Ranolazine is known for its antiarrhythmic, antianginal, anti-ischemic properties, as well as its favorable effects on glycemic control. This study aimed to evaluate the effects of ranolazine on oxidative-antioxidative balance and angiogenesis using an in vivo experimental model. A total of 40 Ross 308 chick embryos were used and randomly divided into four groups (n = 10 per group). On the eighth day of incubation, vascular density was assessed. Following vascular evaluation, 4-5 mL of albumen was aspirated using a syringe to measure oxidative stress markers. The groups were as follows: Control, Bevacizumab (BC), Ranolazine 10-4, and Ranolazine 10-5. Total antioxidant capacity (TAC) levels were significantly higher in the bevacizumab group compared to the control group (p < 0.05). Similarly, oxidative stress index (OSI) levels were also significantly elevated in the bevacizumab group (p < 0.05). Both Ranolazine 10-4 and 10-5 groups demonstrated significantly increased TAC levels compared to the control group (p < 0.05). In terms of angiogenesis scores, bevacizumab exhibited a marked anti-angiogenic effect compared to control. However, no statistically significant difference was observed between the ranolazine groups and the control group regarding angiogenesis scores (p > 0.05). This study provides the first in vivo evidence that Ranolazine enhances total antioxidant capacity but does not influence angiogenesis in the CAM model. Future research should explore the molecular mechanisms underlying this effect.

Chemotherapy can cause several long-term side effects that can affect cancer survivors' quality of life-, notably cognitive decline in response to select chemotherapeutic agents. Studies using both human patients and animal models have been employed to determine the regions of the brain that are subject to the most considerable changes, furthermore, elucidating possible molecular mechanisms of chemotherapy-induced cognitive impairment (CICI). However, the reason behind the differences in symptoms and duration of CICI between patients have yet to be identified. This study focused on understanding whether the systemic delivery of doxorubicin and cyclophosphamide (AC chemotherapeutics) causes any epigenetic factors to change in the female rat prefrontal cortex (PFC), possibly providing an insight into the variability of clinical manifestations of CICI. We evaluated DNA methylation levels and patterns in the PFC after AC-chemotherapy administration. We also demonstrated changes in histone deacetylase and acetyl transferase activity levels in the murine PFC in response to treatment. Despite no change in the global DNA methylation level, we found that several genes related to neuronal development and maintenance were differentially methylated in the promoter and exon regions in the rat PFC. Our study showed a significant increase in the expression of the de novo DNA methyl transferase DNMT3a compared to the control.

Silibinin, a major bioactive compound extracted from Silybum marianum, possesses notable antioxidant, antitumor, hepatoprotective, and antibacterial activities. However, its poor solubility limits its clinical applications. This study aimed to enhance the delivery of silibinin by synthesizing magnetic nanocomposites (MNCs) and evaluating their efficacy against clinical isolates of Pseudomonas aeruginosa and HepG2 cancer cells. The physicochemical properties of the Fe3O4@SiPr@Silibinin nanocomposites were characterized by FT-IR, TGA-DTG, TEM, FE-SEM, XRD, and VSM analysis. Clinical isolates and a standard strain of P. aeruginosa were treated with Fe3O4@SiPr@Silibinin (at sub-MIC level) in combination with ciprofloxacin (sub-MIC), and the results were compared to treatment with ciprofloxacin alone. Additionally, the anticancer effects of Fe3O4@SiPr@Silibinin were evaluated in HepG2 cells. The nanocomposites, with particle sizes ranging from 40 to 80 nm, significantly enhanced the antimicrobial activity of ciprofloxacin when used in combination. Treatment with Fe3O4@SiPr@Silibinin plus ciprofloxacin led to a downregulation of biofilm and efflux pump-related gene expression compared to ciprofloxacin treatment alone. Furthermore, Fe3O4@SiPr@Silibinin exhibited anti-cancer activity against HepG2 cells, with an IC₅₀ value of 35.79 µg/mL In Silibinin-treated HepG2 cells, upregulation of the P53 gene and downregulation of the Bcl2 gene were observed. Our findingssuggest that Fe3O4@SiPr@Silibinin MNCs, with high stability and water solublity, can efficiently deliver silibinin into pathogenic and tumorigenic cells, thereby enhancing its therapeutic effects against P. aeruginosa and HepG2 cells. Given the antimicrobial and antitumor properties of silibinin, these magnetic nanocarriers represent a promising strategy for its targeted delivery.

