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Cancer vaccines are an approach to elicit amplified antigen-specific immune responses. Induced pluripotent stem cells (iPSC) have potential utility for the development of universal vaccines because of their intrinsic antigenic epitopes. Concurrently, iPSCs can undergo pluripotent differentiation and are thus a stable source of both antigen-presenting cells for producing immune cell-based vaccines and tumor organoids for facilitating the exploration and adaptive assessment of tumor vaccines. This review describes the specific contributions of iPSCs to vaccine development, summarizes their diverse developmental trajectories, and discusses the obstacles to their application along with potential solutions., (©2024 American Association for Cancer Research.)

T-BOX factors belong to an evolutionarily conserved family of transcription factors. T-BOX factors not only play key roles in growth and development but are also involved in immunity, cancer initiation, and progression. Moreover, the same T-BOX molecule exhibits different or even opposite effects in various developmental processes and tumor microenvironments. Understanding the multiple roles of context-dependent T-BOX factors in malignancies is vital for uncovering the potential of T-BOX-targeted cancer therapy. We summarize the physiological roles of T-BOX factors in different developmental processes and their pathological roles observed when their expression is dysregulated. We also discuss their regulatory roles in tumor immune microenvironment (TIME) and the newly arising questions that remain unresolved. This review will help in systematically and comprehensively understanding the vital role of the T-BOX transcription factor family in tumor physiology, pathology, and immunity. The intention is to provide valuable information to support the development of T-BOX-targeted therapy., (© 2024. The Author(s).)

Granzyme B (GrB) is a pivotal killer factor in immunotherapy whose application is limited by hyposensitivity and unsatisfactory cellular uptake by tumor cells. In this study, it was proved that SerpinB9 (Sb9) downregulation can enhance the GrB susceptibility of tumor cells. Moreover, a nanocarrier fused with M1 macrophage exosomes (M1 Exo) and photothermal sensitive liposomes was constructed to efficiently transport GrB and siRNA of Sb9 to the cells. The nanocarrier is characterized by cascade tumor targeting acquired by photothermal effect-triggered increased expression of vascular cell adhesion molecule-1 (VCAM-1) in tumor tissue. Furthermore, the innate cytokines in M1 Exo are capable of regulating the tumor microenvironment by repolarizing M2 macrophages to the M1 type. Collectively, the multifunctional nanoplatform (S+G@ELP) enhances the lethality of GrB to tumor cells, activates a widespread immune response uniting with photothermal therapy (PTT), restrains the tumor progression and metastasis effectively, which is expected to provide new insights into GrB-based combinational tumor therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Biomimetic drug delivery systems offer new opportunities to mimic biological components for enhancing tumor targeting efficiency and promoting therapeutic efficacy. Therefore, in this study, the platelet exosomes and photothermal sensitive liposomes were coalesced and incorporated glucose oxidase (GOx, G) and ferric ammonium (FAC, F) to constitute a laser controlled nanosystem (FG@PEL). Results confirmed that FG@PEL possessed two cascade therapeutic strategies. As the first cascade therapeutic strategy, FG@PEL had achieved cascade targeting effect due to the inheritance of biological property of platelet exosomes to adhere cancer cells and respond on the vascular damage triggered by photothermal effect. Subsequently, GOx was used to oxidize glucose to produce hydrogen peroxide which could be catalyzed by FAC to realize cascade reaction for enhancing chemodynamic therapy (CDT). Meanwhile, photothermal effect could accelerate the reaction rate to further improve the therapeutic effect by producing more hydroxyl radicals. So significant therapeutic effect could be acquired through the synergistic modality of FG@PEL, and the mechanism of mutual promotion among different treatment was also clarified. Hence, this research may provide a promising strategy for curative tumor therapy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: As an efficient tumor immunotherapy, PD-1 antibody has been gradually used in clinical tumor treatment, but the low response rate and excessive immune response limit its extensive application., Results: Herein, a therapeutic regime for the reinvigoration and activation of the tumor immune microenvironment is introduced to improve the anti-tumor effect of the PD-1 antibody. To comprehensively improve the effect of the immunotherapy and reduce excessive immune response, a biomimetic cascade targeting nanosystem, siRNA@PLOV, which was fused by photothermal sensitive liposomes (PTSLs) and attenuated Salmonella outer membrane vesicles (OMVs), was administered in the tumor therapy for targeting of tumor tissues and T cells within tumor respectively. The fused PLOVs which not only retained the biological character of the OMVs, but also enhanced the drug loading ability. The results demonstrated that the immunogenicity of OMVs and photothermal effects can obviously increase the infiltration of T cells and the silencing of CD38 can effectively improve the T cell cytotoxicity, especially combining with PD-1 antibody., Conclusions: Interesting, this study revealed that anti-PD-1 administration on the 5th day after siRNA@PLOV treatment had the best performance in killing tumors compared with other groups. In addition, this new therapeutic regime also presents a novel strategy for inducing "vaccine effects", conclusively highlighting its potential in preventing tumor recurrence and improving prognosis., (© 2021. The Author(s).)

