Chiral inorganic nanomaterials in the tumor microenvironment: A new chapter in cancer therapy.

Chirality plays a crucial function in the regulation of normal physiological processes and is widespread in organisms. Chirality can be imparted to nanomaterials, whether they are natural or manmade, through the process of asymmetric assembly and/or grafting of molecular chiral groups or linkers. Chiral inorganic nanomaterials possess unique physical and chemical features that set them apart from regular nanomaterials. They also have the ability to interact with cells and tissues in a specific manner, making them useful in various biomedical applications, particularly in the treatment of tumors. Despite the growing amount of research on chiral inorganic nanomaterials in the tumor microenvironment (TME) and their promising potential applications, there is a lack of literature that comprehensively summarizes the intricate interactions between chiral inorganic nanomaterials and TME. In this review, we introduce the fundamental concept, classification, synthesis methods, and physicochemical features of chiral inorganic nanomaterials. Next, we briefly outline the components of TME, such as T cells, macrophages, dendritic cells, and weak acids, and then discuss the anti-tumor effects of several chiral inorganic nanoparticles targeting these components and their potential for possible application during cancer therapy. Finally, the present challenges faced by chiral inorganic nanomaterials in cancer treatment and their future areas of investigation are disclosed.

Malic enzymes in cancer: Regulatory mechanisms, functions, and therapeutic implications.

Malic enzymes (MEs) are metabolic enzymes that catalyze the oxidation of malate to pyruvate and NAD(P)H. While researchers have well established the physiological metabolic roles of MEs in organisms, recent research has revealed a link between MEs and carcinogenesis. This review collates evidence of the molecular mechanisms by which MEs promote cancer occurrence, including transcriptional regulation, post-transcriptional regulation, post-translational protein modifications, and protein-protein interactions. Additionally, we highlight the roles of MEs in reprogramming energy metabolism, suppressing senescence, and modulating the tumor immune microenvironment. We also discuss the involvement of these enzymes in mediating tumor resistance and how the development of novel small-molecule inhibitors targeting MEs might be a good therapeutic approach. Insights through this review are expected to provide a comprehensive understanding of the intricate relationship between MEs and cancer, while facilitating future research on the potential therapeutic applications of targeting MEs in cancer management.

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.

BACKGROUND: Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood. METHODS: The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2-/-Il2rg-/- mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly. RESULTS: Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features-IL-23 and CD4+ Tems-that may have predictive potential for severe irAEs and ICIs response. CONCLUSIONS: Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.

Cordycepin Modulates Microglial M2 Polarization Coupled with Mitochondrial Metabolic Reprogramming by Targeting HKII and PDK2.

The microenvironment mediated by the microglia (MG) M1/M2 phenotypic switch plays a decisive role in the neuronal fate and cognitive function of Alzheimer's disease (AD). However, the impact of metabolic reprogramming on microglial polarization and its underlying mechanism remains elusive. This study reveals that cordycepin improved cognitive function and memory in APP/PS1 mice, as well as attenuated neuronal damage by triggering MG-M2 polarization and metabolic reprogramming characterized by increased OXPHOS and glycolysis, rather than directly protecting neurons. Simultaneously, cordycepin partially alleviates mitochondrial damage in microglia induced by inhibitors of OXPHOS and glycolysis, further promoting MG-M2 transformation and increasing neuronal survival. Through confirmation of cordycepin distribution in the microglial mitochondria via mitochondrial isolation followed by HPLC-MS/MS techniques, HKII and PDK2 are further identified as potential targets of cordycepin. By investigating the effects of HKII and PDK2 inhibitors, the mechanism through which cordycepin targeted HKII to elevate ECAR levels in the glycolysis pathway while targeting PDK2 to enhance OCR levels in PDH-mediated OXPHOS pathway, thereby inducing MG-M2 polarization, promoting neuronal survival and exerting an anti-AD role is elucidated.

Early signs of neurodegenerative diseases: Possible mechanisms and targets for Golgi stress.