Inhibitors of protein synthesis hold promise for cancer therapy because many cancer driver proteins are unstable and blocking synthesis leads to their depletion. We described previously SVC112, a small molecule inhibitor of translation elongation that inactivates Head and Neck Squamous Cell Carcinoma (HNSCC) stem cells in vitro and prevents the regrowth of HNSCC tumor xenografts in mice after radiation treatment. Here we report that SVC112 also shows activity on its own (without radiation) but with a 1600-fold range in growth inhibition among cancer cell lines of various origins. Our efforts to define molecular correlates of SVC112 sensitivity found that basal expression of apoptosis/survival factors correlates with SVC112-induced apoptosis in hematologic cancer cell lines, while phosphorylation of c-Myc correlates with sensitivity to SVC112 in colorectal cancer cell lines. Apoptosis induction by SVC112 predicts tumor growth control and survival benefit in mouse xenograft models. We suggest a paradigm wherein utility of translation inhibitors is defined by (1) inherent dependence of cancer cells on specific survival factors and (2) post-translational modifications that affect the stability of oncogenic driver proteins.

Bone is the most common site of prostate cancer metastasis, leading to significant morbidity, treatment resistance, and mortality. A major challenge in understanding treatment response is the complex, bone metastatic niche. Here, we report the first patient-specific microphysiological system (MPS) to incorporate six primary human stromal cell types found in the metastatic bone niche (mesenchymal stem cells, adipocytes, osteoblasts, osteoclasts, fibroblasts, and macrophages), alongside an endothelial microvessel, and prostate tumor epithelial spheroids in an optimized media that supports their viability and phenotype. We tested two standard of care drugs, darolutamide and docetaxel, in addition to sacituzumab govitecan (SG), currently in clinical trials for prostate cancer, demonstrating that the MPS accurately replicates androgen response sensitivity and captures stromal microenvironment-mediated resistance. This advanced MPS provides a robust platform for investigating the biological mechanisms of treatment response and for identification and testing of therapeutics to advance patient-specific MPS towards personalized clinical-decision making.

Vitiligo, a depigmentation disorder, significantly impacts the well-being of affected individuals. The induction of vitiligo by pharmacological agents is a critical concern, with prior research establishing a link between antineoplastic medications and the onset of vitiligo. This study aims to assess the reported association between vitiligo and antineoplastic drugs using the FAERS. The study encompassed FAERS reports spanning the years 2004 to 2024. Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of vitiligo. The Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayes Geometric Mean were calculated to assess the reported associations between available drugs and vitiligo. A significant statistical association was considered when a drug signal met the criteria of all four algorithms. Our analysis of the FAERS database revealed 533 adverse event (AE) reports implicating antineoplastic drugs in the development of vitiligo, with a higher prevalence among females compared to males. The 18-65 age group accounted for the majority of cases, with the United States contributing the most reports. Malignant melanoma was the most frequently reported underlying condition. Nivolumab and Pembrolizumab were the most commonly implicated drugs, with 147 and 126 reports, respectively. Disproportionality analysis identified 14 antineoplastic drugs with a significant association with vitiligo-related AEs, including the monoclonal antibody Mogamulizumab, immune checkpoint inhibitor Ipilimumab, and oncolytic virus Talimogene Laherparepvec, with Mogamulizumab exhibiting the highest correlation. These findings underscore the necessity for heightened clinical vigilance regarding the safety profiles of specific medications. This study represents the inaugural investigation into the real-world incidence of antineoplastic drug-induced vitiligo utilizing the FAERS database. Our findings reveal a strong association between vitiligo and immunomodulatory therapies, including immune checkpoint inhibitors and monoclonal antibodies. There is an imperative need for vigilant patient monitoring during the clinical administration of these agents to promptly identify and address potential AEs such as vitiligo.

