Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy.

UNASSIGNED: Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ε-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound.
UNASSIGNED: The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry.
UNASSIGNED: In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype.
UNASSIGNED: In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo.

BACKGROUND: Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown.
METHODS: Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis.
RESULTS: The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers.
CONCLUSIONS: We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

The chiral amine (R)-2-(1-aminoethyl)-4-fluorophenol has attracted increasing attentions in recent years in the field of pharmaceuticals because of its important use as a building block in the synthesis of novel anti-tumor drugs targeting tropomyosin receptor kinases. In the present study, a ω-transaminase (ωTA) library consisting of 21 (R)-enantioselective enzymes was constructed and screened for the asymmetric biosynthesis of (R)-2-(1-aminoethyl)-4-fluorophenol from its prochiral ketone. Using (R)-α-methylbenzylamine, D-alanine, or isopropylamine as amino donor, 18 ωTAs were identified with target activity and the enzyme AbTA, which was originally identified from Arthrobacter sp. KNK168, was found to be a potent candidate. The E. coli whole cells expressing AbTA could be used as catalysts. The optimal temperature and pH for the activity were 35-40 °C and pH8.0, respectively. Simple alcohols (such as ethanol, isopropanol, and methanol) and dimethyl sulfoxide were shown to be good cosolvents. High activities were detected when using ethanol and dimethyl sulfoxide at the concentrations of 5-20%. In the scaled-up reaction of 1-liter containing 13 mM ketone substrate, about 50% conversion was achieved in 24 h. 6.4 mM (R)-2-(1-aminoethyl)-4-fluorophenol was generated. After a simple and efficient process of product isolation and purification (with 98.8% recovery), 0.986 g yellowish powder of the product (R)-2-(1-aminoethyl)-4-fluorophenol with high (R)-enantiopurity (up to 100% enantiomeric excess) was obtained. This study established an overall process for the biosynthesis of the high value pharmaceutical chiral amine (R)-2-(1-aminoethyl)-4-fluorophenol by ωTA. Its applicable potential was exemplified by gram-scale production.

Immune checkpoint inhibitor (ICI)- and phosphatidylinositol-3-kinase inhibitor (PI3Ki)-related diabetes mellitus are common side effects of anti-tumor drug use that present mainly as hyperglycemia. Here, we present two case reports of diabetes mellitus caused by the use of tremelimumab and apalutamide, respectively, in cancer treatment, and a comprehensive, comparative review of the literature on these forms of diabetes. Case 1 presented with diabetic ketoacidosis and was diagnosed with ICI-related diabetes mellitus and treated with insulin. Case 2 was diagnosed with PI3Ki-related diabetes mellitus, and her blood glucose level returned to normal with the use of metformin and dapagliflozin. We systematically searched the PubMed database for articles on ICI- and PI3Ki-related diabetes mellitus and characterized the differences in clinical features and treatment between these two forms of diabetes.

Background: Although immune microenvironment-related chemokines, extracellular matrix (ECM), and intrahepatic immune cells are reported to be highly involved in hepatitis B virus (HBV)-related diseases, their roles in diagnosis, prognosis, and drug sensitivity evaluation remain unclear. Here, we aimed to study their clinical use to provide a basis for precision medicine in hepatocellular carcinoma (HCC) via the amalgamation of artificial intelligence. Methods: High-throughput liver transcriptomes from Gene Expression Omnibus (GEO), NODE (https://www.bio.sino.org/node), the Cancer Genome Atlas (TCGA), and our in-house hepatocellular carcinoma patients were collected in this study. Core immunosignals that participated in the entire diseases course of hepatitis B were explored using the \"Gene set variation analysis\" R package. Using ROC curve analysis, the impact of core immunosignals and amino acid utilization related gene on hepatocellular carcinoma patient\'s clinical outcome were calculated. The utility of core immunosignals as a classifier for hepatocellular carcinoma tumor tissue was evaluated using explainable machine-learning methods. A novel deep residual neural network model based on immunosignals was constructed for the long-term overall survival (LS) analysis. In vivo drug sensitivity was calculated by the \"oncoPredict\" R package. Results: We identified nine genes comprising chemokines and ECM related to hepatitis B virus-induced inflammation and fibrosis as CLST signals. Moreover, CLST was co-enriched with activated CD4+ T cells bearing harmful factors (aCD4) during all stages of hepatitis B virus pathogenesis, which was also verified by our hepatocellular carcinoma data. Unexpectedly, we found that hepatitis B virus-hepatocellular carcinoma patients in the CLSThighaCD4high subgroup had the shortest overall survival (OS) and were characterized by a risk gene signature associated with amino acids utilization. Importantly, characteristic genes specific to CLST/aCD4 showed promising clinical relevance in identifying patients with early-stage hepatocellular carcinoma via explainable machine learning. In addition, the 5-year long-term overall survival of hepatocellular carcinoma patients can be effectively classified by CLST/aCD4 based GeneSet-ResNet model. Subgroups defined by CLST and aCD4 were significantly involved in the sensitivity of hepatitis B virus-hepatocellular carcinoma patients to chemotherapy treatments. Conclusion: CLST and aCD4 are hepatitis B virus pathogenesis-relevant immunosignals that are highly involved in hepatitis B virus-induced inflammation, fibrosis, and hepatocellular carcinoma. Gene set variation analysis derived immunogenomic signatures enabled efficient diagnostic and prognostic model construction. The clinical application of CLST and aCD4 as indicators would be beneficial for the precision management of hepatocellular carcinoma.

