Cancer immunotherapy exhibits limited efficacy in immunologically "cold" tumors due to insufficient T-cell infiltration and immunosuppressive tumor microenvironment. The efficacy of photodynamic therapy (PDT) is restricted by inadequate tumor-specific aggregation of photosensitizers and therapeutic resistance regulated by epigenetics. Herein, we engineered a light-driven, ROS-responsive hydrogel (PACL@Gel) for loading peptide-lipid scaffold nanoparticles encapsulating proteolysis targeting chimera (PROTAC) molecule and photosensitizer to enhance cancer immunotherapy. The system utilizes both endogenous and photodynamically amplified ROS to drive controlled hydrogel degradation and nanoparticle release, establishing a self-sustaining ROS feedback loop to overcome the limitations of insufficient endogenous ROS. The released PACL nanoparticles synergistically combine PDT with epigenetic BRD4 protein degradation to robustly amplify Caspase-3/GSDME dependent pyroptosis. Pyroptotic tumor cells would trigger immunogenic cell death, releasing inflammatory mediators and damage-associated molecular patterns that promote dendritic cells maturation and T-cell activation and infiltration to effectively remodel the immunosuppressive tumor niche and promote antitumor immunity. Experimental results validated that under laser irradiation, PACL@Gel demonstrated potent local tumor suppression and distant abscopal effect, prevented postoperative recurrence and established long-term immune memory. Collectively, this integrated PROTAC-PDT hydrogel platform effectively reprograms the immunosuppressive tumor microenvironment, providing a robust and actionable approach to enhance PDT therapy in immunologically cold tumors combined with epigenetic strategies.

The development and progression of leukemia are driven not only by intrinsic genetic and epigenetic alterations in leukemia cells,but also by the dynamic remodeling of immune niches within the bone marrow microenvironment(BMM).Accumulating evidence has indicated that leukemic cells can reshape the immune microenvironment through cytokine secretion,metabolic reprogramming,and other mechanisms,inducing T-cell dysfunction/exhaustion,impaired NK-cell effector functions,and immunosuppressive polarization of myeloid cells,thereby establishing a protective niche that facilitates disease progression,drug resistance,and relapse.In parallel,epigenetic mechanisms such as DNA methylation,histone modification,and RNA modifications bridge the phenotypic plasticity of leukemic cells and immune evasion processes by regulating antigen presentation,interferon signaling pathways,chemokine profiles,and immune checkpoint expression,thereby influencing the response to immunotherapy.This review centers on the core conceptual framework of"immune microenvironment remodeling-epigenetic regulation-drug resistance and relapse-combination therapy strategies".It systematically outlines the key immunosuppressive networks and their epigenetic foundations across different leukemia subtypes.Emphasis is placed on the advances and challenges in combining epigenetic drugs,such as demethylating agents and histone deacetylase inhibitors,with immune checkpoint inhibitors,BCL-2 inhibitors,and microenvironment-targeted therapies.Furthermore,it outlines future directions in microenvironment subtyping and precision interventions driven by single-cell and spatial multi-omics technologies,aiming to provide a theoretical basis for optimizing combination treatment strategies in leukemia.

Myeloid differentiation protein 2 (MD2) is an indispensable co-receptor for Toll-like receptor 4 (TLR4) and also serves as a key recognition protein for lipopolysaccharide (LPS). Binding of LPS to TLR4-MD2 complex triggers downstream signaling cascades that regulate the production of pro-inflammatory cytokines, thereby contributing to the pathogenesis of inflammation-related diseases such as acute lung injury, sepsis, and cardiac fibrosis. Targeting MD2 has emerged as an important therapeutic strategy for human diseases. Currently, significant progress has been made in the development of MD2 inhibitors, among which ACT001, TAK-242, and eritoran have entered clinical studies for the treatment of diffuse midline glioma, alcoholic hepatitis and septic shock, etc. In this review, we provide a systematic summary of reported MD2 inhibitors, focusing on their structural characteristics, biological functions, binding modes with MD2, and the role of MD2 in related diseases, with the goal of providing reference for the development of novel anti-inflammatory drugs.

Histone deacetylases (HDACs) are attractive therapeutic targets due to their established role in tumorigenesis. In this study, a series of naphthalene-based hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among them, compound 6e showed excellent inhibitory activities against HDAC1 and 4T1 cancer cell line, and it also increased the levels of acetylated histones H3 and H4. Moreover, 6e induced significant cell apoptosis and cycle arrest. Importantly, 6e exhibited significant antitumor activity in the 4T1 orthotopic autograft mouse model. Collectively, these results identify the naphthalene-hydroxamate scaffold as a promising template for the development of novel HDAC-targeted anticancer agents.