The clinical manifestations of intrahepatic cholangiocarcinoma (ICC) are non-specific, and few patients qualify for surgical resection at diagnosis, thus limiting treatment options. Anticancer peptides (ACPs) exhibit potent tumour inhibition, minimal side effects, easy modification, and low production costs, making them promising for clinical use. Simultaneously, the development of patient-derived three-dimensional organoids as a novel disease model has enabled the replication of the structure and heterogeneity of solid tumours. These organoids provide valuable tools for understanding disease mechanisms, conducting drug sensitivity tests, and developing targeted therapies. However, ACPs' effect on ICC organoids remain unclear. Therefore, this study aims to explore the potential of ACPs in treating ICC using patient-derived organoids (PDOs). We designed and synthesised a series of ACPs sequences and applied them to PDOs model. The organoid model exhibits histological and genomic characteristics similar to those of maternal tumours. Drug sensitivity revealed that ACPs affected the growth of tumour cells and exerted anticancer effects through direct membrane disruption and indirect induction of apoptosis. In this study, organoids can be used as an in vitro model to evaluate the therapeutic response of ACPs and offer novel insight for the study of ICC.

Anti-angiogenesis has been recognized as a crucial strategy in anti-tumor therapy, and the early assessment of its efficacy is equally significant. In this study, we developed a magnetic resonance (MR) probe specifically targeting angiogenesis to facilitate targeted imaging for the early evaluation of anti-angiogenic effects. We synthesized DOTA-G3CNGRC, conjugated it with gadolinium(III), and subsequently evaluated the labeled probe in vitro. The tumor-bearing mouse models of HT-29 (negative for CD13 expression) and HT-1080 (positive for CD13 expression) were successfully established. Magnetic resonance imaging was conducted via intraperitoneal injection of labeled probes and Gd-DOTA, both before and after treatment with ubenimex at a dose of 0.5 mg/kg/day for seven consecutive days. The average signal intensity ratio of the transplanted tumor (target tissue, T) to the left hind leg (non-target tissue, NT) was determined using the region of interest technique (ROI), while changes in tumor size were meticulously recorded. Additionally, APN/CD13 expression levels in transplanted tumors were assessed both prior to and following treatment. The labeling rate of probes was 88.99%. The IC50 of the probes was 7.03 µM. The T/NT ratio of HT-1080 was significantly higher than that of HT-29 (P < 0.001, n = 5). Following treatment, the T/NT ratio of the HT-1080 transplanted tumors was significantly reduced (P < 0.001, n = 5), accompanied by a notable decrease in CD13 expression and negligible changes in the sum of the long and short diameters (P = 0.39, n = 5). The research findings revealed that Gd-DOTA-G3CNGRC can serve as a highly specific gadolinium-based magnetic resonance imaging probe for monitoring the efficacy of anti-angiogenic therapy.

Kaempferol (KMF) possesses notable anti-tumor bioactivity, which indicates its promising action in the therapy of gynecologic cancers. Here, we examined the therapeutic potential of the naturally occurring flavonoid kaempferol coated on niosome nanoparticles (NPs) and its impact on the breast cancer cell line MCF-7. Niosome NPs containing KMF were prepared by thin-layer hydration. The generated niosome/KMF NPs cytotoxicity on MCF-7 and MCF-10 cell lines were assessed by MTT assay. The physicochemical properties of the niosome/KMF NPs were characterized by SEM, DLS zeta potential, and FTIR. Flow cytometry was used to quantify primary and secondary apoptosis, necrosis and cell cycle arrest. Finally, the expression of apoptosis (Bax and caspase 3) and metastasis genes (ITGA5 and MMP2) was analyzed by Real-time PCR. A Scratch test was performed to investigate the anti-metastatic effect of synthesized nanoparticles. The results showed that the synthesized niosome/KMF NPs have a diameter of 500 nm, a zeta potential of 33.9 mV and a PDI of 0.169. The FTIR spectrum of niosome NPs containing KMF showed distinct peaks in the range of 600-3400 cm- 1 belonging to different components. The results of the MTT assay showed that treatment of the MCF-7 cell line with a concentration of 0.0873 µMol of niosome NPs containing KMF resulted in the death of 50% of the cells. Niosome/KMF NPs caused 64% apoptosis in MCF-7 cells. Real-time PCR results showed a 2.95- and 2.75-fold increase in Bax and caspase 3 gene expression compared to the control group (p < 0.001). After 72 h of treatment with niosome NPs containing KMF, ITGA5 and MMP2 gene expression decreased by 0.58- and 0.53-fold, respectively (p < 0.001). In summary, KMF-loaded niosome NPs efficiently induced apoptosis and inhibited metastasis-related gene expression in MCF-7 cells, exhibiting notable anti-cancer activity.

