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.

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.

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.

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.

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.

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.

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.

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].

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.

Peptide-drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

Peptide-drug conjugates (PDCs) are the next generation of targeted therapeutics drug after antibody-drug conjugates (ADCs), with the core benefits of enhanced cellular permeability and improved drug selectivity. Two drugs are now approved for market by US Food and Drug Administration (FDA), and in the last two years, the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer, coronavirus disease 2019 (COVID-19), metabolic diseases, and so on. The therapeutic benefits of PDCs are significant, but poor stability, low bioactivity, long research and development time, and slow clinical development process as therapeutic agents of PDC, how can we design PDCs more effectively and what is the future direction of PDCs? This review summarises the components and functions of PDCs for therapeutic, from drug target screening and PDC design improvement strategies to clinical applications to improve the permeability, targeting, and stability of the various components of PDCs. This holds great promise for the future of PDCs, such as bicyclic peptide‒toxin coupling or supramolecular nanostructures for peptide-conjugated drugs. The mode of drug delivery is determined according to the PDC design and current clinical trials are summarised. The way is shown for future PDC development.

Cell adhesion molecules and immunotherapy in advanced non-small cell lung cancer: Current process and potential application.

Advanced non-small cell lung cancer (NSCLC) is a severe disease and still has high mortality rate after conventional treatment (e.g., surgical resection, chemotherapy, radiotherapy and targeted therapy). In NSCLC patients, cancer cells can induce immunosuppression, growth and metastasis by modulating cell adhesion molecules of both cancer cells and immune cells. Therefore, immunotherapy is increasingly concerned due to its promising anti-tumor effect and broader indication, which targets cell adhesion molecules to reverse the process. Among these therapies, immune checkpoint inhibitors (mainly anti-PD-(L)1 and anti-CTLA-4) are most successful and have been adapted as first or second line therapy in advanced NSCLC. However, drug resistance and immune-related adverse reactions restrict its further application. Further understanding of mechanism, adequate biomarkers and novel therapies are necessary to improve therapeutic effect and alleviate adverse effect.

METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism.

N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m6A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m6A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m6A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.

A Comprehensive Description of Hypoxia-inducible Factor 2α Inhibitors as Anticancer Agents: A Mini-review.

Targeting the tumor microenvironment is a promising strategy to prevent metastasis, overcome acquired drug resistance, and improve the therapeutic effect. Hypoxia is one of the characteristics of the tumor microenvironment, which is mainly regulated by hypoxia-inducible factors. Hypoxia-inducible factors (HIFs) including HIF-1α, HIF-2α, and HIF-3α, of which HIF-2α has assumed a more important role in tumor hypoxia environment. It has been demonstrated that HIF-2α plays an important role in tumor diseases, including renal cell carcinoma, breast cancer, non-small cell lung cancer, and gastric cancer, among others. Therefore, targeting HIF-2α has become one of the important strategies for treating cancers. HIF-2α inhibitors can be divided into two categories: specific inhibitors and non-specific inhibitors. The former includes synthetic monomer compounds and traditional Chinese medicine extracts. In this review, we summarized, classified, and discussed current research on the structure, structure-activity relationship (SAR), and pharmacology of HIF-2α inhibitors, which is helpful to the rational design of effective drugs for various types of malignant tumors.

Cordycepin improved neuronal synaptic plasticity through CREB-induced NGF upregulation driven by MG-M2 polarization: a microglia-neuron symphony in AD.

PURPOSE: Microglia-neuron crosstalk is critically involved in synaptic plasticity and degeneration by releasing diverse mediators in Alzheimer's disease (AD). Therefore, determining contributors that modulate the systemic microenvironment is essential. Cordycepin (CCS) is a novel neuroprotective compound obtained from Cordyceps militaris. However, the anti-AD efficacy and potential mechanism of CCS treatment remain unclear. This study aimed to elucidate the microglia-neuron symphony in AD after CCS treatment and to explore the possible mechanisms of its neuroprotective efficacy. METHODS AND RESULTS: CCS treatment improved learning and memory impairment in 9-month-old APP/PS1 mice by behavioral tests. CCS polarized the microglia from M1 to M2, inhibited neuronal apoptosis and promoted synaptic remodeling accompanied by in vivo and in vitro upregulation of NGF. The cAMP-response element-binding protein (CREB) was also activated after MG-M2 polarization. Further, we verified that the sg3 promoter region of NGF (-1018 to -1011) is the key binding site for CREB-induced NGF transcription, which increased NGF expression and secretion. Finally, microglia-derived NGF was confirmed as an important mediator in microglia-neuron symphony to improve the neuronal microenvironment after CCS treatment. CONCLUSIONS: CCS improved the neuronal synaptic plasticity and senescence by promoting MG-M2 activation driven by CREB-induced NGF upregulation and facilitated symphony communication between the microglia and neuron in AD. This study provides a new perspective on the development of a novel strategy for anti-AD therapy and offers new targets for anti-AD drug development.