Combining radiotherapy with immune checkpoint inhibitors is a promising approach to improve the effectiveness of cancer treatment. However, the success rates of these clinical studies are limited. It is essential to determine the optimal irradiation scheme that maximizes the therapeutic effect by taking into account the balance between the positive and negative effects of radiation on immunity. In this context, we developed a mathematical mechanistic model that simulates (1) the balance between effector and exhausted cytotoxic T-lymphocytes (CTLs), (2) the number of neoantigens released by high-dose irradiation, and (3) the impact of radiation on draining lymph nodes (DLNs) for systemic anti-tumor immunity, and tested whether this mathematic model fits in several animal experiments. Our mechanistic model reproduced the anti-tumor effects of several cancer treatment models for combination therapies with radiation, immune checkpoint inhibitors, and/or a metabolic modulator. Furthermore, this mechanistic model simulated that tumor suppression in distant metastatic foci, known as the abscopal effect, was dysregulated by hypofractionated high-dose irradiation or by the direct radiation exposure on DLN. The mechanistic model successfully reproduced tumor control under various treatment conditions with appropriate parameters, indicating that it may be useful for optimizing immunoradiotherapy prescriptions.

Chemotherapy is an important treatment for glioblastoma (GBM) and a key component of comprehensive GBM therapy. However, the blood-brain barrier (BBB) and complex tumor microenvironment (TME) restrict the diffusion of drugs, which greatly reduces the chemotherapeutic effect on GBM. Single strategies, such as cell-based nanobots to cross the BBB or enzymatic nanobots propelled by enriched substrates in the TME for deep tumor penetration, remain inadequate to address multiple barriers and achieve precise targeting. Here, we develop a Trojan horse-inspired enzymatic nanobot-in-neutrobot system (Trojanbot) to greatly enhance targeted GBM therapy. Trojanbots traverse the BBB by leveraging positive chemotaxis in response to tumor-derived chemokine gradients, after which the released catalase-driven nanobots (CatNbot) undergo directional movement along the H2O2 gradients in TME, facilitating deep tumor penetration. This multi-stage targeting strategy improves drug delivery efficiency, providing considerable potential as a clinical approach for brain tumor treatment.

Local anesthetics promote anticancer immune responses. A machine learning-based algorithm trained with information on the biological effects and molecular descriptors of analgesics, anesthetics, hypnotics and opioids predicted antitumor effects for dexmedetomidine (DEX). DEX is a sedative acting as an alpha2-adrenoceptor (ADRA2) agonist. Based on these premises, we investigated the putative antineoplastic effects of DEX.

Glioblastoma (GBM) is the most malignant primary intracranial tumor. Owing to its unfavorable prognosis and frequent recurrence, patient outcomes are poor even with standard treatment. Recent studies have reported that FTY720, a structurally modified sphingosine extracted from Cordyceps sinensis, has preclinical antitumor efficacy and can regulate the microenvironment of GBM. However, the mechanism and effective utilization of FTY720, i.e., avoiding adverse reactions during systemic application in GBM remain unclear.

The development of targeted drug delivery systems has become a cornerstone of modern cancer therapy which provides a pathway to maximize treatment effectiveness while reducing side effects. Among the plethora of innovative strategies, biotinylated nanoparticles have evolved as a hopeful tool due to their ability to exploit the elevated expression of biotin receptors on cancerous cells. The design, synthesis, and functionalization of biotinylated nanoparticles for cancer treatment are thoroughly examined in this review article. By leveraging biotin's high affinity for biotin receptors, these nanoparticles achieve selective cancerous cell targeting, leading to enhanced drug bioavailability and cellular uptake. The discussion extends to the underlying mechanisms of drug release, receptor-mediated endocytosis, and strategies for achieving endosomal escape or pH-sensitive drug activation. Furthermore, the article also emphasizes how biotinylation in combination therapy allows for synergistic effects with immunomodulators, nucleic acids, and chemotherapeutic drugs. Preclinical studies are examined to underscore the translational potential of these systems. The review concludes by addressing current challenges, including scalability, and potential immunogenicity, while proposing future directions for optimizing biotinylated nanoparticles as a transformative approach in cancer treatment.