Glioblastoma (GBM), the most common adult primary brain tumor, has an average survival of only 15-18 months. Recently, the combination of immune checkpoint blockers paired with radiotherapy has shown promise in preclinical murine GBM models. Human clinical trials have largely failed. One reason for this may be the discrepancy between radiation protocols utilized in preclinical models versus clinical practice. For translational relevance, defining correct and comparable radiation dosages and schedules to achieve optimal synergy with immunotherapeutic drugs, is essential. We used the GL261-based syngeneic mouse GBM model to compare the effects of two radiation regimens on tumor cell growth and survival. We assessed the in vivo effects of a single dose of 10 Gy (10Gyx1) or five consecutive doses of 2 Gy (2Gyx5) on the tumor immune microenvironment over time and compared their efficacy when combined with anti-PD-1 in vivo. Our data show that the 10Gyx1 regimen is more effective than 2Gyx5 at inhibiting tumor cell proliferation and growth in vitro and in vivo. Both regimens preserved the antigen-presenting ability of both dendritic cells and local microglia, but 10Gyx1 led to the highest lymphocyte infiltration. The combination of radiation with the checkpoint blocker anti-PD-1 was advantageous for both radiation regimens with animals treated with the 10Gyx1 regimen surviving the longest. Our study highlights how radiation regimen choices may impact the translation of preclinical findings, and in particular, the effects of radiation and immunotherapy in GBM. This work and literature data on the effects of positive hypofractionation in human GBM patients suggest that applying fewer, higher-dose radiation fractions may benefit GBM patients and lead to tumoricidal effects without sacrificing favorable anti-tumor immune responders.

In the modern age of drug discovery sulfanilamide derivatives are known to have great anti-cancerous potential, the current study aimed to synthesize these derivatives in order to evaluate their biological properties against carbonic anhydrase II (CA-II) and Dickkopf - 1(Dkk1) protein which are highly expressed in many cancers including lung cancer. A series of 10 sulfanilamide derivatives was synthesized under controlled conditions using reflux condensation method. Among all the synthesized derivatives (5a-5j), the compound 5d was found to possess highest antioxidant activity (90.7397 ± 0.0732 µg/mL) comparable to vitamin C (95.1571 ± 0.057 µg/mL) and also exhibited maximum inhibition against CA-II with an IC50 value of 0.00690 ± 0.1119 µM, indicating that 5d is significantly more potent as compared to standard i.e., acetazolamide IC50 = 0.9979 ± 0.0024 µM. Keeping in view the importance of Dkk1 protein in cancer progression, the molecular docking investigations were performed, where compound 5d was proved to be the potential dual inhibitor of CA-II as well as Dkk1 with the binding energy of 8.9 and 9.7 kcal/mol, respectively. In addition to this DNA binding studies also confirmed the significance of compound 5d where it had maximum binding constant value of 6.7 × 104 mol- 1, supporting the other biological investigations and was in agreement with the reported values. All the experimental and computational results reveals the excellent potential of 5d as a candidate medicine in future. Conclusively, the current study may lead to the new therapeutic strategies for the treatment of cancer associated with the aberrant expression of CA-II and less explored DDK1 target.