Synthetic lethality represents a novel paradigm in molecular targeted cancer therapy. In synthetic lethality, perturbation of one gene alone does not hinder cell viability, yet simultaneous perturbation of both genes results in a loss of cellular viability. The presence of gene mutations in cancer cells, as opposed to normal cells, provides an opportunity for targeted therapies that mimic the effects of the second genetic mutation, enabling selective eradication of cancer cells. Recent advances in high-throughput screening technologies, such as CRISPR-Cas9 and RNA interference, have significantly enhanced the identification of synthetic lethal interactions, expanding the potential targets for therapeutic intervention. Challenges in exploiting synthetic lethality for cancer treatment include the complexities of tumor biology, limited comprehension of synthetic lethal interactions, drug resistance, and impediments in screening and clinical translation. Emerging strategies, such as combination therapies and novel drug designs, are being developed to overcome these obstacles. By virtue of its selective lethality towards cancer cells bearing specific genetic alterations, targeting synthetic lethal genes holds the promise to provide wider therapeutic windows compared to traditional cytotoxic chemotherapy. This review describes the current state of synthetic lethality applications in cancer treatment, encompassing both biological and methodological perspectives. It highlights the latest advancements in synthetic lethality with emerging interventional strategies. Furthermore, it explores future directions for research and clinical implementation, aiming to refine and expand the therapeutic potential of synthetic lethality in oncology.

BackgroundThe hematopoietic ecosystem comprises both cellular components such as hematopoietic stem cells (HSCs) and immune cells as well as non-cellular components including iron. Systemic iron overload, which leads to serious complications and affects both patients’ quality of life and overall survival, is a common clinical challenge in patients with acute myeloid leukemia (AML). We previously elucidated the direct effects of iron overload on AML cells. It’s worth noting that iron overload remodels the hematopoietic ecosystem. However, whether and how remodeled leukemic microenvironment with overloaded iron regulates normal HSCs and immune cells, especially leukemia-associated macrophages (LAMs), in AML have not been elucidated.MethodsThe MLL-AF9-induced AML (MA9) cells were originated from c-kit+ BM cells enriched from C57BL/6J mice that infected with MSCV-MLL-AF9-GFP retrovirus. The MA9 AML mouse model was established by transplantation of MA9 cells into C57BL/6 mice. MA9 mice were i.p. administered with iron dextran every other day for a total of 6 times to established the iron overload MLL-AF9-induced AML mouse model (MA9/FE). HSC maintenance and differentiation was assessed by flow cytometry, cell proliferation, cell apoptosis, colony forming and competitive transplantation assays. LAM activation and function was analyzed by RNA-sequencing, flow cytometry and coculture assay. Intravenous clodronate liposome administration was employed to reduce LAMs in AML.ResultsIron overload skewed myeloid differentiation of normal HSCs. Furthermore, iron overload affected LAMs in the AML microenvironment by promoting LAM polarization toward an M2 phenotype. Functionally, iron overload decreased the phagocytic function of LAMs against leukemia cells and inhibited LAM-induced T cell activation by acquiring a tolerogenic phenotype with aberrant immune checkpoints. Moreover, depletion of LAMs attenuated iron overload caused acceleration of AML progression.ConclusionsCollectively, this study reveals the significance of iron overload in remodeling hematopoietic ecosystem and affecting HSC and LAM function in AML, providing new insights into the multifaceted role of iron overload in leukemia.

Owing to the presence of the blood-brain barrier and the lack of significant specificity towards tumor cells after entry into the brain, the unsuccessful delivery of anticancer drugs to the treatment of brain tumors. The hypothesis that cholesterol-PEG co-modified poly (N-butyl) cyanoacrylate nanoparticles (CLS-PEG NPs) are an effective carrier for the treatment of brain tumors was verified, and the mechanism of its treatment for brain tumors was preliminarily explored. In this study, we used multifunctional poly (N-butyl) cyanoacrylate nanoparticles modified with cholesterol and polyethylene glycol (PEG) as a drug delivery system to encapsulate the anticancer drug docetaxel (DTX). Cell anti-proliferation tests showed that CLS-PEG NPs increased the inhibitory effect of DTX. A pharmacokinetic study indicated that CLS-PEG NPs achieved sustained release for 8 h. These experimental results demonstrated that CLS-PEG NPs amplified the concentration of the drug transported to the brain and sustained drug release in the brain. In addition, CLS-PEG NPs led to better pharmacological efficacy in an orthotopic brain glioma rat model. The survival rate of rats in the CLS-PEG NPs group was significantly prolonged to 28 d. We also found that CLS-PEG NPs inhibited M2 microglial polarization. These results indicate that CLS-PEG NPs are a prospective drug delivery system for targeting brain tumors.