Breast cancer is the most commonly diagnosed and leading cause of cancer death among women worldwide. Mitogen-activated protein kinase-interacting kinases (MNKs) promote the expression of several oncogenic proteins and are overexpressed in several types of cancer. In human cells, there are four isoforms of MNKs. The truncated isoform MNK1b, first described in our laboratory, has a higher basal activity and is constitutively active. Aptamers are emerging in recent years as potential therapeutic agents that show significant advantages over drugs of other nature. We have previously obtained and characterized a highly specific aptamer against MNK1b, named apMNK2F, with a dissociation constant in the nanomolar range, which produces significant inhibition of proliferation, migration, and colony formation in breast cancer cells. Furthermore, its sequence analysis predicted two G-quadruplex structures. In this work, we show the optimization process of the aptamer to reduce its size, improving its stability. The obtained aptamer, named apMNKQ2, is able to inhibit proliferation, colony formation, migration, and invasion in breast cancer cells. In murine models of breast cancer, apMNKQ2 has demonstrated its efficacy in reducing tumor volume and the number of metastases. In conclusion, apMNKQ2 could be used as an anti-tumor drug in the future.

Recently, the potential toxic effects of various pharmaceuticals on the thyroid endocrine system have raised considerable concerns. In this study, we evaluated the adverse effects of sorafenib and sunitinib, two widely used anti-tumor drugs, on the developmental toxicities and thyroid endocrine disruption by using zebrafish (Danio rerio) model. Zebrafish embryos/larvae were exposed to different contentions (0, 10, 50 and 100 nM) of sorafenib and sunitinib for 96 hpf. The results revealed that waterborne exposure to sorafenib and sunitinib exhibited remarkable toxic effects on the survival and development in zebrafish embryos/larvae, which was accompanied by obvious disturbances of thyroid endocrine system (e.g., decreased T3 and T4 content, increased TSH content) and genes\' transcription changes within the hypothalamus-pituitary-thyroid (HPT) axis. In addition, we verified a strikingly abnormal thyroid gland organogenesis in zebrafish larvae in response to sorafenib and sunitinib, by assessing the development of thyroid follicles using the WISH staining of tg, the Tg (tg:GFP) zebrafish transgenic line, and histopathological analysis. Taken together, our results indicated sorafenib and sunitinib exposure could induce obvious developmental toxicities and thyroid function disruption in zebrafish embryos/larvae, which might involve a regulatory mechanism, at least in part, by destroying the thyroid follicle structure, and by disturbing the balance of the HPT axis.

Autophagy, originally described as a mechanism for intracellular waste disposal and recovery, has been becoming a crucial biological process closely related to many types of human tumors, including breast cancer, osteosarcoma, glioma, etc., suggesting that intervention of autophagy is a promising therapeutic strategy for cancer drug development. Therefore, a high-quality database is crucial for unraveling the complicated relationship between autophagy and human cancers, elucidating the crosstalk between the key autophagic pathways, and autophagic modulators with their remarkable antitumor activities. To achieve this goal, a comprehensive database of autophagic modulators (AMTDB) was developed. AMTDB focuses on 153 cancer types, 1,153 autophagic regulators, 860 targets, and 2,046 mechanisms/signaling pathways. In addition, a variety of classification methods, advanced retrieval, and target prediction functions are provided exclusively to cater to the different demands of users. Collectively, AMTDB is expected to serve as a powerful online resource to provide a new clue for the discovery of more candidate cancer drugs.