Development of alternative linear peptides for targeting αvβ3 integrin has attracted much attention, as the traditional peptide ligand, cyclic RGD, is limited by inferior water-solubility and complex synthesis. Using pharmacophore-based virtual screening and high-throughput molecular docking, we identified two novel linear small peptides RWr and RWrNM with high affinity and specificity to αvβ3 integrin. The competitive binding with cyclic RGD (c(RGDyK)) and cellular uptake related to the integrin expression levels verified their affinity to αvβ3 integrin. The intermolecular interaction measurement and dynamics simulation demonstrated the high binding affinity and stability, especially for RWrNM. In vivo peptide-guided tumor imaging and targeted therapy further confirmed their specificity. Results indicated that the newly identified small linear peptide RWrNM, with high affinity and specificity to αvβ3 integrin, better water-solubility, and simplified synthetic process, could overcome limitations of the current cyclic RGD peptides, paving the way for diverse use in diagnosis and therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

In response to the challenges of cancer chemotherapeutics, including poor physicochemical properties, low tumor targeting ability, and harmful side effects, we developed a new tumor-targeted multi-small molecule drug delivery platform. Using paclitaxel (PTX) as a model therapeutic, we prepared two prodrugs, ie, folic acid-fluorescein-5(6)-isothiocyanate-arginine-paclitaxel (FA-FITC-Arg-PTX) and folic acid-5-aminofluorescein-glutamic-paclitaxel (FA-5AF-Glu-PTX), composed of folic acid (FA, target), amino acids (Arg or Glu, linker), and fluorescent dye (fluorescein in vitro or near-infrared fluorescent dye in vivo) in order to better understand the mechanism of PTX prodrug targeting. In vitro and acute toxicity studies demonstrated the low toxicity of the prodrug formulations compared with the free drug. In vitro and in vivo studies indicated that folate receptor-mediated uptake of PTX-conjugated multi-small molecule carriers induced high antitumor activity. Notably, compared with free PTX and with PTX-loaded macromolecular carriers from our previous study, this multi-small molecule-conjugated strategy improved the water solubility, loading rate, targeting ability, antitumor activity, and toxicity profile of PTX. These results support the use of multi-small molecules as tumor-targeting drug delivery systems.

Adriamycin (ADM) has been effective against many types of solid tumors in clinical applications. However, its use is limited because of systemic toxicities, primarily cardiotoxicity, and multidrug resistance. In this study, a new active receptor-mediated complex, ADM conjugated with 2-amino-2-deoxy-d-glucose and succinic acid (2DG-SUC-ADM), was designed to target tumor cells through glucose transporter 1 (GLUT1). MTT assay and confocal images showed that the complex had better inhibition rate to tumor cells and low toxicity to normal cells. Most importantly, the complex displayed a potential to reverse overcome multidrug resistance in cancer cells, with more complex transported into the nucleus of tumor cells. Our in vivo experiments also showed that this new complex could significantly decrease organ toxicity and enhance the antitumor efficacy compared with free ADM, indicating a promising drug of 2DG-SUC-ADM for targeted cancer therapy.

A fast clearing hydrophilic near-infrared (NIR) dye ICG-Der-02 was used to constitute tumor targeting contrast agents. Cell adhesion molecule integrin α(v)β(3) served as the target receptor because of its unique expression on almost all sprouting tumor vasculatures. The purpose of this study was to synthesize and compare the properties of integrin α(v)β(3)-targeted, fast clearing NIR probes both in vitro and in vivo for tumor diagnosis. ICG-Der-02 was covalently conjugated to three kinds of RGD peptide including linear, monoeric cyclic and dimeric RGD to form three RGD-based NIR probes. The integrin receptor specificities of these probes were evaluated in vitro by confocal microscopy. The dynamic bio-distribution and elimination ratse were in vivo real-time monitored by a near-infrared imaging system in normal mice. Further, the in vivo tumor targeting abilities of the RGD-based NIR probes were compared in α(v)β(3) -positive MDA-MB-231, U87MG and α(v)β(3)-negtive MCF-7 xenograft mice models. Three RGD-based NIR probes were successfully synthesized with good optical properties. In vitro cellular experiments indicated that the probes have a clear binding affinity to α(υ)β(3) -positive tumor cells, with a cyclic dimeric RGD probe owing the highest integrin affinity. Dynamic bio-distributions of these probes showed a rapid clearing rate through the renal pathway. In vivo tumor targeting ability of the RGD-based porbes was demonstrated on MDA-MB-231 and U87MG tumor models. As expected, the c(RGDyK)(2)-ICG-Der-02 probe displayed the highest tumor-to-normal tissue contrast. The in vitro and in vivo block experiments confirmed the receptor binding specificity of the probes. The hydrophilic dye-labeled NIR probes exhibited a fast clearing rate and deep tissue penetration capability. Further, the α(υ)β(3) receptor affinity of the three RGD-based NIR probes followed the order of dimer cyclic > monomer cyclic > linear. The results demonstrate potent fast clearing probes for in vivo early tumor diagnosis., (Copyright © 2012 John Wiley & Sons, Ltd.)