Depletion of circulatory asparagine (Asn) by L-asparaginase (ASNase) has been used for clinical treatment of leukemia, whereas solid tumors are unresponsive to this therapy owing to their active Asn biosynthesis. Herein, we develop a type of core-shell structured cascade-responsive nanoparticles (NPs) for sequential modulation of exogenous Asn supply and endogenous Asn production. The reactive oxygen species-sensitive NP shells disintegrate in the tumor microenvironment and liberate ASNase to scavenge extracellular Asn. The acid-labile NP cores subsequently decompose in the tumor cells and release rotenone to block intracellular Asn biosynthesis. Administration of the dual Asn-depriving NPs in murine models of triple-negative breast cancer and colorectal cancer substantially suppress the growth and epithelial-mesenchymal transition of primary and relapsed tumors, fully eradicate spontaneous and post-surgical metastasis, and confer long-term T cell memory for complete resistance to tumor rechallenge. This study represents a generalized strategy to harness amino acid depletion therapy against solid tumors.

Reactivating the human epicardium post-cardiac injury holds promise for cardiac tissue regeneration. Despite successful differentiation protocols yielding pure, self-renewing epicardial cells from induced pluripotent stem cells (iPSCs), these cells maintain an embryonic, proliferative state, impeding adult epicardial reactivation investigation. We introduce an optimized method that employs mammalian target of rapamycin (mTOR) signaling inhibition in embryonic epicardium, inducing a quiescent state that enhances multi-step epicardial maturation. This yields functionally mature epicardium, valuable for modeling adult epicardial reactivation. Furthermore, we assess cardiac organoids with cardiomyocytes and mature epicardium, probing molecular mechanisms governing epicardial quiescence during cardiac maturation. Our results highlight iPSC-derived mature epicardium's potential in investigating adult epicardial reactivation, pivotal for effective cardiac regeneration. Additionally, the cardiac organoid model offers insight into intricate cardiomyocyte-epicardium interactions in cardiac development and regeneration.

The involvement of tumour-resident memory T (TRM) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103+CD8 TRM cells are involved in response to PD-1 blockade, CD49a+CD4 TRM cells are required for the response to anti-CTLA-4. Using preclinical mouse models, we demonstrate that the benefits of anti-PD-1 treatment are compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. By contrast, the benefits of anti-CTLA-4 are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumour-infiltrating T-lymphocytes (TIL) reveals a CD49a+CD4 TRM signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49a+CD4 TRM cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a+CD4 TRM signature enriched in CTLA-4 and cytotoxicity-linked transcripts is also identified in human TILs. Multiplex immunohistochemistry in a cohort of anti-CTLA-4-plus-anti-PD-1-treated melanomas reveals an increase in CD49a+CD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49a+CD4 TRM cells may correspond to a predictive biomarker of response to combined immunotherapy.

Despite advances in precision oncology, developing effective cancer therapeutics remains a significant challenge due to tumor heterogeneity and the limited availability of well-defined drug targets. Recent progress in generative artificial intelligence (AI) offers a promising opportunity to address this challenge by enabling the design of hit-like anti-cancer molecules conditioned on complex genomic features. We present Genotype-to-Drug Diffusion (G2D-Diff), a generative AI approach for creating small molecule-based drug structures tailored to specific cancer genotypes. G2D-Diff demonstrates exceptional performance in generating diverse, drug-like compounds that meet desired efficacy conditions for a given genotype. The model outperforms existing methods in diversity, feasibility, and condition fitness. G2D-Diff learns directly from drug response data distributions, ensuring reliable candidate generation without separate predictors. Its attention mechanism provides insights into potential cancer targets and pathways, enhancing interpretability. In triple-negative breast cancer case studies, G2D-Diff generated plausible hit-like candidates by focusing on relevant pathways. By combining realistic hit-like molecule generation with relevant pathway suggestions for specific genotypes, G2D-Diff represents a significant advance in AI-guided, personalized drug discovery. This approach has the potential to accelerate drug development for challenging cancers by streamlining hit identification.

