Immunogenic clearance combined with PD-1 blockade elicits antitumor effect by promoting the recruitment and expansion of the effector memory-like CD8T cell.

Immune checkpoint inhibition shows promise for cancer treatment, but only a minority of patients respond. Combination strategies have been explored to overcome this resistance. Combining immunogenic clearance using immunogenic cell death inducers with a rho kinase inhibitor enhances phagocytosis of immunogenically dying cancer cells by antigen-presenting cells, stimulating tumor-specific immune responses by activating CD8T cells via dendritic cell-mediated priming.

Novel insights into paclitaxel's role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment.

Background: Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear.

Methods: We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients.

The identification of effective tumor-suppressing neoantigens using a tumor-reactive TIL TCR-pMHC ternary complex.

Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUS and VACINUS VACINUS incorporates physical binding between peptides and MHCs (pMHCs), and VACINUS integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs).

Novel Personalized Cancer Vaccine Using Tumor Extracellular Vesicles with Attenuated Tumorigenicity and Enhanced Immunogenicity.

Cancer vaccines offer a promising avenue in cancer immunotherapy by inducing systemic, tumor-specific immune responses. Tumor extracellular vesicles (TEVs) are nanoparticles naturally laden with tumor antigens, making them appealing for vaccine development. However, their inherent malignant properties from the original tumor cells limit their direct therapeutic use.

Harnessing Oncolytic Extracellular Vesicles for Tumor Cell-Preferential Cytoplasmic Delivery of Misfolded Proteins for Cancer Immunotherapy.

In this study, extracellular vesicles (EVs) are reimagined as more than just a cellular waste disposal system and are repurposed for cancer immunotherapy. Potent oncolytic EVs (bRSVF-EVs) loaded with misfolded proteins (MPs) are engineered, which are typically considered cellular debris. By impairing lysosomal function using bafilomycin A1 and expressing the respiratory syncytial virus F protein, a viral fusogen, MPs are successfully loaded into the EVs expressing RSVF.

Protein-based nanocages for vaccine development.

Protein nanocages have attracted considerable attention in various fields of nanomedicine due to their intrinsic properties, including biocompatibility, biodegradability, high structural stability, and ease of modification of their surfaces and inner cavities. In vaccine development, these protein nanocages are suited for efficient targeting to and retention in the lymph nodes and can enhance immunogenicity through various mechanisms, including excellent uptake by antigen-presenting cells and crosslinking with multiple B cell receptors. This review highlights the superiority of protein nanocages as antigen delivery carriers based on their physiological and immunological properties such as biodistribution, immunogenicity, stability, and multifunctionality.

Advantage of extracellular vesicles in hindering the CD47 signal for cancer immunotherapy.

The cluster of differentiation 47 (CD47) protein is abundantly expressed on various malignant cells and suppresses the phagocytic function of macrophages and dendritic cells. High CD47 expression levels are correlated with poor cancer survival. Antagonizing CD47 antibodies with potent antitumor effects have been developed in clinical trials, but have critical side effects, inducing anemia and thrombocytopenia.

A Multivalent Vaccine Based on Ferritin Nanocage Elicits Potent Protective Immune Responses against SARS-CoV-2 Mutations.

The SARS-CoV-2 pandemic has created a global public crisis and heavily affected personal lives, healthcare systems, and global economies. Virus variants are continuously emerging, and, thus, the pandemic has been ongoing for over two years. Vaccines were rapidly developed based on the original SARS-CoV-2 (Wuhan-Hu-1) to build immunity against the coronavirus disease.

Statin in combination with cisplatin makes favorable tumor-immune microenvironment for immunotherapy of head and neck squamous cell carcinoma.