Regulating membrane protein abundance through Lysosome Targeting Chimera (LYTAC) holds significant promise in addressing various diseases. However, the precise structural control of LYTAC molecules and how to improve their treatment efficacy remain elusive. In this study, we develop a multifunctional phototriggered LYTAC platform, named PT-LYTAC, to enhance targeted protein degradation using a photoactive bispecific aptamer chimera (PBAC). PBAC is designed with a precise modular approach that integrates an NIR photosensitive molecule into a bispecific aptamer chimera. Taking advantage of the low molecular weight and easy synthesis of the DNA aptamers, PBAC can efficiently transport the therapeutically relevant membrane protein PTK7 to lysosomes for degradation through the lysosomal pathway. Moreover, our investigation reveals that the multifunctional PT-LYTAC platform, enabled by DNA aptamers, promotes protein degradation by modulating cellular autophagy. By the combination of targeted protein degradation and spatiotemporally controllable regulation of intracellular oxidative stress, the function of tumor cells can be significantly inhibited. Under NIR laser irradiation, PT-LYTAC completely suppresses colorectal cancer growth with just one dose and a single laser treatment, all without any apparent side effects. We anticipate that this novel PT-LYTAC will expand the use of DNA-based LYTAC drugs and provide a new dimension for targeted protein degradation.

Nitrogen mustards are a family of clinically used anticancer drugs that contain a DNA-alkylating bis(2-chloroethyl)amino group. Appending the bis(2-chloroethyl)amino alkylating agent to noncovalent DNA-binding groups such as intercalators, polyamides, or polyamines has the potential to yield DNA-targeted anticancer agents with improved potency. In the work reported here, substituted quinoxaline groups were explored as minimal intercalators expected to confer noncovalent DNA-binding properties on a bis(2-chloroethyl)anilino mustard alkylating unit. A quinoxaline unit with a cationic dimethylamino-containing side chain was found to be a more potent DNA-alkylating and cross-linking agent than the clinically used mustard chlorambucil (Chb). The results of dye displacement and multiple DNA alkylation assays showed that the quinoxaline ring binds noncovalently to duplex DNA, likely via intercalation. The quinoxaline-mustard conjugate was more active than Chb against a variety of cancer cell lines. Evidence is presented, showing that both the quinoxaline-mustard and the clinically used drug Chb formed aggregates in aqueous buffer; however, the results clearly show that the propensity to form aggregates clearly does not abrogate the DNA-alkylating properties or bioactivity of these compounds.

Advanced synovial sarcomas are associated with poor outcomes and a lack of efficacious therapeutic agents. The aim of this study was to assess the efficacy and safety of a novel, low-dose, continuous schedule of regorafenib in these patients.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common DPYD variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated.

Improving our understanding of the ocular pharmacokinetics and pharmacodynamics of anti-vascular endothelial growth factor (VEGF) therapies, such as ranibizumab, is essential to enhance treatment strategies for a range of retinal diseases, and will help inform the development of novel anti-VEGF drug candidates.

Selective prodrug activation at tumor sites through noninvasive external stimuli represents a promising strategy in enhancing the therapeutic index. Here, we report a p-azidobenzyloxycarbonyl (PAzBC)-based prodrug platform activated by physiotherapy-grade ultrasound (2.0 W/cm2, 1 MHz) through radical-mediated cascade elimination. Mechanistic studies reveal that ultrasound initiates single-electron-transfer (SET) and hydrogen-atom-transfer (HAT) processes, enabling efficient azide-to-amine reduction. This activation is further amplified by superoxide anion radicals generated via acoustic sensitizers, as confirmed by DFT calculations and radical trapping experiments. The PAzBC platform demonstrates broad applicability with diverse drug functionalities (amino, hydroxyl, sulfhydryl), achieving >99% azide reduction efficiency and approximately 40% active drug release under optimized sonication conditions. Cellular studies reveal a 4.1-115.5-fold reduction in prodrug toxicity and a 11.9-169.5-fold enhancement in selective activation, highlighting its potential for clinical translation. This work establishes a robust platform for spatiotemporally controlled drug delivery, advancing the field of ultrasound-mediated precision cancer therapy.

The rapid increase in the number of elderly patients with cancer necessitates treatment strategies based on the effects of aging because of drastic side effects of cytotoxic anticancer agents. Immune checkpoint inhibitors (ICIs) are relatively less toxic and can be easily administered to vulnerable and aged patients suffering from cancer. The diversity of gut microbiota and specific bacteria affects the efficacy and safety of ICIs. Therefore, this study aimed to assess the effect of aging on gut microbiota that play crucial roles in determining antitumor efficacy of drugs.