Hepatocellular carcinoma (HCC) poses a major global health challenge owing to limited treatment efficacy and drug resistance to therapies such as the tyrosine kinase inhibitor (TKI) sorafenib. We utilized a microfluidic three-dimensional (3D) drug testing system to assess drug responses in 37 fresh clinical samples and performed immunohistochemical analysis of 41 tumor tissue samples that received sorafenib therapy. Results revealed that Wnt/β-catenin activation was associated with sorafenib resistance, with higher nuclear β-catenin levels predicting poor response. Targeting Wnt/β-catenin via genetic intervention enhanced TKI sensitivity by promoting apoptosis and reducing clonogenicity. Through a large scale of drug and inhibitor library screening, we identified PRI-724, a potent CREB-binding protein (CBP)/β-catenin transcription antagonist, which synergistically induces apoptosis with sorafenib in vitro and in vivo by inhibiting β-catenin/CBP/c-myc, β-catenin nuclear localization and ERK/AKT signaling. The microfluidic 3D drug testing system confirmed the synergistic anti-tumor effects of this combination, underscoring its clinical application potential. Conclusively, our study provides a new combination therapy with sorafenib and PRI-724 to overcome TKI resistance and improve clinical outcomes in patients with HCC. Schematic representation of the speculative molecular mechanism model. Our study revealed that β-catenin activation drives sorafenib resistance in HCC, and disrupting β-catenin enhances sorafenib efficacy by promoting apoptosis and inhibiting proliferation. The combination of sorafenib and PRI-724, a Wnt/β-catenin inhibitor, showed synergistic anti-tumor effects in vitro across various HCC cell lines, in vivo using xenograft models, ex vivo utilizing MDT chip system to explore clinical applications, offering a novel therapeutic strategy for HCC patients.

Calreticulin (CALR) has been implicated in the genesis and progression of numerous tumors. Nevertheless, its impact on multiple myeloma (MM) remains ambiguous. This study aimed to explore the effect of CALR on the proliferation and drug sensitivity of MM cells and to delve into its underlying mechanism.

Ovarian cancer is the most lethal tumor in female reproductive system, which seriously threatens the life and health of women. Our previous study found that LAMC3 was down-regulated in ovarian cancer tissues and correlated with ovarian cancer resistance. However, the effects of LAMC3 interference on drug resistance in carboplatin-resistant ovarian cancer cells remain unknown. In the present study, the effects of LAMC3 interference on drug resistance, cell proliferation, cycle, apoptosis, and ultrastructure of carboplatin-resistant ovarian cancer cells were examined. The results showed that LAMC3 interference lowered drug resistance of carboplatin-resistant ovarian cancer cells. The cell proliferation was inhibited and cell apoptosis was promoted in carboplatin-resistant ovarian cancer cells with LAMC3 interference. Besides, LAMC3 interference arrested cell cycle and affected cell ultrastructure of carboplatin-resistant ovarian cancer cells. Furthermore, transcriptome sequencing and WB verification results revealed cell cycle, autophagy, ferroptosis, lysosome related key pathway proteins may be involved in LAMC3 interference regulating drug resistance of carboplatin-resistant ovarian cancer cells. This study indicated LAMC3 interference reduced drug resistance of carboplatin-resistant ovarian cancer cells principal by affecting cell cycle, autophagy, ferroptosis, and lysosome. The present study provides a potential target for clinical treatment of drug resistance in ovarian cancer.

