Cancer treatment experienced a paradigm shift with the emergence of immunotherapy, a method that effectively inhibits cancer progression by activating the patient's immune response. Recent advancements in cancer immunotherapy, particularly checkpoint blockades, adoptive cellular therapies, cancer vaccines, and tumor microenvironment modulation, have yielded remarkable clinical results. However, the broad use of immunotherapy in treating cancer has been limited by a low response rate amongst patients and the presence of side effects, including autoimmune-related toxicities. Nanotechnology's advancements have paved the way for nanomedicine to effectively navigate biological obstacles for successful drug delivery. The design of precise cancer immunotherapy is greatly enhanced by the spatiotemporal control offered by light-responsive nanomedicine. Current research on light-sensitive nanoplatforms is reviewed here, demonstrating their potential for boosting checkpoint blockade immunotherapy, facilitating precise cancer vaccine delivery, activating immune cell responses, and modifying the tumor microenvironment. Highlighting the potential for clinical application of these designs, the challenges to achieving the next major advance in cancer immunotherapy are also discussed.
The prospect of inducing ferroptosis in cancer cells as a therapeutic intervention is being examined in various types of cancer. Tumor-associated macrophages (TAMs) contribute substantially to the worsening of tumor characteristics and the development of resistance to therapeutic interventions. Nonetheless, the parts played by TAMs in the regulation of tumor ferroptosis are still obscure and puzzling. Research into cervical cancer has revealed the therapeutic promise of ferroptosis inducers in both in vitro and in vivo environments. Cervical cancer cell ferroptosis has been found to be impeded by the presence of TAMs. Through a mechanistic action, macrophage-derived miRNA-660-5p, contained within exosomes, are transferred to cancer cells. To inhibit ferroptosis in cancer cells, miRNA-660-5p lessens the expression of ALOX15. In addition, the autocrine IL4/IL13-activated STAT6 pathway is crucial for the upregulation of miRNA-660-5p in macrophages. In cervical cancer, ALOX15 levels demonstrate a negative association with macrophage infiltration, which implies a possible regulatory mechanism through which macrophages might reduce the levels of ALOX15 in these tumors. Additionally, ALOX15 expression, as assessed by both univariate and multivariate Cox regression analysis, proves to be an independent prognostic factor, positively linked to a favorable clinical outcome in cervical cancer. This study, overall, highlights the potential benefits of focusing on TAMs in ferroptosis-based therapies, and ALOX15 as markers of prognosis for cervical cancer.
A close relationship exists between the dysregulation of histone deacetylases (HDACs) and the process of tumor development and progression. As promising targets in anticancer research, HDACs have been a focus of extensive study. Two decades of sustained effort have yielded the approval of five HDAC inhibitors (HDACis). Nevertheless, despite the effectiveness of current HDAC inhibitors in their approved indications, they are plagued by considerable off-target toxicities and a lack of sensitivity to solid tumors, driving the development of advanced HDAC inhibitor classes. This review examines the biological functions of HDACs, the involvement of HDACs in cancer development, the structural characteristics of various HDAC isoforms, isoform-selective inhibitors, combined treatment strategies, agents targeting multiple proteins, and HDAC PROTAC technology. We trust that these data will motivate readers to generate novel HDAC inhibitors featuring optimal isoform specificity, robust anticancer action, reduced adverse reactions, and lessened drug resistance.
The prevalence of neurodegenerative movement disorders is largely dominated by Parkinson's disease. Dopaminergic neurons in the substantia nigra are characterized by the abnormal aggregation of alpha-synuclein (-syn). Protein aggregates and other cellular contents are degraded by the evolutionarily conserved cellular process of macroautophagy (autophagy), ensuring cellular homeostasis. A natural alkaloid, Corynoxine B, also known as Cory B, was identified within the Uncaria rhynchophylla plant. Jacks. has been shown to induce autophagy, leading to the observed clearance of -syn within cellular models. The molecular mechanism by which Cory B induces autophagy is uncertain, and the demonstrated reduction of α-synuclein by Cory B has not been validated in animal tests. This report details Cory B's enhancement of the Beclin 1/VPS34 complex's activity, resulting in heightened autophagy by facilitating the binding of Beclin 1 to HMGB1/2. Cory B-mediated autophagy was compromised by the reduction of HMGB1/2 levels. This study, for the first time, demonstrates that HMGB2, much like HMGB1, is essential for autophagy, and its depletion caused a decrease in autophagy levels and phosphatidylinositol 3-kinase III activity, both in the absence and presence of stimuli. Utilizing a multifaceted approach encompassing cellular thermal shift assay, surface plasmon resonance, and molecular docking, we demonstrated the direct binding of Cory B to HMGB1/2, situated near amino acid C106. Intriguingly, in vivo experiments using a wild-type α-synuclein transgenic Drosophila Parkinson's disease model and an A53T α-synuclein transgenic mouse Parkinson's disease model demonstrated Cory B's role in strengthening autophagy, promoting the elimination of α-synuclein, and improving abnormal behaviors. Cory B's interaction with HMGB1/2 results in an augmentation of phosphatidylinositol 3-kinase III activity and autophagy, a phenomenon proven neuroprotective in Parkinson's disease, according to this study's consolidated results.