Marijuana use is associated with HPV-positive head and neck squamous cell carcinoma (HNSCC). However, cannabinoid use continues to increase in the US general population for recreational purposes as well as in cancer patients for palliative care. In this study, we explored the role of cannabidiol (CBD) in promoting anti-tumor activity by modulating immune response in HPV-positive HNSCC by using pre-clinical models.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally, characterized by high heterogeneity and drug resistance, which significantly impacts clinical outcomes. The tumor microenvironment (TME) plays a critical role in HCC initiation and progression, with immune cell infiltration and immune checkpoint expression closely linked to tumor prognosis. N-glycosylation of proteins modulates immune responses within the TME. ALG3, a key N-glycosylation enzyme, is involved in protein glycosylation. Although ALG3 expression has been studied in various tumors, its role in regulating the immune microenvironment and its prognostic significance in HCC remain unclear.

Limited curative therapies can effectively prevent the most malignant form of breast cancer, triple-negative breast cancer (TNBC), from growing and multiplying. Metal-NHC complexes offer a robust foundation for designing an innovative anticancer pharmacophore. Herein, we report the synthesis and characterization of PdII (2), PtII (3), and AuIII (4) complexes containing pincer (N^C^N) N-heterocyclic carbene ligands derived from 1,3-bis-(1-methyl-1H-benzo[d]imidazol-2-yl-methyl)-1H-imidazol-3-ium hexafluorophosphate (1·HPF6). The square-planar type molecular geometries of complexes 2 and 4 were confirmed by X-ray diffraction studies. The synthesized complexes displayed potent in vitro cytotoxic activity against TNBC cells (MDA-MB-231) with IC50 values ranging from 4.00 to 9.25 μM, significantly lower than that of cisplatin (27 μM); complex 4 was the most active at inducing apoptosis. According to mechanistic investigations, the complexes caused apoptosis in MDA-MB-231 cells in a mitochondria-mediated manner, mostly by overproducing intracellular reactive oxygen species (ROS), depolarizing the mitochondrial membrane potential (ΔΨm), activating pro-apoptotic proteins (BAX) and releasing cytochrome c. Additional studies revealed that the complexes were also potentially targeting thioredoxin reductase (TrxR) and possessed significant inhibitory effects. Among all tested compounds, complex 4 exhibited the highest inhibitory potential, which was also evidenced by molecular docking studies. The findings of the present investigation collectively emphasize the encouraging potential of the gold(III)-NHC pincer complex as a viable chemotherapeutic drug candidate for treating TNBC, supporting the need for additional research into its therapeutic potential.

Thymidine phosphorylase (TP) is a key enzyme involved in angiogenesis, tumour growth and closely linked to cancer progression and metastasis. This study represents the first comprehensive 3D-QSAR pharmacophore-based approach to identifying potential 1,3,4-oxadiazole derivatives as targeted TPIs for anticancer therapy. A dataset of 76 analogues with an experimental IC50 values was used to develop pharmacophore models. The BEST conformation method identified an optimal model (Hypo 2), featuring HBA, HBD and RA as key activity determinants with strong statistical validation (r2 = 0.69, ΔCost = 77.41, Q2 = 0.68 and MAE = 0.23). A virtual screening of 12,353 drug-like 1,3,4-oxadiazole compounds from PubChem and ChEMBL yielded 329 potential TPIs (IC50 < 10 μM). MD Docking using CDOCKER (PDB ID: 1UOU) identified the top hits interacting with critical TP residues (Thr151, Gly152, Lys221, Ser217, Thr118). ADMET analysis confirmed their drug-likeness with no significant toxicity. ChEMBL2058305 exhibited the highest binding stability (-85.508 kcal/mol), the lowest HOMO-LUMO gap (0.066 ha), and superior TP affinity, highlighting its potential as a promising TP inhibitor for anticancer therapy. This first report with integration of pharmacophore modelling, virtual screening, MD Docking, ADMET, MMGBSA and DFT will be beneficial for the discovery of novel TPIs.