Cholangiocarcinoma (CCA) is a prevalent bile duct cancer with limited treatment options. Cisplatin-based chemotherapy is a common approach, but response rates vary. Recently, chromosome aberrations have emerged as predictors of chemotherapy response in various malignancies. This study aimed to identify chromosomal aberrations associated with cisplatin response in CCA. A histoculture drug response assay was conducted on 20 fresh CCA tissues to determine cisplatin sensitivity. In parallel, chromosome aberration analysis was performed using chromosome microarray. Using chromosome microarray analysis on 20 CCA samples, we found distinct chromosomal aberration patterns between cisplatin responders and non-responders. Gains in 18q and 20q, and losses in 1p and 8p were more common in non-responders. Conversely, the responders exhibited gains in 8q and losses in 16q. Our heatmap analysis of log-2 ratio demonstrated difference in various chromosomes including 2, 3p, 5q, 6q, 7, 9p, 11q, 14q, 15q, 18q, 20q, and 22q between the response and the non-response to cisplatin. Further analysis using machine learning with random forest model identified genes like NCOA3, TPK1, CEP57L1, DEPDC5, and PLXNA4 as potential predictors of cisplatin response. Validation in a separate cohort of 33 CCA samples confirmed the association of NCOA3 and DEPDC5 with cisplatin response. Our findings suggest that chromosomal aberrations and specific genes may predict cisplatin response in CCA, potentially guiding personalized treatment strategies.

Pancreatic cancer (PC) is a highly aggressive and fatal malignancy, primarily affecting older males. Curcumin, a potential anti-cancer agent, has been shown to regulate key molecules in cancer progression, but its specific mechanisms in PC remain unclear. We conducted a comprehensive database search to identify curcumin-related targets in PC. Gene expression and immune correlations were analyzed using the GEO database, identifying differentially expressed hub genes (DEHGs). A method involving machine learning was employed to identify feature genes and create a nomogram, using external datasets and molecular docking for preliminary validation. Consensus clustering and subgroup comparisons were also performed based on DEHGs expression. We identified 35 DEHGs strongly associated with immune cell infiltration. Five feature genes (VIM, CTNNB1, CASP9, AREG, HIF1A) were used to build a nomogram, with the classification model showing AUC values above 0.9 in both training and validation groups. Molecular docking highlighted potential binding sites of five feature genes for curcumin. Clustering analysis categorized PC samples into four distinct subgroups: C1 and CII, which showed high expression and elevated immune cell infiltration, and C2 and CI, which exhibited the opposite pattern. Significant variations in scores of DEHG were seen between C1 and C2, in addition to between CI and CII. Curcumin may target DEHGs to influence PC, regulating immune and tumor proliferation mechanisms. These outcomes provide potential insights for medical applications and upcoming research.

A novel quinazoline-containing 1,2,3-triazole (4-TCPA) was synthesized to target VEGFR2 signaling for cancer treatment. Although current VEGFR2 inhibitors exhibit strong anticancer activity, their clinical use is limited due to severe side effects. Structural analysis of effective VEGFR2 inhibitors guided the design of 4-TCPA, ensuring the retention of Erlotinib's essential pharmacophoric features for optimal receptor binding. The compound was tested for its anticancer efficacy against A549 (lung cancer), MCF7 (breast cancer), K562 (leukemia), and human normal fibroblast HFF2 cells. 4-TCPA demonstrated inhibitory activity in nearly all assays, with IC50 concentrations of 35.70 μM for A549, 19.50 μM for MCF7, 5.95 μM for K562, and 135.2 μM for HFF2. Further in vitro biological evaluations examined its mechanistic impact on EGFR, mTOR, Akt, MAPK, and PIK3CA. Apoptotic activity was assessed through Annexin V/PI double staining and caspase-3/7 activation, confirming its ability to induce both early and late apoptosis. Additionally, real-time quantitative PCR (qRT-PCR) was conducted to evaluate the expression levels of Akt, mTOR, MAPK, PIK3CA, EGFR, and VEGFR2. Results showed that 4-TCPA down-regulates these targets in a time-dependent manner, triggering apoptosis across all tested cancer cell lines. The study suggests that 4-TCPA may serve as a promising anticancer agent due to its targeted VEGFR2 inhibition and apoptotic induction, warranting further investigation. These findings support the potential of 4-TCPA as an effective treatment strategy for various cancers.