The purpose of this study was to determine whether statins can enhance anticancer effects in head and neck squamous cell carcinoma (HNSCC) when used with cisplatin and act as immunogenic cell death (ICD) inducers that can be used in cancer immunotherapy. Statins alone showed both in vitro and in vivo inhibitory effects against HNSCC, and synergistic antitumor effects were observed when combined with cisplatin in a syngeneic murine HNSCC model. Statins increased calreticulin exposure and endoplasmic reticulum stress-related signals in HNSCC cells.

Nanocages displaying SIRP gamma clusters combined with prophagocytic stimulus of phagocytes potentiate anti-tumor immunity.

Antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), play a crucial role in bridging innate and adaptive immunity; thereby, innate immune checkpoint blockade-based therapy is an attractive approach for the induction of sustainable tumor-specific immunity. The interaction between the cluster of differentiation 47 (CD47) on tumor and signal-regulatory protein alpha (SIRPα) on phagocytic cells inhibits the phagocytic function of APCs, acting as a "don't eat me" signal. Accordingly, CD47 blockade is known to increase tumor cell phagocytosis, eliciting tumor-specific CD8 T-cell immunity.

Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer.

Background: Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of -mutant () tumors.

Cancer-activated doxorubicin prodrug nanoparticles induce preferential immune response with minimal doxorubicin-related toxicity.

The effective chemotherapeutic drug, doxorubicin (DOX), elicits immunogenic cell death (ICD) and additional anticancer immune responses during chemotherapy. However, it also induces severe side effects and systemic immunosuppression, hampering its wide clinical application. Herein, we constructed cancer-activated DOX prodrug by conjugating the cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in FRRG-DOX that self-assembled into cancer-activated DOX prodrug nanoparticles (CAP-NPs).

Design of PD-1-decorated nanocages targeting tumor-draining lymph node for promoting T cell activation.

Targeted delivery of immunomodulatory molecules to the lymph nodes is an attractive means of improving the efficacy of anti-cancer immunotherapy. In this study, to improve the efficacy of PD-1 blockade-based therapy, nanocages were designed by surface engineering to decorate a programmed cell death protein 1 (PD-1) that is capable of binding against programmed death-ligand 1 (PD-L1) and -ligand 2 (PD-L2). This nanocage-mediated multivalent interaction remarkably increases the binding affinity and improves the antagonistic activity compared to free soluble PD-1.

In situ immunogenic clearance induced by a combination of photodynamic therapy and rho-kinase inhibition sensitizes immune checkpoint blockade response to elicit systemic antitumor immunity against intraocular melanoma and its metastasis.

Background: Uveal melanoma (UM) is the most frequent intraocular malignancy and is resistant to immunotherapy. Nearly 50% of patients with UM develop metastatic disease, and the overall survival outcome remains very poor. Therefore, a treatment regimen that simultaneously targets primary UM and prevents metastasis is needed.

Overcoming therapeutic efficiency limitations against TRAIL-resistant tumors using re-sensitizing agent-loaded trimeric TRAIL-presenting nanocages.

Tumor-specific apoptosis-inducing ligands have attracted considerable attention in cancer therapy. But, the evasion of apoptosis by tumors can cause acquired resistance to the therapy. TNF-related apoptosis-inducing ligand (TRAIL) has been investigated as an ideal antitumor agent owing to its inherent tumor cell-specific apoptotic activity.

The right Timing, right combination, right sequence, and right delivery for Cancer immunotherapy.

Cancer immunotherapy (CI) represented by immune checkpoint inhibitors (ICIs) presents a new paradigm for cancer treatment. However, the types of cancer that attain a therapeutic benefit from ICIs are limited, and the efficacy of these treatments does not meet expectations. To date, research on ICIs has mainly focused on identifying biomarkers and patient characteristics that can enhance the therapeutic effect on tumors.

Emerging Prospects of Exosomes for Cancer Treatment: From Conventional Therapy to Immunotherapy.