Pancreatic cancer is a highly malignant tumor with a poor prognosis, making it a leading cause of cancer-related deaths. While immune checkpoint inhibitors (ICIs) have shown efficacy in treating various solid tumors, their effectiveness in pancreatic cancer is limited due to its unique tumor immune microenvironment (TIME). Thus, developing novel combination therapies is critical. Ginsenoside compound K (CK), a natural product with antitumor and immunomodulatory properties, holds the potential for combination therapy with ICIs. This study investigates the therapeutic effects of CK combined with Anti-PD1 inhibitors in a Panc02 tumor model. The combination therapy significantly improved survival, enhanced T-cell infiltration and activation, remodeled the tumor stroma by reducing collagen I and α-SMA, and improved vasculature formation. RNA sequencing revealed changes in genes associated with T-cell activation, chemokines, and angiogenesis. These findings suggest that CK combined with Anti-PD1 therapy offers a promising strategy for pancreatic cancer treatment by modulating TIME and enhancing antitumor activity.

The advent of research using drug-delivery vehicles with nanoparticles (NPs) in treating and diagnosing lung cancer has created a potential development in cancer therapeutics. Using certain NP-based compositions, specifically hybrid NPs, the cancer cells could be detected with enhanced fluorescence ability and treated using targeted drug release while minimizing adverse effects. A modified microwave-based synthesis approach was used in this study to synthesize spherical core-shell hybrid cobalt oxide carbon nanodot (Co3O4@CND) NPs of a smaller size of around 20 nm. Four different targeting ligands─folic acid, heparin, PEGylated silica (SiO2), and transferrin─and the anticancer drug doxorubicin (DOX) were conjugated to the hybrid NPs, and their physicochemical characterizations were evaluated for their applications. The bioimaging, antioxidant, biocompatibility, cancer-targeting ability, and anticancerous specificity effect of the hybrid NPs were examined using A549 (lung cancer) cells and compared with CNDs, Co3O4 NPs, and the ligand-conjugated NPs. The Co3O4@CND NPs demonstrated high fluorescence from their synergistic properties, leading to a better bioimaging ability in human cells. The Co3O4@CND hybrid NP-transferrin-DOX composite targeted 50% of A549 cells with a much less adverse effect on EAhy926 (endothelial) cells at the same concentrations. Increased anticancer activity of the Co3O4@CNDs and improved biocompatibility were achieved via a receptor-mediated active targeting approach using specific ligands, proving the potential multifunctional applications such as bioimaging, antioxidant, and anticancer activity. After transferrin conjugation, the NP composite is more anticancerous to A549 and shows decreased toxicity to EAhy926 cells. The outcomes, while in the early stage, suggest that the Co3O4@CND hybrid NPs with ligand conjugation are a potential approach to the development of a multifunctional theranostic agent.

Recurrence and metastasis remain significant challenges in the clinical treatment of hepatocellular carcinoma (HCC). The integration of photodynamic therapy and immunotherapy has emerged as a promising strategy for treating cancer in terms of safety and efficacy. However, conventional photodynamic therapy and anti-tumor immunotherapy face several limitations, including inadequate light source penetration, poor targeting precision, low response rates, and immune-related adverse effects. To address these issues, we developed a tumor microenvironment responsive polymer nano-immunomodulator for precise photodynamic immunotherapy of HCC. The nano-immunomodulator is self-assembled from glutathione responsive amphiphilic polymers (TPS) and pH-activatable photosensitizers (LET-Br), and is further loaded with the anticancer drug docetaxel. Additionally, it is conjugated with small-molecule agonists of Toll-like receptor 7/8 (TLR 7/8) and cyclic RGD (cRGD) targeting peptides. Upon reaching the tumor site, the PNI undergoes hydrolysis, enabling the efficient release of anticancer drugs in response to the tumor microenvironment. Furthermore, under near-infrared (NIR) photoirradiation, the PNI exerts potent photodynamic effects to directly eliminate tumors. Remarkably, the PNI also functions as an in situ light-activated cancer vaccine, capable of inducing systemic antitumor immune responses and remodeling the immunosuppressive tumor microenvironment to establish long-lasting immune memory. This synergistic combination of photodynamic therapy and targeted antitumor immune responses effectively inhibits tumor growth. Thus, this study not only presents a novel strategy for designing vaccine-like prodrugs to precisely modulate cancer immunotherapy, but also opens new avenues for the development of advanced therapies for HCC.

Dose-expansion cohort (DEC) has been increasingly used as the pivotal trial to demonstrate preliminary efficacy and safety of target anticancer drugs. We aimed to investigate the reporting quality in the published articles of DECs.