Immunotherapy has revolutionized cancer treatment by leveraging the body's immune system to combat malignancies. However, on-target, off-tumour (OTOT) toxicity poses significant challenges, often leading to the failure of clinical trials for the development of immunotherapeutic drugs. The molecular engineering of clinically relevant, tumour-selective prodrugs, activated in a targeted way, could help minimize systemic toxicity while maximizing anti-tumour efficacy. Here, we propose a Single Atom Engineering for Radiotherapy-Activated Prodrug (SAE-RAP) technique for the development of radiotherapy-activatable small-molecule immune agonist prodrugs. We show that introducing a single oxygen atom into the TLR7/8 agonist R848 significantly reduces the EC50 value by over 4000-fold, hence mitigating severe side effects following systemic administration. In preclinical tumour mouse models, exposure to radiotherapy removes the protective mask provided by the oxygen atom and locally rescues the activity of the prodrugs, triggering anti-tumour immunity and limiting the growth of primary and distal tumours. The SAE-RAP technique may be further utilized for developing radiotherapy-activated prodrugs for next-generation combination therapies that transcend traditional limitations.

Drug resistance remains a major challenge in cancer therapy. Emerging evidence has revealed that protein lactylation, a newly discovered post-translational modification of lysine residues in histone and non-histone proteins, contributes to drug resistance in cancers. In this review, we aimed to provide an overview of the newly identified lactylation regulators (lactylation writers, erasers, and readers) and their roles and summarize the recent advances in the mechanisms by which lactylation modulates cancer drug resistance to highlight the role of lactylation in mediating cancer cell resistance to chemotherapy, immunotherapy, and targeted cancer therapy. We also aimed to provide an overview of the recent findings and emerging concepts that leverage lactylation through pharmacological inhibition to overcome drug resistance in cancers.

Basal cell carcinoma (BCC) is the most common cancer in the world, and its incidence continues to rise. Known risk factors for BCC include chronic UV exposure, advanced age, and genetic predisposition. A large majority of BCC cases have an altered Hedgehog (Hh) signaling pathway. When a large BCC develops on the face, it can pose unique treatment challenges due to functional and cosmetic considerations-even with Mohs micrographic surgery (MMS). Traditional treatment options may be limited, prompting the use of targeted therapies such as vismodegib for unresectable cases. Vismodegib, an Hh inhibitor, is approved by the US Food and Drug Administration for treatment of locally advanced or metastatic BCC. This case report details the successful management of a large BCC on the nose of an elderly patient using vismodegib.

Recently, essential oils (EOs) have garnered attention for their biological properties as a source of natural compounds with anticancer, antibacterial, and antioxidant effects. Chiliadenus iphionoides (Boiss.& Blanche) Brullo is a fragrant aromatic species indigenous to Palestine and the neighboring countries. It is utilized by the Bedouins for the treatment of many ailments. This study aimed to analyze the chemical composition of essential oil extracted from the desiccated leaves of Chiliadenus iphionoides (Boiss.& Blanche) Brullo and to assess its in vitro antioxidant, anticancer, and α-amylase and lipase inhibitory activities. The EO obtained during hydrodistillation was analyzed using gas chromatography-mass spectrometry to ascertain their chemical composition. GC-MS analysis of the EO from dried Chiliadenus iphionoides (Boiss.& Blanche) Brullo leaves identified 47 compounds, comprising 98.81% of the total oil. The predominant constituents included cresol methyl ether (52.93%), ethyl 2-octynoate (14.36%), epi-α-cadinol (6.56%), 1,8-cineole (4.25%), and 7-epi-α-eudesmol (3.66%). The EO exhibited significant antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) with an IC50 value of 19.83 ± 0.99 μg/mL. Nevertheless, it exhibited limited lipase activity and subpar α-amylase activity. Chiliadenus iphionoides (Boiss.& Blanche) Brullo EO exhibited significant cytotoxicity against B16F10 and MCF-7 cancer cell lines, with IC50 values of 8.74 ± 0.11 and 13.68 ± 0.17 μg/mL, respectively. The combination of the anticancer medication Taxol (10 ng) with Chiliadenus iphionoides (Boiss.& Blanche) Brullo EO at concentrations of 25 μg/mL and 50 μg/mL significantly enhanced the inhibitory efficacy of Taxol against MCF-7 and B16F10 cells.