Immune checkpoint inhibitors (ICIs) combined with conventional cytotoxic agents have become the new standard of care for extensive-stage small cell lung cancer (SCLC). The platinum-based agents in these regimens are highly emetogenic, necessitating prophylactic antiemetic steroids. This study evaluated the impact of prophylactic antiemetic steroid use on survival outcomes and efficacy in patients with SCLC undergoing combination therapy. Using data from the National Health Insurance Service of Korea database, patients treated with atezolizumab, etoposide, and carboplatin between 2020 and 2022 were categorized by antiemetic steroid dosage. Primary outcomes included overall survival (OS) and time to next treatment (TTNT), assessed using multivariable Cox proportional hazards models. After propensity score matching, 2,116 patients were categorized into low-dose (0-12 mg), moderate-dose (13-24 mg), and high-dose (25-36 mg) groups. Median OS was 10.2 months (interquartile range [IQR] 5.2-18.5), and median TTNT was 8.6 months (IQR 4.8-15.5), with no significant differences among groups. Subgroup analysis revealed increased mortality associated with higher antiemetic steroid doses in patients concurrently receiving non-antiemetic steroids. Although antiemetic steroids did not significantly impact survival outcomes overall, reducing their dosage in patients already on steroid therapy for other indications is recommended.

The objective of this study was to convert homopterocarpin derived from Pterocarpus macrocarpus Kurz. heartwood to medicarpin using Aspergillus niger (strain UI X-172) and assess its antioxidant, antiplasmodial, and anticancer activities in silico and in vitro. This study highlighted biotransformation of homopterocarpin to medicarpin via demethylation. Medicarpin demonstrated antioxidant activity against 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS, IC50 = 0.61 ± 0.05 µg/mL) and 1,1-diphenyl-2-picrylhydrazyl (DPPH, IC50 = 7.50 ± 1.6 µg/mL), antiplasmodial activity against the Plasmodium falciparum strain 3D7 (IC50 = 0.45 ± 0.35 µg/mL), and anticancer efficacy against a hepatocyte-derived carcinoma cell line (Huh7it-1 cells, IC50 = 34.32 ± 5.56 µg/mL). Medicarpin also showed favorable antioxidant, antiplasmodial, and anticancer properties in silico with a binding affinity lower than commercial drugs. These results highlight the green synthesis of medicarpin by microbial transformation using A. niger, which demonstrates promising in vitro and computational activity, however, further studies are required for clinical development.

Some studies have developed machine learning (ML) models for the prediction of pneumonitis following immunotherapy and radiotherapy for patients with lung cancer (LC). However, the prediction accuracy of these models remains a topic of debate. Thus, this study aims to summarize the advantages of ML methods in the early prediction of radiation pneumonitis (RP) and checkpoint inhibitor pneumonitis (CIP) in LC patients. PubMed, Cochrane, Embase, and Web of Science were searched up to March 23, 2025. The Prediction Model Risk of Bias Assessment Tool (PROBAST) was utilized to explore the risk of bias (RoB) in the included studies. A subgroup analysis was conducted based on variables including radiomics, dosiomics, and clinical characteristics. Fifty-six studies comprising 12,803 LC patients were included. Of these, 43 studies focused on the early prediction of RP, 11 studies on CIP, and 2 studies on differentiating RP and CIP. The meta-analysis revealed that the c-index of dosiomics-based models, radiomics-based models, and models based on radiomics and clinical characteristics for predicting RP was 0.82 (95% CI: 0.76-0.87), 0.80 (95% CI: 0.71-0.89), and 0.90 (95% CI: 0.86-0.94), respectively. In the prediction of CIP, the c-index for the clinical characteristics model was 0.83 (95% CI: 0.81-0.85), while the integrated radiomics and clinical characteristics model achieved a c-index of 0.86 (95% CI: 0.80-0.92). The ML-based models exhibit strong performance for predicting RP and CIP. Models that integrate dosiomics and radiomics demonstrate superior predictive performance for RP. In addition, hybrid models combining radiomics with clinical features provide excellent predictive value for CIP.