Although mevalonate metabolism is pivotal in governing tumor growth and metastasis, its precise role in immune system escape and modulation of immune checkpoints is still elusive. In non-small cell lung cancer (NSCLC) patients, we found a link between a higher plasma mevalonate response and a superior response to anti-PD-(L)1 therapy, as indicated by extended progression-free survival and overall survival. Plasma mevalonate levels were found to be positively correlated with the expression of programmed death ligand-1 (PD-L1) within the tumor. autobiographical memory Mevalonate, when added to NSCLC cell lines and patient-originating cells, produced a significant rise in PD-L1 expression, an effect that was reversed by removing mevalonate, resulting in a decrease in PD-L1 expression. Despite an increase in CD274 mRNA levels brought on by mevalonate, the transcription of CD274 remained unaffected. learn more We subsequently confirmed that mevalonate elevated the stability profile of CD274 mRNA. Mevalonate elevated the attraction of the AU-rich element-binding protein, HuR, to the 3'-untranslated region of the CD274 messenger RNA, thereby increasing the stability of this mRNA. Our in vivo investigation further confirmed that mevalonate administration synergistically increased the anti-tumor effect of anti-PD-L1 therapy, augmenting CD8+ T cell infiltration and improving the cytotoxic function of the T cells. The combined results of our study show a positive association between plasma mevalonate levels and the efficacy of anti-PD-(L)1 antibody treatments, thus suggesting mevalonate supplementation as a potential immunosensitizer in non-small cell lung cancer (NSCLC).
The clinical utilization of c-mesenchymal-to-epithelial transition (c-MET) inhibitors for non-small cell lung cancer, while showing potential, is constrained by the ever-present threat of drug resistance. Immune mechanism Hence, the development of novel strategies specifically targeting c-MET is essential. Employing rational structural optimization, we synthesized novel, exceptionally potent, and orally active c-MET proteolysis targeting chimeras (PROTACs), designated D10 and D15, based on thalidomide and tepotinib scaffolds. In EBC-1 and Hs746T cells, D10 and D15 demonstrated cell growth inhibition with low nanomolar IC50 values, achieving picomolar DC50 values and exceeding 99% of the maximum degradation (Dmax). D10 and D15 demonstrably induced cell apoptosis, G1 cell cycle arrest, and inhibited cell migration and invasion via a mechanistic pathway. Intriguingly, intraperitoneal delivery of D10 and D15 demonstrably curtailed tumor development within the EBC-1 xenograft model, while oral administration of D15 produced near-total tumor regression in the Hs746T xenograft model, employing well-tolerated dose regimens. D10 and D15 exhibited considerable anticancer activity in cells with c-METY1230H and c-METD1228N mutations, which are clinically resistant to tepotinib. The results of this study highlighted D10 and D15 as potential candidates for treating tumors with MET-related alterations.
A rising tide of expectations from both the pharmaceutical industry and healthcare services is impacting new drug discovery efforts. Drug development relies heavily on assessing drug efficacy and safety before human trials, a process that merits more attention to expedite discovery and reduce costs. The combination of microfabrication and tissue engineering has resulted in the creation of organ-on-a-chip, an in vitro system replicating human organ functionalities within the controlled environment of a lab, revealing insights into disease pathologies and providing a potential alternative to animal models for enhancing preclinical drug candidate evaluation. This review initially presents a concise overview of general considerations relevant to the design of organ-on-a-chip devices. Subsequently, we provide a thorough examination of the latest advancements in organ-on-a-chip technology for pharmaceutical screening applications. Concluding our discussion, we identify the main challenges hindering the advancement of this field and explore the future directions of organ-on-a-chip development. In essence, this review underscores the crucial role organ-on-a-chip platforms play in the evolution of pharmaceutical innovation, the development of groundbreaking therapies, and precision medicine.