Exosomes are a class of extracellular vesicles of around 100 nm in diameter that are secreted by most cells and contain various bioactive molecules reflecting their cellular origin and mediate intercellular communication. Studies of these exosomal features in tumor pathogenesis have led to the development of therapeutic and diagnostic approaches using exosomes for cancer therapy. Exosomes have many advantages for conveying therapeutic agents such as small interfering RNAs, microRNAs, membrane-associated proteins, and chemotherapeutic compounds; thus, they are considered a prime candidate as a delivery tool for cancer treatment.

Xenogenization of tumor cells by fusogenic exosomes in tumor microenvironment ignites and propagates antitumor immunity.

Many cancer patients not responding to current immunotherapies fail to produce tumor-specific T cells for various reasons, such as a lack of recognition of cancer cells as foreign. Here, we suggest a previously unidentified method for xenogenizing (turning self to non-self) tumors by using fusogenic exosomes to introduce fusogenic viral antigens (VSV-G) onto the tumor cell surface. We found that xenogenized tumor cells were readily recognized and engulfed by dendritic cells; thereby, tumor antigens were efficiently presented to T lymphocytes.

Functionalized exosome harboring bioactive molecules for cancer therapy.

Exosomes are nanosized vesicles with a lipid membrane that are secreted by most cells and play a crucial role as intermediates of intercellular communication because they carry bioactive molecules. Exosomes are promising for drug delivery of chemicals, proteins, and nucleic acids owing to their inherent properties such as excellent biocompatibility, high tumor targetability, and prolonged circulation in vivo. In this review, we cover recent approaches and advances made in the field of exosome-mediated delivery of bioactive molecules for cancer therapy and factors that affect the clinical use of exosomes.

Dendritic cell activation by an E. coli-derived monophosphoryl lipid A enhances the efficacy of PD-1 blockade.

Cancer immunotherapy is a powerful approach for cancer treatment, but its clinical effects rely on the tumor's immune conditions. In particular, low response rates to PD-1 blockades are highly correlated with impaired T cell priming. Here, we demonstrate that E.

Targeted delivery of anti-inflammatory cytokine by nanocarrier reduces atherosclerosis in Apo E mice.

Unresolved inflammation is a hallmark of many deadly diseases including atherosclerosis, a silent pathological condition behind majority of cardiovascular diseases. Yet, anti-inflammatory drugs are not clinically used in the treatment of patients with atherosclerosis. The currently approved treatment regimen against atherosclerosis is mainly focused on lowering the cholesterol/lipid levels in blood and has little to do with controlling inflammation, the underlying cause.

Degradation of tumour stromal hyaluronan by small extracellular vesicle-PH20 stimulates CD103 dendritic cells and in combination with PD-L1 blockade boosts anti-tumour immunity.

Highly accumulated hyaluronan (HA) not only provides a physiological barrier but also supports an immune-suppressive tumour microenvironment. High-molecular-weight (HMW)-HA inhibits the activation of immune cells and their access into tumour tissues, whereas, low-molecular-weight oligo-HA is known to potentially activate dendritic cells (DCs). In this paper, we investigated whether small extracellular vesicle (EVs)-PH20 hyaluronidase induces tumour HA degradation, which, in turn, activates DCs to promote anti-cancer immune responses.

Intrinsic cancer vaccination.

Immunotherapy is revolutionizing the treatment of cancer, and the current immunotherapeutics have remarkably improved the outcomes for some cancer patients. However, we still need answers for patients with immunologically cold tumors that do not benefit from the current immunotherapy treatments. Here, we suggest a novel strategy that is based on using a very old and sophisticated system for cancer immunotherapy, namely "intrinsic cancer vaccination", which seeks to awaken our own immune system to activate tumor-specific T cells.

An optimized protocol to determine the engulfment of cancer cells by phagocytes using flow cytometry and fluorescence microscopy.

The engulfment of cancer cells by macrophages is an important cellular process in innate cancer immunity. Antitumor immunotherapy that utilizes the enhanced engulfment of cancer cells by phagocytic cells has attracted much attention. Therefore, there is a growing demand for methods of measuring cancer cell phagocytosis.