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of mesenchymal origin with two main variants, the embryonal, less aggressive, and the alveolar RMS, more metastatic. The role of the extracellular matrix (ECM) in the growth and migration of RMS, as in other cancers, is becoming increasingly important. This work aims to study the RMS after the silencing of the proteoglycan Glypican 3, overexpressed in RMS. Using classical 2D cell culture with RMS cell lines and 3D hyaluronic acid-based hydrogel, the involvement of Glypican 3 in adhesion, proliferation, matrix degradation, and consequent cell motility was demonstrated. Functional assays were performed with the antineoplastic drug doxurubicin and the WNT3a inhibitor, ipafricept. Both in 2D and in 3D model, cell motility and proliferation were significantly impaired after Glypican 3 silencing and inhibition of the proteoglycan releasing the sulfatase enzyme SULF2. When the in vivo cell-ECM interactions were mimicked in the hyaluronic acid-based hydrogel, Doxorubicin and ipraficept were particularly effective against the GPC3-silenced RMS cells. This study lay the fundation for a different therapeutic approach against pediatric RMS that aim to dysregulate the protein microenvironment not only beat the cancer cells.

Chemotherapy-induced peripheral neuropathy (CIPN) resulting from neurodegeneration due to chemotherapy is a challenging complication of widely administered anticancer drugs including paclitaxel. Although CIPN is common and limits the use of chemotherapies, no curative treatment for CIPN has been developed. Recently, stimulation of mitophagy has emerged as a promising strategy for treating neurodegenerative diseases, but studies on its therapeutic effects on CIPN are limited. In this study, we examined the therapeutic effect of the recently developed mitophagy inducer ALT001 on paclitaxel-induced peripheral neuropathy model in Drosophila and mice. Importantly, ALT001 administration in a paclitaxel-induced Drosophila model of peripheral neuropathy significantly ameliorated paclitaxel-induced alterations in sensory neurons and the thermal hyperalgesia phenotype in a mitophagy-dependent manner. Moreover, we demonstrated that ALT001 administration significantly ameliorated paclitaxel-induced mechanical allodynia and the reduction in intraepidermal nerve fiber density in a mouse model. Interestingly, ALT001 did not interfere with the cytotoxic effect of paclitaxel on lung cancer or breast cancer cells. Our results suggest that ALT001 is a potential candidate for the treatment of paclitaxel-induced peripheral neuropathy and that stimulation of mitophagy is a promising strategy for CIPN treatment that does not affect the cytotoxic effect of chemotherapy.

This study investigated the anti-inflammatory, anticancer, antiviral, and antibacterial effects of allicin and its complexes (Allicin/C₂₄, Allicin/B₁₂N₁₂, and Allicin/Al₁₂N₁₂) using advanced computational techniques such as Density Functional Theory (DFT), Quantum Theory of Atoms in Molecules (QTAIM), and molecular docking. The interactions were analyzed in two phases: gas and aqueous. Results revealed that the Allicin/Al₁₂N₁₂ complex exhibited the highest adsorption energy (Ead = -44.43 kcal/mol in the gas phase) and thermodynamic stability (ΔH = -44.36 kcal/mol, ΔG = -29.19 kcal/mol). QTAIM analysis revealed that the Allicin/C₂₄ complex involves very weak noncovalent interactions, the Allicin/B₁₂N₁₂ complex shows weak covalent bonding with considerable ionic character; and the Allicin/Al₁₂N₁₂ complex exhibits stronger covalent interactions with significant electron density sharing. The Allicin/Al₁₂N₁₂ complex showed a reduced energy gap (3.44 eV) and higher reactivity than free allicin (5.42 eV). Molecular docking demonstrated that this complex had the strongest binding affinity with biological targets, such as HER2, TNF-α, COVID-19 main protease, and Staphylococcus aureus. UV-Vis and IR spectroscopy revealed significant electronic and vibrational modifications in the complexes, particularly Allicin/Al₁₂N₁₂. These findings suggest that nanocages, especially Al₁₂N₁₂, can significantly enhance the stability, bioavailability, and therapeutic potential of allicin. The Allicin/Al₁₂N₁₂ complex, with its strong binding affinity and favorable electronic properties, has emerged as a promising candidate for treating cancer, inflammation, bacterial infections, and COVID-19. This study highlights the importance of natural products in drug discovery and the role of computational methods in understanding complex biological interactions.