Axitinib is a second-generation tyrosine kinase inhibitor that works by selectively inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3). Through this mechanism of action, axitinib blocks angiogenesis, tumor growth and metastases and therefor it shows significant promise as a chemotherapeutic agent for various types of cancer. Nevertheless, the clinical efficacy of this substance is hindered by its restricted solubility in water and inadequate stability. To address these challenges, we developed spanlastics with polyethylene glycol (PEG) to improve the efficacy and stability of axitinib against breast and ovarian tumor malignancies in a targeted manner. Moreover, the study conducts a thorough examination of the interactions between the ligand Axitinib alone or after coating with PEG and a diverse array of protein types in breast (Dopamine, VEGFR) and ovarian cancer (EGFR, BCL-xL). The fabrication of axitinib- spanlastics was achieved through a thin-film hydration method. The evaluation of the impact of formulation factors on the features of nanovesicles was conducted using the I- optimal design. Subsequently, the optimum formulation was calculated. The optimal formulation was coated with polyethylene glycol (axitinib-PEG-spanlastics). An in vitro assessment was computed to evaluate the efficiency of the optimized axitinib-PEG-spanlastics against the MCF-7 breast cancer cell line and the OV-2774 ovarian cancer cell line. The optimized axitinib-PEG-spanlastics formulation exhibited a diameter of 563.42 ± 8.63 nm, accompanied by a zeta potential of -46.44 ± 0.09 mV. The formulation demonstrated an 84.32 ± 3.64% entrapment percent and a cumulative release of 73.58 ± 3.37% during a 4-hour period. The results obtained from the WST-1 assay showed a significant decrease in the percentage of cell survival, reaching 50% at a concentration of 0.68 µM for the PEG-spanlastics. In contrast, the axitinib free drug suspension exhibited 50% cell survival at a concentration of 1.1 µM in the breast cancer (MCF-7) cell line. In MCF-7 cells, the percentage of apoptotic cells generated by axitinib-PEG-spanlastics compared to the free drug suspension was 70.76 ± 4.971% vs. 32.6 ± 1.803%, while in OV-2774 cells, it was 43.55 ± 4.243% vs. 24.44 ± 4.950%. These results propose that Axitinib-PEG-spanlastics have the potential to be a successful nanoplatform for targeting breast and ovarian cancer and effectively managing tumors.

Immune checkpoint inhibitors (ICIs) have emerged as a highly effective treatment option for patients with metastatic melanoma. As not all patients respond to ICI immunotherapy, imaging biomarkers are required to accurately monitor early response to therapy. Therefore, the aim of this study was to evaluate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for monitoring the effects of combined anti-PD-L1/anti-CTLA-4 immunotherapy in a murine melanoma model.

This study aimed to investigate the efficacy of cyclocryotherapy applied at the 3 o'clock and 9 o'clock positions in combination with intravitreal anti-vascular endothelial growth factor (VEGF) injections in patients with advanced neovascular glaucoma (NVG).

To report real-life data of eyes with neovascular age-related macular degeneration (nAMD) treated with vascular endothelial growth factor (VEGF) inhibitors for an average of 10 years.

Small molecule inhibitors of lysine deacetylases (KDACs), exemplified by histone deacetylases (HDACs), exhibit significant promise as cancer therapeutics. Using a modular combinatorial chemistry approach, a novel class of KDAC inhibitors (KDACi) containing the aminophenyl-benzamide headgroup have been developed, which incorporate a vinyl group within the linker region for active site stabilisation and a trifluoromethyl moiety within the capping group to exploit enzyme surface topology. Consequently, a class I selective KDACi (7) with a preference towards HDAC1 over other class I KDACs was identified. This KDACi orientates differently within the KDAC active site and exhibits an improved antitumour profile relative to the benchmark class I selective KDACi Entinostat (1). The clinical potential of 7 is further exemplified by the inhibition of tumour growth in an in vivo model of ovarian cancer. These results offer significant scope for the rational development of KDACi with improved selectivity against specific KDAC and widespread therapeutic potential.

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.