The Golgi apparatus plays a crucial role in mediating the modification, transport, and sorting of intracellular proteins and lipids. The morphological changes occurring in the Golgi apparatus are exceptionally important for maintaining its function. When exposed to external pressure or environmental stimulation, the Golgi apparatus undergoes adaptive changes in both structure and function, which are known as Golgi stress. Although certain signal pathway responses or post-translational modifications have been observed following Golgi stress, further research is needed to comprehensively summarize and understand the related mechanisms. Currently, there is evidence linking Golgi stress to neurodegenerative diseases; however, the role of Golgi stress in the progression of neurodegenerative diseases such as Alzheimer's disease remains largely unexplored. This review focuses on the structural and functional alterations of the Golgi apparatus during stress, elucidating potential mechanisms underlying the involvement of Golgi stress in regulating immunity, autophagy, and metabolic processes. Additionally, it highlights the pivotal role of Golgi stress as an early signaling event implicated in the pathogenesis and progression of neurodegenerative diseases. Furthermore, this study summarizes prospective targets that can be therapeutically exploited to mitigate neurodegenerative diseases by targeting Golgi stress. These findings provide a theoretical foundation for identifying novel breakthroughs in preventing and treating neurodegenerative diseases.

Potential therapeutic strategy for cancer: Multi-dimensional cross-talk between circRNAs and parental genes.

In many ways, circular RNAs (circRNAs) have been demonstrated to be crucial in the onset and advancement of cancer throughout the last ten years and have become a new focus of intense research in the field of RNAs. Accumulating studies have demonstrated that circRNAs can regulate parental gene expression via a variety of biological pathways. Furthermore, research into the complex interactions between circRNAs and their parental genes will shed light on their biological roles and open up new avenues for circRNAs' potential clinical translational uses. However, to date, multi-dimensional cross-talk between circRNAs and parental genes have not been systematically elucidated. Particularly intriguing is circRNA's exploration of tumor targeting, and potential therapeutic uses based on the parental gene regulation perspective. Here, we discuss their biogenesis, take a fresh look at the molecular mechanisms through which circRNAs control the expression of their parental genes in cancer. We further highlight We further highlight the latest circRNA clinical translational applications, including prognostic diagnostic markers, cancer vaccines, gDNA, and so on. Demonstrating the potential benefits and future applications of circRNA therapy.

When will the immune-stimulating antibody conjugates (ISACs) be transferred from bench to bedside?

Immunostimulatory antibody conjugates (ISACs) as a promising new generation of targeted therapeutic antibody-drug conjugates (ADCs), that not only activate innate immunity but also stimulate adaptive immunity, providing a dual therapeutic effect to eliminate tumor cells. However, several ISACs are still in the early stages of clinical development or have already failed. Therefore, it is crucial to design ISACs more effectively to overcome their limitations, including high toxicity, strong immunogenicity, long development time, and poor pharmacokinetics. This review aims to summarize the composition and function of ISACs, incorporating current design considerations and ongoing clinical trials. Additionally, the review delves into the current issues with ISACs and potential solutions, such as adjusting the drug-antibody ratio (DAR) to improve the bioavailability of ISACs. By leveraging the affinity and bioavailability-enhancing properties of bispecific antibodies, the utility between antibodies and immunostimulatory agents can be balanced. Commonly used immunostimulatory agents may induce systemic immune reactions, and BTK (Bruton's tyrosine kinase) inhibitors can regulate immunogenicity. Finally, the concept of grafting ADC's therapeutic principles is simple, but the combination of payload, linker, and targeted functional molecules is not a simple permutation and combination problem. The development of conjugate drugs faces more complex pharmacological and toxicological issues. Standing on the shoulders of ADC, the development and application scenarios of ISAC are endowed with broader space.

Biological factors driving colorectal cancer metastasis.

Approximately 20% of colorectal cancer (CRC) patients present with metastasis at diagnosis. Among Stage I-III CRC patients who undergo surgical resection, 18% typically suffer from distal metastasis within the first three years following initial treatment. The median survival duration after the diagnosis of metastatic CRC (mCRC) is only 9 mo. mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue, allowing cancer cells to spread from primary to distant organs; however, increasing evidence suggests that the mCRC process can begin early in tumor development. CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations. Different genomic and nongenomic events can induce subclone diversity, which leads to cancer and metastasis. Throughout the course of mCRC, metastatic cascades are associated with invasive cancer cell migration through the circulatory system, extravasation, distal seeding, dormancy, and reactivation, with each step requiring specific molecular functions. However, cancer cells presenting neoantigens can be recognized and eliminated by the immune system. In this review, we explain the biological factors that drive CRC metastasis, namely, genomic instability, epigenetic instability, the metastatic cascade, the cancer-immunity cycle, and external lifestyle factors. Despite remarkable progress in CRC research, the role of molecular classification in therapeutic intervention remains unclear. This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.

Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment.

In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired off-target reactions. To tackle these limitations and enhance bioavailability, polymer micelles present potential solutions by enabling precise drug delivery to the target site, thus amplifying the effectiveness of immunotherapy. This review article offers an extensive survey of recent progress in cancer immunotherapy strategies utilizing micelles. These strategies include responsive and remodeling approaches to the tumor microenvironment (TME), modulation of immunosuppressive cells within the TME, enhancement of immune checkpoint inhibitors, utilization of cancer vaccine platforms, modulation of antigen presentation, manipulation of engineered T cells, and targeting other components of the TME. Subsequently, we delve into the present state and constraints linked to the clinical utilization of polymeric micelles. Collectively, polymer micelles demonstrate excellent prospects in tumor immunotherapy by effectively addressing the challenges associated with conventional cancer immunotherapies.

Identification of novel lactate metabolism-related lncRNAs with prognostic value for bladder cancer.

Background: Bladder cancer (BCA) has high recurrence and metastasis rates, and current treatment options show limited efficacy and significant adverse effects. It is crucial to find diagnostic markers and therapeutic targets with clinical value. This study aimed to identify lactate metabolism-related lncRNAs (LM_lncRNAs) to establish a model for evaluating bladder cancer prognosis. Method: A risk model consisting of lactate metabolism-related lncRNAs was developed to forecast bladder cancer patient prognosis using The Cancer Genome Atlas (TCGA) database. Kaplan‒Meier survival analysis, receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA) were used to evaluate the reliability of risk grouping for predictive analysis of bladder cancer patients. The results were also validated in the validation set. Chemotherapeutic agents sensitive to lactate metabolism were assessed using the Genomics of Drug Sensitivity in Cancer (GDSC) database. Results: As an independent prognostic factor for patients, lactate metabolism-related lncRNAs can be used as a nomogram chart that predicts overall survival time (OS). There were significant differences in survival rates between the high-risk and low-risk groups based on the Kaplan‒Meier survival curve. decision curve analysis and receiver operating characteristic curve analysis confirmed its good predictive capacity. As a result, 22 chemotherapeutic agents were predicted to positively affect the high-risk group. Conclusion: An lactate metabolism-related lncRNA prediction model was proposed to predict the prognosis for patients with bladder cancer and chemotherapeutic drug sensitivity in high-risk groups, which provided a new idea for the prognostic evaluation of the clinical treatment of bladder cancer.

Advancement of anti-LAG-3 in cancer therapy.

Immune checkpoint inhibitors have effectively transformed the treatment of many cancers, particularly those highly devastating malignancies. With their widespread popularity, the drawbacks of immune checkpoint inhibitors are also recognized, such as drug resistance and immune-related systematic side effects. Thus, it never stops investigating novel immune checkpoint inhibitors. Lymphocyte Activation Gene-3 (LAG-3) is a well-established co-inhibitory receptor that performs negative regulation on immune responses. Recently, a novel FDA-approved LAG-3 blocking agent, together with nivolumab as a new combinational immunotherapy for metastatic melanoma, brought LAG-3 back into focus. Clinical data suggests that anti-LAG-3 agents can amplify the therapeutic response of other immune checkpoint inhibitors with manageable side effects. In this review, we elucidate the intercellular and intracellular mechanisms of LAG-3, clarify the current understanding of LAG-3 in the tumor microenvironment, identify present LAG-3-associated therapeutic agents, discuss current LAG-3-involving clinical trials, and eventually address future prospects for LAG-3 inhibitors.

Improving the efficacy of anti-EGFR drugs in GBM: Where we are going?