Targeted protein degradation has emerged as a promising anticancer strategy. Bringing disease-related proteins into proximity with the degradation system is crucial but often hindered by the availability of suitable ligands for proteins of interest (POIs). In this study, we utilize the interactions between intracellular supramolecular nanofibers and certain guest proteins to establish a ligand-free strategy for protein degradation. As the enterokinase (ENTK)-instructed supramolecular assemblies interact with the histone protein H2B for its translocation, the tetrazine-bearing supramolecular nanofibers conjugate with a cereblon E3 ligase ligand to recruit CRBN and directly degrade wild-type H2B. Using the same bioorthogonal ligation, another reactive oxygen species (ROS)-induced supramolecular assemblies localize to mitochondria and efficiently degrade Cofilin-2. Both in situ formed intracellular supramolecular assemblies are dependent on cancer-related conditions (either overexpressed enzymes or overproduced ROS), owning the merit of cell selectivity. These assemblies synergize with bioorthogonal ligation to exhibit significant biological activities, including chemotherapeutic sensitization and induced apoptosis, thereby inhibiting cancer cell growth.

Spatiotemporally-tailored activation of dendritic cells (DC) in lymph nodes (LN) remains a critical challenge for effective cancer vaccination therapy. In this study, we show that photo/sonodynamic effect can trigger the nuclear transcription factor-kappa B (NF-κB) and stimulator of interferon genes (STING) pathways activation in DC. We engineers a library of spatiotemporally-tailored STING nanoadjuvants (SNA) by conjugating the photo/sonosensitizer and STING agonist onto the biodegradable polypeptide, and co-assembling with charge-modified polypeptides. The combination of antigen-loaded SNA vaccine (SNVac) with laser irradiation or ultrasound stimulation (namely SNVac-L or SNVac-US) efficiently facilitates DC activation and induces antigen-specific CD8+ T cell response in vivo comparing to the free mixture of antigen with STING agonist. We further demonstrate that SNVac-L monotherapy or combination therapy with immune checkpoint blockade (ICB) elicits antitumor immunity to reduce tumor size and prevent tumor relapse in multiple mouse tumor models. This study thus provides a potential translational strategy for spatiotemporally-tailored innate immunity stimulation of DC to potentiate cancer immunotherapy.

Tumor stromal remodeling is an obstacle for immune checkpoint inhibitors (ICI). A stroma modifying small interfering RNA (siRNA) to carbohydrate sulfotransferase 15 (CHST15) was recently shown to enhance tumor-infiltrating T cells, yet its impact on antitumor response of ICI remains unexplored. In mouse pancreatic cancer KPC and Pan02 subcutaneous syngeneic tumor models, mice were divided into 4 groups for treatment; (1) control, (2) CHST15 siRNA monotherapy, (3) anti-programmed death receptor 1 (PD-1) monotherapy, and (4) combination therapy with CHST15 siRNA and anti-PD-1 antibody. Mice were sacrificed after 2 week-treatments and anti-tumor effects were evaluated by immunohistochemistry for KPC and flow cytometry for Pan02 model, respectively. In the KPC model, combination treatment with intratumoral CHST15 siRNA (0.9-1.0 mg/kg) and systemic anti-PD-1 antibody (5 mg/kg) synergistically and robustly suppressed tumor growth with a significant increase of tumor-infiltrating CD4+ and CD8+ T cells compared to anti-PD-1 monotherapy. In the Pan02 model, combination treatment with CHST15 siRNA and anti-PD-1 showed anti-tumor effect with significant increases in % necrosis area of the tumor, and tumor-infiltrating T cells compared to the control. Notably, the combination therapy dramatically diminishes Ly6C+Ly6G+ granulocytic myeloid-derived suppressor cells (MDSCs) compared to anti-PD-1 monotherapy. The present study demonstrated the robust synergy between systemic anti-PD-1 antibody and a single stroma modifying agent. Combination usage of intratumoral CHST15 siRNA would provide a novel therapeutic option to trigger the remarkable effect of ICI on this most hard-to-treat solid tumor.