Nanoparticle-Based Drug Delivery Systems Targeting Tumor Microenvironment for Cancer Immunotherapy Resistance: Current Advances and Applications
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Cancer immunotherapy has shown impressive anti-tumor activity in patients with advanced and early-stage malignant tumors, thus improving long-term survival. However, current cancer immunotherapy is limited by barriers such as low tumor specificity, poor response rate, and systemic toxicities, which result in the development of primary, adaptive, or acquired resistance. Immunotherapy resistance has complex mechanisms that depend on the interaction between tumor cells and the tumor microenvironment (TME). Therefore, targeting TME has recently received attention as a feasibility strategy for re-sensitizing resistant neoplastic niches to existing cancer immunotherapy. With the development of nanotechnology, nanoplatforms possess outstanding features, including high loading capacity, tunable porosity, and specific targeting to the desired locus. Therefore, nanoplatforms can significantly improve the effectiveness of immunotherapy while reducing its toxic and side effects on non-target cells that receive intense attention in cancer immunotherapy. This review explores the mechanisms of tumor microenvironment reprogramming in immunotherapy resistance, including TAMs, CAFs, vasculature, and hypoxia. We also examined whether the application of nano-drugs combined with current regimens is improving immunotherapy clinical outcomes in solid tumors.Keywords:
Cancer Immunotherapy
Reprogramming
This chapter contains sections titled: Introduction Reprogramming during Fertilization Reprogramming during Somatic Cell Nuclear Transfer (SCNT) Reprogramming with Cell Extracts Reprogramming with Transcription Factors: Induced Pluripotent Stem (iPS) Cells Conclusion References
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Pluripotent stem cells (PSCs) derived from somatic cells represent a powerful experimental tool for investigating the molecular mechanisms underlying the disease phenotype; with prospects to advance medical therapies. They also have significant potential as a renewable source of autologous cells for cellular therapy. Various approaches for PSC derivation from somatic cells have been reported in the literature. The method used for reprogramming is particularly relevant as it may affect the characteristics and quality of PSCs. This review will present an overview of the basic strategies and methods for reprogramming to pluripotency. These strategies will be briefly discussed in the context of how the mechanism of reprogramming could influence PSC characteristics with respect to safety and quality. Aspects of the reprogramming approach that can influence PSC properties, such as culture conditions and donor cell source, are also discussed. Keywords: iPSCs, nuclear reprogramming, pluripotent stem cells, reprogramming, reprogramming strategies, reprogramming technology.
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Induced pluripotent stem cells (iPSCs) can be generated from somatic cells by ectopically expressing a set of reprogramming factors. iPSCs hold tremendous promise for cell replacement therapy, drug discovery, and disease modeling. However, the efficiency of iPSC generation is extremely low and the quality of derived iPSCs is often poor. Many small molecules that are able to improve reprogramming by either modifying epigenetic barriers or targeting signaling pathways have recently been identified. Chemical compounds are a unique tool that can not only facilitate reprogramming but perhaps also improve our understanding of the reprogramming mechanism that allows us to generate safe iPSCs for therapeutic use.
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Functional reprogramming of a differentiated cell toward pluripotent cell may have long-term applications in numerous aspects, especially in regenerative medicine. Evidences accumulating from recent studies suggest that cellular extracts from stem cells or pluripotent cells can induce epigenetic reprogramming and facilitate pluripotency in otherwise highly differentiated cell types. Epigenetic reprogramming using cellular extracts has gained increasing attention and applied to recognize the functional factors, acquire the target cell types, and explain the mechanism of reprogramming. Now, more and more researches have proved that cellular extract treatment is an important strategy of cellular reprogramming. Thus, this review mainly focused on the progresses and potential mechanisms in epigenetic reprogramming using cellular extracts.
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Cancer immunotherapy has been a favorable strategy for facilitating antitumor immunity. However, immune tolerance and an ultimate immunosuppressive tumor microenvironment (ITM) are primary obstacles. To achieve the goals of remodeling the ITM and promoting cancer immunotherapy, a versatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown siRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly induce the immunogenic cell death (ICD) of tumor cells, leading to increased dendritic cell maturation. Moreover, SK/siR-NPs can cause an efficacious inhibition of PD-L1, leading to enhanced cytotoxic T lymphocyte response to tumor cells. Most importantly, SK/siR-NPs can restrain lactate production via the downregulation of pyruvate kinase-M2 (PKM2) and eventually repolarize tumor associated macrophages (TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs suppress regulatory T lymphocytes to fight with the ITM. Overall, the developed co-delivery system presents a significant potential for cancer immunotherapy through simultaneously inducing ICD, repolarizing M2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.
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Abstract Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.
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Direct reprogramming of somatic cells into a pluripotent state has been achieved with a set of just four transcription factors. Many scientists and medical doctors are trying to elucidate the causes of intractable diseases and discover new drugs using the newest types of technology. Various methods have been developed to produce clinical‐grade fully reprogrammed cells for cell transplantation therapy. Augmenting agents, such as small‐molecules, have been extensively screened to improve the reprogramming efficiency. The molecular mechanisms of reprogramming have been revealed by embryonic stem cell research. The accumulation of knowledge by the pioneers has driven the reprogramming field. In the present article, the contents of gift boxes from the studies of pluripotency to the nuclear reprogramming field are introduced.
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Nanoscience has long been lauded as a method through which tumor-associated barriers could be overcome. As successful as cancer immunotherapy has been, limitations associated with the tumor microenvironment or side effects of systemic treatment have become more apparent. In this Review, we seek to lay out the therapeutic challenges associated with the tumor microenvironment and the ways in which nanoscience is being applied to remodel the tumor microenvironment and increase the susceptibility of many cancer types to immunotherapy. We detail the nanomedicines on the cutting edge of cancer immunotherapy and how their interactions with the tumor microenvironment make them more effective than systemically administered immunotherapies.
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The slow and inefficient of reprogramming of somatic cells in mammals imposes limitations to mechanistic studies and potential clinical translation.The reprogramming progress involves the changes of cellular genes expression,understanding and controlling epigenetic modification is the key to successful reprogramming.Here,we reviewed progresses on epigenetic influences on gene expression,epigenetic control in dedifferentiation and transdifferentiation,the usage of chemical inhibitors and signaling molecules that could either enhance reprogramming efficiency or replace core reprogramming factors in order to benefit the elucidation of reprogramming of somatic cells and provide reference for the formation of pluripotent stem cells induced from differentiated somatic cells with only chemicals.
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