Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface-conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo.

Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery

Abstract The use of nanotechnology has the potential to revolutionize the detection and treatment of cancer. Developments in protein engineering and materials science have led to the emergence of new nanoscale targeting techniques, which offer renewed hope for cancer patients. While several nanocarriers for medicinal purposes have been approved for human trials, only a few have been authorized for clinical use in targeting cancer cells. In this review, we analyze some of the authorized formulations and discuss the challenges of translating findings from the lab to the clinic. This study highlights the various nanocarriers and compounds that can be used for selective tumor targeting and the inherent difficulties in cancer therapy. Nanotechnology provides a promising platform for improving cancer detection and treatment in the future, but further research is needed to overcome the current limitations in clinical translation. Graphical Abstract 

Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation

Both T-cell deprivation and insufficient tumor immunogenicity seriously hinder the efficacy of immune-mediated tumor destruction in melanoma. In this work, an amphiphilic polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane) copolymer with a thermally sensitive flowable core (mPEG-b-PHEP) was chosen to incorporate IR780 dye and manganese zinc sulfide nanoparticles (ZMS) to form polymer micelles (denoted PPIR780-ZMS), which precisely controlled the release of ZMS after being triggered by near-infrared light (NIR). Mn2+-mediated chemodynamic therapy (CDT) by photothermal trigger boosted the generation of reactive oxygen species (ROS), making the PPIR780-ZMS smart bomblets in vivo. It was demonstrated that PPIR780-ZMS could maximize immunogenic cell death (ICD) in cancer, which is characterized by abundant damage-associated molecular pattern (DAMP) exposure. As a result, the cytotoxic T cells (CD8+) and helper T cells (CD4+) expanded and infiltrated the neoplastic foci, which further reprogrammed the suppressive tumor microenvironment (TME) against the primary tumor and pulmonary metastases with safe systemic cytokine expression. In addition, Mn2+-mediated cGAS-STING signaling pathway activation enhanced the antitumor immunity of this nanocomposite, providing a practical strategy for expanding the use of Mn-based nanostructures.

Immunogenic Cell Death Augmented by Manganese Zinc Sulfide Nanoparticles for Metastatic Melanoma Immunotherapy.

https://doi.org/10.1016/j.apsb.2022.11.001

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

Despite their potential, conventional whole-cell cancer vaccines prepared by freeze–thawing or irradiation have shown limited therapeutic efficacy in clinical trials. Recent studies have indicated that cancer cells treated with certain chemotherapeutics, such as mitoxantrone, can undergo immunogenic cell death (ICD) and initiate antitumor immune responses. However, it remains unclear how to exploit ICD for cancer immunotherapy. Here, we present a new material-based strategy for converting immunogenically dying tumor cells into a powerful platform for cancer vaccination and demonstrate their therapeutic potential in murine models of melanoma and colon carcinoma. We have generated immunogenically dying tumor cells surface-modified with adjuvant-loaded nanoparticles. Dying tumor cells laden with adjuvant nanodepots efficiently promote activation and antigen cross-presentation by dendritic cells in vitro and elicit robust antigen-specific CD8α+ T-cells in vivo. Furthermore, whole tumor-cell vaccination combin...

Immunogenic Cell Death Amplified by Co-localized Adjuvant Delivery for Cancer Immunotherapy

Immunotherapy techniques, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cell therapies and cancer vaccines, have been burgeoning with great success, particularly for specific cancer types. However, side effects with fatal risks, dysfunction in tumor microenvironment and low immune response rates remain the bottlenecks in immunotherapy. Nano metal-organic frameworks (nMOFs), with an accurate structure and a narrow size distribution, are emerging as a solution to these problems. In addition to their function of temporospatial delivery, a large library of their compositions, together with flexibility in chemical interaction and inherent immune efficacy, offers opportunities for various designs of nMOFs for immunotherapy. In this review, we overview state-of-the-art research on nMOFs-based immunotherapies as well as their combination with other therapies. We demonstrate that nMOFs are predominantly customized for vaccine delivery or tumor-microenvironment modulation. Finally, a prospect of nMOFs in cancer immunotherapy will be discussed.