The therapies targeting mutations of driver genes in cancer have advanced into clinical trials for a variety of tumors. In glioblastoma (GBM), epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene, and targeting EGFR has been widely investigated as a promising direction. However, the results of EGFR pathway inhibitors have not been satisfactory. Limited blood-brain barrier (BBB) permeability, drug resistance, and pathway compensation mechanisms contribute to the failure of anti-EGFR therapies. This review summarizes recent research advances in EGFR-targeted therapy for GBM and provides insight into the reasons for the unsatisfactory results of EGFR-targeted therapy. By combining the results of preclinical studies with those of clinical trials, we discuss that improved drug penetration across the BBB, the use of multi-target combinations, and the development of peptidomimetic drugs under the premise of precision medicine may be promising strategies to overcome drug resistance in GBM.

The novel HLA-A*02:405 allele characterized by sequencing-based typing.

HLA-A*02:405 differs from HLA-A*02:06:01:01 by one nucleotide substitution in codon 161 in exon 3.

Nanoparticle-mediated synergistic anticancer effect of ferroptosis and photodynamic therapy: Novel insights and perspectives.

Current antitumor monotherapy has many limitations, highlighting the need for novel synergistic anticancer strategies. Ferroptosis is an iron-dependent form of nonapoptotic cell death that plays a pivotal regulatory role in tumorigenesis and treatment. Photodynamic therapy (PDT) causes irreversible chemical damage to target lesions and is widely used in antitumor therapy. However, PDT's effectiveness is usually hindered by several obstacles, such as hypoxia, excess glutathione (GSH), and tumor resistance. Ferroptosis improves the anticancer efficacy of PDT by increasing oxygen and reactive oxygen species (ROS) or reducing GSH levels, and PDT also enhances ferroptosis induction due to the ROS effect in the tumor microenvironment (TME). Strategies based on nanoparticles (NPs) can subtly exploit the potential synergy of ferroptosis and PDT. This review explores recent advances and current challenges in the landscape of the underlying mechanisms regulating ferroptosis and PDT, as well as nano delivery system-mediated synergistic anticancer activity. These include polymers, biomimetic materials, metal organic frameworks (MOFs), inorganics, and carrier-free NPs. Finally, we highlight future perspectives of this novel emerging paradigm in targeted cancer therapies.

Alternative splicing events and function in the tumor microenvironment: New opportunities and challenges.

Alternative splicing controls gene expression at the transcriptional level, producing structurally and functionally distinct protein heterodimers. Aberrant alternative splicing greatly affects cell development and plays an important role in the invasion and metastasis of many types of cancer. Recently, it has been shown that alternative splicing can alter the tumor microenvironment and regulate processes such as remodeling, immunity, and inflammation in the tumor microenvironment. However, there is no comprehensive literature review of the complex relationship between alternative splicing and the tumor microenvironment. Therefore, this review aims to collect all the latest data on this topic and provide a new perspective on the therapeutic and potential prognostic markers of cancer.

TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal.

TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (m5C) modification in TSPAN13 mRNA; YBX1 specifically recognizes the m5C modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m5C demethylase.

Mesenchymal stem cells influence monocyte/macrophage phenotype: Regulatory mode and potential clinical applications.

Mesenchymal stem cells (MSCs) are pluripotent stem cells derived from a variety of tissues, such as umbilical cord, fat, and bone marrow. Today, MSCs are widely recognized for their prominent anti-inflammatory properties in a variety of acute and chronic inflammatory diseases. In inflammatory diseases, monocytes/macrophages are an important part of the innate immune response in the body, and the alteration of the inflammatory phenotype plays a crucial role in the secretion of pro-inflammatory/anti-inflammatory factors, the repair of injured sites, and the infiltration of inflammatory cells. In this review, starting from the effect of MSCs on the monocyte/macrophage phenotype, we have outlined in detail the process by which MSCs influence the transformation of the monocyte/macrophage inflammatory phenotype, emphasizing the central role of monocytes/macrophages in MSC-mediated anti-inflammatory and damage site repair. MSCs are phagocytosed by monocytes/macrophages in various physiological states, the paracrine effect of MSCs and mitochondrial transfer of MSCs to macrophages to promote the transformation of monocytes/macrophages into anti-inflammatory phenotypes. We also review the clinical applications of the MSCs-monocytes/macrophages system and describe novel pathways between MSCs and tissue repair, the effects of MSCs on the adaptive immune system, and the effects of energy metabolism levels on monocyte/macrophage phenotypic changes.