The dysfunction of HDACs is closely related to tumorigenesis and development, which has emerged as an attractive target for cancer therapy. In this study, a series of thiazole-containing hydroxamate derivatives were designed and synthesized as novel HDAC inhibitors. Among these inhibitors, compounds 15a and 15d showed excellent inhibitory activities against HDAC1 and HepG2 cancer cell line, these two compounds increased the levels of acetylated histone H3 and H4. Moreover, 15a and 15d significantly arrested HepG2 cells at the G0/G1 phase. Additionally, these two compounds could induce apoptosis and pyroptosis. Moreover, 15a exhibited significant antitumor activity in the HepG2 xenograft model. Molecular docking and molecular dynamics simulation studies revealed the possible interaction mode of compound 15a with HDAC1. Besides, the preliminary pharmacokinetics study of compound 15a in vivo was evaluated. These results suggested that these novel thiazole-based HDAC inhibitors might become a promising scaffold for further structural optimization.

In the absence of tumor antigen specificity, direct chemokine administration carries the risk of significant “on-target, off-tumor” toxicities, highlighting the need for small-molecule approaches with reduced immunogenicity. This study investigates the synergistic potential of norcantharidin (NCTD) and lomitapide (lomi) in selectively restoring CCL4 expression by deactivating the tumor intrinsic β-catenin pathway. Due to its similar lipophilicity to lomi and potential to suppress β-catenin, NCTD prodrug (C12) was selected to be co-encapsulated with lomi in a nanoparticle-mediated co-delivery system (NP“C12 + lomi”). The NP“C12 + lomi” formulation exhibited a high encapsulation rate, uniform particle size, and suitability for therapeutic use. It effectively inhibited the proliferation of 4T1 cells and restored CCL4 expression. In both primary breast tumor and surgically resected tumor mouse models, NP“C12 + lomi” significantly increased the proportion of CD8+ cells in primary tumors, blood, and lung metastases, approximately doubling their presence. This led to a prolongation of median survival in mice to 59 days. Furthermore, when combined with an immune checkpoint inhibitor, NP“C12 + lomi” substantially inhibited tumor growth and lung metastasis without affecting body weight or causing major tissue or organ damage. This was attributed to the controlled dissociation of the nanoparticle and the subsequent modulation of C12 and lomi, which mitigated CCL4-related toxicity. This study provides valuable insights into the safe production of chemokines using a small-molecule pair through a nanosystem and presents a robust chemo-immunological cascade therapy strategy, demonstrating significant efficacy against malignant metastatic tumors.

Bromodomain-containing protein 4, an epigenetic reader, was considered as a promising drug target for human diseases, such as cancers and cardiac remodeling. This protein contains a pair of bromodomains (BD1 and BD2). Selective inhibition of bromodomains is critical for maintaining cell homeostasis. In the present work we made use of the molecular hybridization strategy to design and synthesize a novel series of indole derivatives, specifically (3-[5-(methylsulfanyl)-4-m-tolyl-4H-1,2,4-triazol-3-yl]-1H-indole, 5-(1H-indol-3-yl)-4-p-tolyl-4H-1,2,4-triazole-3-thiol; 5-(1H-indol-3-yl)-4-(o-tolyl)-4H-1,2,4-triazole-3-thiol, and 4-(3-chlorophenyl)-5-(1H-indol-3-yl)-4H-1,2,4-triazole-3-thiol), as well as 3-[5-(methylsulfanyl)-4-m-tolyl-4H-1,2,4-triazol-3-yl]-1H-indole as potential BRD4 inhibitors. 3-[5-(Methylsulfanyl)-4-(m-tolyl)-4H-1,2,4-triazol-3-yl]-1H-indole showed the highest inhibitory activity against BRD4 BD2 with an inhibition rate of 62

Diabetes is the most common type of chronic diseases word wide, accompanied by inadequate local angiogenesis and vascular lesions which is characterized by a gradual disorder function of the endothelial cells. Vascular complications which includes lower limb ischemia and chronic wound healing, are the main cause of death and disability in diabetic patients. Previous evidence has shown that restoring angiogenesis function of endothelial cells was detected as a key treatment project of diabetic complications. However, there is no specific medicine to treat the above diseases currently. Here, we make an effort to develop a new small molecule compound that promotes angiogenesis. To do this, we screen a library of small molecules and identify compound 361B, which significantly promote endothelial cell sprouting, tube formation, microvessels formation from aortic ring and neovascularization in mouse corneal. Moreover, 361B enhances the ability of angiogenesis in a diabetic mouse hindlimb ischemia model and a wound model. Meanwhile, 361B prevented HUVECs from starvation-induced apoptosis. Through Pull-down assays and SPR experiments, we have confirmed that 361B directly binds to vimentin in endothelial cells. Finally, it has been demonstrated through QPCR and Western Blotting Assay that 361B activates Akt/eNOS pathway to promote angiogenesis. As a conclusion, our data proves that 361B could be considered as a promising compound with the potential to treat diabetic vascular complications.