/pdf/bioengineering-of-nano-metal-organic-frameworks-for-cancer-2kqfsgs123.pdf

Bioengineering of nano metal-organic frameworks for cancer immunotherapy

Abstract As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44−CXCR2− neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.

/pdf/a-yap-taz-cd54-axis-is-required-for-cxcr2-cd44-tumor-1q7taea7.pdf

A YAP/TAZ-CD54 axis is required for CXCR2−CD44− tumor-specific neutrophils to suppress gastric cancer

Pyroptosis is a novel form of programmed cell death (PCD), which is characterized by DNA fragmentation, chromatin condensation, cell swelling and leakage of cell contents. The process of pyroptosis is performed by certain inflammasome and executor gasdermin family member. Previous researches have manifested that pyroptosis is closely related to human diseases (such as inflammatory diseases) and malignant tumors, while the regulation mechanism of pyroptosis is not yet clear. Non-coding RNA (ncRNA) such as microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) have been widely identified in the genome of eukaryotes and played a paramount role in the development of cell function and fate after transcription. Accumulating evidences support the importance of ncRNA biology in the hallmarks of pyroptosis. However, the associations between ncRNA and pyroptosis are rarely reviewed. In this review, we are trying to summarize the regulation and function of ncRNA in cell pyroptosis, which provides a new research direction and ideas for the study of pyroptosis in different diseases.

/pdf/regulation-of-pyroptosis-by-ncrna-a-novel-research-direction-1ziagaf8.pdf

Regulation of Pyroptosis by ncRNA: A Novel Research Direction

Chronic liver injury could gradually progress to liver fibrosis, cirrhosis, and even hepatic carcinoma without effective treatment. The massive production and activation of abnormal cell differentiation is vital to the procession of liver diseases. Epithelial-mesenchymal transformation (EMT) is a biological process in which differentiated epithelial cells lose their epithelial characteristics and acquire mesenchymal cell migration capacity. Emerging evidence suggests that EMT not only occurs in the process of hepatocellular carcinogenesis, but also appears in liver cells transforming to myofibroblasts, a core event of liver disease. Non-coding RNA (ncRNA) such as microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA) are important regulatory factors in EMT, which can regulate target gene expression by binding with RNA single-stranded. Various studies had shown that ncRNA regulation of EMT plays a key role in liver disease development, and many effective ncRNAs have been identified as promising biomarkers for the diagnosis and treatment of liver disease. In this review, we focus on the relationship between the different ncRNAs and EMT as well as the specific molecular mechanism in the liver diseases to enrich the pathological progress of liver diseases and provide reference for the treatment of liver diseases. 

Non-coding RNAs regulating epithelial-mesenchymal transition: Research progress in liver disease.

It has been suggested that immunogenic cell death (ICD) has therapeutic potential; however, its anticancer immunity is considerably hampered by the in situ immunosuppressive microenvironment within the tumor area, such as the dysfunction of antigen-presenting cells. Herein, we present an in vitro ICD-inducing modality to circumvent such impairment of immune activation. To this end, a "hot", i.e., immunogenic, whole tumor cell vaccine is generated in vitro and subcutaneously vaccinated in the normal tissue, departing from the site of the in situ immunosuppressive tumor area, to fully leverage the ICD-inducing antitumor immunity. In particular, the immunogenic dying tumor cells, caged by cellular disulfide-thiol exchange, are mediated by photoactivation. After subcutaneous vaccination, the photoactivated caged live cell vaccine (CLCV) exerts multi-durable immunostimulatory property, which, when adjuvanted by CpG, efficiently promotes dendritic cell (DC) activation and elicits robust CD8+ T-cell responses in vivo. Importantly, the generated T-cell responses are shown to protect 75% mice preimmunized with CLCV against tumor initiation and significantly retards tumor growth in the therapeutic setting. The strategy presented here may help to enrich the current vaccine design for cancer immunotherapy.

A vaccine for photodynamic immunogenic cell death: tumor cell caged by cellular disulfide–thiol exchange for immunotherapy

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