The interplay between non-coding RNAs and alternative splicing: from regulatory mechanism to therapeutic implications in cancer.

Alternative splicing (AS) is a common and conserved process in eukaryotic gene regulation. It occurs in approximately 95% of multi-exon genes, greatly enriching the complexity and diversity of mRNAs and proteins. Recent studies have found that in addition to coding RNAs, non-coding RNAs (ncRNAs) are also inextricably linked with AS. Multiple different types of ncRNAs are generated by AS of precursor long non-coding (pre-lncRNAs) or precursor messenger RNAs (pre-mRNAs). Furthermore, ncRNAs, as a novel class of regulators, can participate in AS regulation by interacting with the cis-acting elements or trans-acting factors. Several studies have implicated abnormal expression of ncRNAs and ncRNA-related AS events in the initiation, progression, and therapy resistance in various types of cancers. Therefore, owing to their roles in mediating drug resistance, ncRNAs, AS-related factors and AS-related novel antigens may serve as promising therapeutic targets in cancer treatment. In this review, we summarize the interaction between ncRNAs and AS processes, emphasizing their great influences on cancer, especially on chemoresistance, and highlighting their potential values in clinical treatment.

The Potential Mechanism of Cannabidiol (CBD) Treatment of Epilepsy in Pentetrazol (PTZ) Kindling Mice Uncovered by Multi-Omics Analysis.

Cannabidiol (CBD) is the main active ingredient in the cannabis plant used for treating epilepsy and related diseases. However, how CBD ameliorates epilepsy and its effect on the hippocampus remains unknown. Herein, we evaluated how CBD ameliorates seizure degree in pentylenetetrazol (PTZ) induced epilepsy mice after being exposed to CBD (10 mg/kg p.o). In addition, transcriptome and metabolomic analysis were performed on the hippocampus. Our results suggested that CBD could alleviate PTZ-induced seizure, of which the NPTX2, Gprc5c, Lipg, and Stc2 genes were significantly down-regulated in mice after being exposed to PTZ. Transcriptome analysis showed 97 differently expressed genes (CBD) and the PTZ groups. Metabonomic analysis revealed that compared with the PTZ group, 41 up-regulated and 67 down-regulated metabolites were identified in the hippocampus of epileptic mice exposed to CBD. The correlation analysis for transcriptome and metabolome showed that (±) 15-HETE and carnitine C6:0 were at the core of the network and were involved in the positive or negative regulation of the related genes after being treated with CBD. In conclusion, CBD ameliorates epilepsy by acting on the metabolism, calcium signaling pathway, and tuberculosis pathways in the hippocampus. Our study provided a practical basis for the therapeutic potential of treating epilepsy using CBD.

Efficacy and safety of PARP inhibitors in the treatment of BRCA-mutated breast cancer: an updated systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Poly-ADP-ribose polymerase inhibitors (PARPis) have emerged as a new class of therapeutic agents for breast cancer patients with breast cancer susceptibility gene (BRCA) mutations. However, the efficacy and toxicity of PARPis have not been clearly established. METHODS: This study comprehensively evaluated the efficacy and safety of PARPis in patients with BRCA-mutated breast cancer. Online databases were systematically searched, and six clinical trials were included. The primary endpoint of efficacy was progression-free survival (PFS), whereas the secondary endpoints were overall survival (OS) and objective response rate (ORR). Additionally, we assessed the safety of PARPis. RESULTS: The results of the meta-analysis showed that PARPis can effectively improve the PFS and OS in patients compared with the control group. The pooled HR (PARPi vs control groups) was 0.63 (95% CI, 0.55 - 0.73) and 0.83 (95% CI, 0.73 to -0.95) for PFS and OS, respectively. In safety, PARPis demonstrated controllable adverse reactions. There were no significant differences in overall AEs or grade ≥3 AEs between the PARP inhibitor and control arms. CONCLUSIONS: Our results confirm the efficacy and safety of PARPis in patients with BRCA-mutated breast cancer, and more specifically clarify the efficacy of PARPis alone or in combination with other chemotherapy drugs. [Figure: see text].