aqueous solubility and bioavailability.

Nitrosylcobalamin (NO-Cbl) is a vitamin B12 analog designed to exploit the "Trojan horse" vulnerability created by the heightened need of cancer cells for cobalamin and one-carbon metabolism. Building on our recent biophysical studies confirming the affinity of NO-Cbl for intrinsic factor, this work aimed to investigate the mechanistic basis for the selective anticancer activity of NO-Cbl through the cobalamin transport axis and lysosomal processing.

Monoclonal antibodies (mAbs) targeting immune checkpoint pathways such as programmed cell death protein 1 (PD-1)/PD-L1 are central to modern immunotherapy, yet scalable methods to assess their functional blockade remain limited. We present a bead-based flow cytometry assay for quantifying the inhibition of PD-1/PD-L1 interaction by antibodies. Recombinant human PD-1 protein was conjugated to polystyrene beads, and its interaction with recombinant human PD-L1 protein labeled with a fluorochrome was measured. The inhibitory activity of an anti-PD-L1 mAb was quantified based on their ability to disrupt this interaction. The assay was validated for intra- and inter-assay precision, in addition, functionality was confirmed using a T cell coculture assay. The assay demonstrated dose-dependent inhibition by the αPD-L1 mAb, with a calculated mean IC50 of 3.122 µg/mL. The method proved to be reproducible for the determination of antibody blocking activity, with relative standard deviation (RSD) < 20% between three independent runs. At the concentration approximating the IC50 detected on the bead assay, the antibody significantly restored CD69 expression on the T cell surface (p = 0.0001) in a coculture in vitro system. In addition, the methodology could successfully distinguish the blocking capacity of two anti-PD-L1 antibodies with different affinities. This high-throughput compatible platform offers a reliable tool for screening PD-1/PD-L1 blocking antibodies, supporting immunotherapy discovery and development.

Single-stranded DNA gaps (ssDNA gaps) have emerged as a potential indicator of therapeutic response in cancer. Accumulation of ssDNA gaps is associated with increased sensitivity of cancer cells to genotoxic therapies like PARP inhibitors (PARPi) and cisplatin chemotherapy. However, efficient repair or suppression of ssDNA gap formation is associated with therapy resistance and treatment failure. Therefore, understanding how ssDNA gaps form and are repaired can help identify biomarkers that can guide new treatment strategies to overcome resistance. In this review, we discuss different sources of ssDNA gap formation and the repair mechanisms that have been characterized to date. We bring together current knowledge on how these gaps are processed and what their ultimate fate may be. Finally, we discuss how established drugs like PARPi, hydroxyurea, and platinum compounds, induce and/or exploit ssDNA gaps. Throughout this review, we highlight ssDNA gaps as a potential therapeutic vulnerability that can be used to advance personalized cancer therapy.

This study aimed to evaluate the predictive value of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score for pulmonary infections in patients with non-small cell lung cancer (NSCLC) undergoing chemotherapy.

To overcome limitations in melanoma therapy by developing a targeted nanoplatform based on reduced graphene oxide quantum dot (rGOQD) that integrates photothermal therapy (PTT), chemodynamic therapy (CDT), and immune modulation.

In the search for new CDDOs (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid derivatives) with higher antitumor activity in vivo, thirty CDDO-imidazole derivatives (1-30) were designed and synthesized. Then, 8 was selected due to its superior anti-proliferative activity against three cancer cell lines (B16F10, A549, and HCT116) and its lower toxicity in zebrafish embryos compared to the other evaluated compounds. Further study found that 8 induced apoptosis in HCT116 cells by downregulating Bcl-2, upregulating Bax, and activating caspase-3 to kill cancer cells. Notably, 8 exhibited significant antitumor efficacy comparable to CDDO-Me (bardoxolone methyl), which had entered clinical trials. Taken together, 8 represents a promising candidate for the treatment of cancer and merits further study.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders driven in large part by aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway via the JAK2 V617F and related mutations. The success of first-generation ATP competitive JAK2 inhibitors has validated JAK2 as a therapeutic target, yet clinical benefits remain constrained by issues of off target toxicity, limited mutation allele burden reduction, and the emergence of persistence or resistance. In this review, we focus on a rapidly emerging design paradigm: targeting novel binding sites on JAK2 beyond the canonical ATP pocket-including allosteric sites, covalent anchor residues, and pseudokinase regulatory domains. We summarize structural and computational insights into these new sites, compare mechanistic and therapeutic advantages (such as enhanced selectivity, reduced cross JAK inhibition and potential to overcome resistance) and evaluate preclinical and early clinical evidence. We further identify remaining challenges in the development of next generation JAK2 inhibitors-such as site validation, ligand residence time, covalent binding safety, and rational combination therapies-and propose future directions for translation into the MPN clinic. By refocusing the JAK2 inhibitor field around novel binding site exploitation, we suggest a path toward more potent, selective and enduring therapies for MPN patients.

Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10-15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead 13 showed favorable potency, ADME properties, and demonstrated proof-of-concept in vivo efficacy in an FGFR2-amplified xenograft model comparable with the standard of care.

The emergence of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape of metastatic melanoma. However, despite its success, reliable biomarkers for predicting primary resistance are not available in clinical practice. This study seeks to identify predictors of primary resistance based on novel gene expression signatures. The transcriptomic profile of the tumor microenvironment was analyzed using tissue samples from 46 metastatic cutaneous melanoma patients collected prior to the initiation of ICIs therapy. A primary resistance predictive model was trained with the Discovery FFPE RNA-seq subcohort and validated using an independent external cohort of 54 samples. Additionally, liquid biopsy samples from peripheral blood mononuclear cells were analyzed in 8 patients using single-cell RNA sequencing (scRNA-seq) and in 46 patients using flow cytometry. We identified an 82-gene transcriptomic signature composed of tumor- and immune-related genes that stratifies metastatic cutaneous melanoma patients based on primary resistance to ICIs, with key markers including CXCL13, WDR63, MZB1, FDCSP, IGKC and GRIK3. This signature achieved an AUC of 0.814. Immune deconvolution guided by scRNA-seq revealed four immune cell subsets (Plasma cells, Pre-B cells, memory CD4⁺ T cells, and naive CD4⁺ T cells) as prognostic indicators of resistance. We propose a transcriptomic biomarker signature that accurately predicts primary resistance to ICIs in metastatic cutaneous melanoma. Through the integration of immune deconvolution with circulating immune cell profiles, we derived an ImmuneSignature linked to patient survival. By combining these approaches, we provide a framework for enhancing the prediction of immunotherapy outcomes and offer a novel strategy for identifying therapeutic targets to overcome resistance.

Metastatic tumors-secondary malignancies arising from the hematogenous or lymphatic dissemination of cancer cells from primary lesions to distant sites-account for nearly 90% of cancer-associated mortality worldwide. Consequently, studying the effect of epithelial-mesenchymal transition (EMT) on metastatic tumors using experimental data and partial differential equation (PDE) modeling is essential. This study innovatively established a phenotype- and density-regulated chemotaxis coefficient to develop a PDE model characterizing cancer cell migration, proliferation, and EMT, enabling analysis of EMT behavior within the tumor microenvironment and its impact on spreading patterns. Subsequently, incorporating the mechanisms of anti-TGF β RII and cyclophosphamide (CTX), three therapeutic models for tumor metastasis were constructed, with parameter estimation based on experimental data. To predict primary tumor distant metastasis risk, we originally established a tumor metastasis incidence index, thereby evaluating the critical roles of EMT-targeting and cytotoxic chemotherapeutic drugs in tumor progression. Our findings demonstrate that appropriate pharmacological intervention effectively suppresses tumor dissemination, with therapeutic efficacy significantly enhanced upon EMT inhibition. This study establishes a theoretical framework for designing cancer treatment strategies and provides foundational insights for developing personalized therapeutic regimens.

Immune checkpoint inhibitors (ICIs) combined with platinum-based compounds are commonly used in the treatment of certain malignant tumors. This study aims to analyze adverse events (AEs) associated with the combination therapy of ICIs and platinum-based compounds by using the FAERS database.

Myocarditis attributable to immune checkpoint inhibitors is regarded as among the most serious complications of immunotherapeutic treatment. We report a case of gastric cancer who developed myocarditis, and subsequent late complications following treatment with nivolumab and ipilimumab. The patient was managed with corticosteroids, mycophenolate mofetil (MMF), and intravenous immunoglobulin G (IVIG), but later developed supraventricular tachycardia and deep vein thrombosis. This report emphasizes the need to enhance recognition of immune-related toxicities within non-oncology specialties to support prompt interdisciplinary collaboration and appropriate patient management. Additionally, patients can develop myocarditis-related complications even when clinically stable or near the end of treatment, underscoring the need for close and ongoing monitoring.

The purpose of this review is to highlight recently published research that can provide insight into how either sex or chemotherapeutics can impact cancer regulation of muscle anabolic resistance. Critical knowledge gaps are emphasized that are linked to cancer and treatment disruptions to muscle anabolic signaling. We speculate and propose a rationale for estrogen's protective effect against cancer-induced muscle anabolic resistance in females. Furthermore, there is growing evidence that many cancer treatments have the potential to exacerbate muscle anabolic resistance in both males and females. We present current evidence and speculate on how nutritional interventions could serve as key modulators of cancer-induced anabolic resistance in these conditions.