As an important trace element,iron is involved in a variety of physiological processes.In recent years,studies have found that the occurrence and development of tumors are closely related to abnormal iron metabolism,and the mode of action is obviously heterogeneous.Tumor cells need more iron to promote their survival and proliferation,but iron overload can also have adverse effects on tumor cells,such as ferroptosis.Ferroptosis is a special regulatory mechanism of cell death,which is different from other regulated cell death pathways.It mainly induces cell death through excessive accumulation of iron-dependent lipid peroxide and reactive oxygen species(ROS).Recent studies have found that in the blood system,tumor cells of lymphoma and multiple myeloma(MM)are more sensitive to ferroptosis and affect disease progression through a variety of mechanisms.In this review,the mechanisms of ferroptosis in some subtypes of lymphoma and MM are described in detail,and the correlation between ferroptosis of hematological tumor cells and the occurrence and development of hematological tumors is revealed,aiming to provide new ideas for the treatment of these hematological diseases.

Histone deacetylases (HDACs) are established as valuable drug targets for cancer therapy. A set of hydroxamate derivatives based on tetrahydro-γ-carboline were specifically designed and synthesized as HDAC inhibitors. Among these, 8-(8-bromo-5-isobutyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)-N-hydroxy-8-oxooctanamide demonstrated potent inhibitory effects on HDAC1 and A549 cancer cell lines. Moreover, this compound was found to increase the levels of acetylated histone H3 and H4. Notably, it effectively arrested A549 cells in the G2/M phase, while also enhancing ROS production and accumulating DNA damage to induce apoptosis. Molecular docking provided insights into the potential interaction between this compound and HDAC1. These results suggested that these novel HDAC inhibitors based on tetrahydro-γ-carboline could represent a promising foundation for further optimization as potential anticancer agents.

Drug candidates with poor solubility have been recognized as the cause of many drug development failures, owing to the fact that low solubility is unfavorable for physicochemical, pharmacokinetic (PK) and pharmacodynamic (PD) properties. Given the imperative role of solubility during drug development, we herein summarize various strategies for solubility optimizations from a medicinal chemistry perspective, including introduction of polar group, salt formation, structural simplification, disruption of molecular planarity and symmetry, optimizations on the solvent exposed region as well as prodrug design. In addition, methods for solubility assessment and prediction are reviewed. Besides, we have deeply discussed the strategies for solubility improvement. This paper is expected to be beneficial for the development of drug-like molecules with good solubility.

Systemic iron overload is a common clinical challenge leading to significantly serious complications in patients with acute myeloid leukemia (AML), which affects both the quality of life and the overall survival of patients. Symptoms can be relieved after iron chelation therapy in clinical practice. However, the roles and mechanisms of iron overload on the initiation and progression of leukemia remain elusive. Here we studied the correlation between iron overload and AML clinical outcome, and further explored the role and pathophysiologic mechanism of iron overload in AML by using two mouse models: an iron overload MLL-AF9-induced AML mouse model and a nude xenograft mouse model. Patients with AML had an increased ferritin level, particularly in the myelomonocytic (M4) or monocytic (M5) subtypes. High level of iron expression correlated with a worsened prognosis in AML patients and a shortened survival time in AML mice. Furthermore, iron overload increased the tumor load in the bone marrow (BM) and extramedullary tissues by promoting the proliferation of leukemia cells through the upregulation of FOS. Collectively, our findings provide new insights into the roles of iron overload in AML. Additionally, this study may provide a potential therapeutic target to improve the outcome of AML patients and a rationale for the prospective evaluation of iron chelation therapy in AML.

Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines. In the current project, the first total synthesis of (±)-MPE was achieved in seven steps and 5.6% overall yield. Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells, with the levoisomer exerting slightly better potency. The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model. Notably, MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage. Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling. In conclusion, our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies.

BackgroundBreast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized.MethodsA substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B.ResultsWe synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice.ConclusionsOur findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.