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.

Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer Therapy.

A series of successes in RNA interference (RNAi) therapies for liver diseases using lipid nanoparticles and -acetylgalactosamine have heralded a current era of RNA therapeutics. However, alternative delivery strategies are required to take RNAi out of the comfort zone of hepatocytes. Here we report SIRPα IgV/anti-CD47 siRNA (vS-siCD47) conjugates that selectively and persistently disrupt the antiphagocytic CD47/SIRPα axis in solid tumors.

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.

Extracellular Vesicles in Therapeutics: A Comprehensive Review on Applications, Challenges, and Clinical Progress.

Small Extracellular Vesicles (sEVs) are typically 30-150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of functions or differentiation of target cells. Owing to these properties, sEVs have recently gained attention as potential carriers for functional molecules and drug delivery tools.

Selective Suppression of Integrin-Ligand Binding by Single Molecular Tension Probes Mediates Directional Cell Migration.

Cell migration interacting with continuously changing microenvironment, is one of the most essential cellular functions, participating in embryonic development, wound repair, immune response, and cancer metastasis. The migration process is finely tuned by integrin-mediated binding to ligand molecules. Although numerous biochemical pathways orchestrating cell adhesion and motility are identified, how subcellular forces between the cell and extracellular matrix regulate intracellular signaling for cell migration remains unclear.

Fugetaxis of Cell-in-Catalytic-Coat Nanobiohybrids in Glucose Gradients.

Manipulation and control of cell chemotaxis remain an underexplored territory despite vast potential in various fields, such as cytotherapeutics, sensors, and even cell robots. Herein is achieved the chemical control over chemotactic movement and direction of Jurkat T cells, as a representative model, by the construction of cell-in-catalytic-coat structures in single-cell nanoencapsulation. Armed with the catalytic power of glucose oxidase (GOx) in the artificial coat, the nanobiohybrid cytostructures, denoted as Jurkat , exhibit controllable, redirected chemotactic movement in response to d-glucose gradients, in the opposite direction to the positive-chemotaxis direction of naïve, uncoated Jurkat cells in the same gradients.

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.

Gulp1 deficiency augments bone mass in male mice by affecting osteoclasts due to elevated 17β-estradiol levels.

The engulfment adaptor phosphotyrosine-binding domain containing 1 (GULP1) is an adaptor protein involved in the engulfment of apoptotic cells via phagocytosis. Gulp1 was first found to promote the phagocytosis of apoptotic cells by macrophages, and its role in various tissues, including neurons and ovaries, has been well studied. However, the expression and function of GULP1 in bone tissue are poorly understood.

TGFBI remodels adipose metabolism by regulating the Notch-1 signaling pathway.

Extracellular matrix proteins are associated with metabolically healthy adipose tissue and regulate inflammation, fibrosis, angiogenesis, and subsequent metabolic deterioration. In this study, we demonstrated that transforming growth factor-beta (TGFBI), an extracellular matrix (ECM) component, plays an important role in adipose metabolism and browning during high-fat diet-induced obesity. TGFBI KO mice were resistant to adipose tissue hypertrophy, liver steatosis, and insulin resistance.

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.

Nuclear transport of STAT6 determines the matrix rigidity dependent M2 activation of macrophages.

Alternatively activated or M2 macrophages, as opposed to the well characterized pro-inflammatory or M1 macrophages, vitally regulate anti-inflammation, wound healing, and tissue repair to maintain tissue homeostasis. Although ubiquitous presence of macrophages in diverse tissues, exposed to different physical environments, infers distinct immune responses of M2 macrophages with high phenotypic heterogeneity, the underlying mechanism of how the varying extracellular mechanical conditions alter their immunological activation remains unclear. Here, we demonstrate that M2 activation requires a threshold mechanical cue from the extracellular microenvironment, and matrix rigidity-dependent macrophage spreading is mediated by the F-actin formation that is essential to regulate mechanosensitive M2 activation of macrophages.

Ferritin - a multifaceted protein scaffold for biotherapeutics.

The ferritin nanocage is an endogenous protein that exists in almost all mammals. Its hollow spherical structure that naturally stores iron ions has been diversely exploited by researchers in biotherapeutics. Ferritin has excellent biosafety profiles, and the nanosized particles exhibit rapid dispersion and controlled/sustained release pharmacokinetics.

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.

Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment.

Solid cancers are composed of malignant cells and their surrounding matrix components. Hypoxia plays a critical role in shaping the tumor microenvironment that contributes to cancer progression and treatment failure. Cancer-associated fibroblasts (CAFs) are one of the most prominent components of the tumor microenvironment.

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.

Targeting angiogenic growth factors using therapeutic glycosaminoglycans on doppel-expressing endothelial cells for blocking angiogenic signaling in cancer.

Growth factors (GF) regulate normal development to cancer progression. GFs interact with extracellular matrix (ECM) biomolecules, such as heparin sulfate (HS) glycosaminoglycan (GAG), to enhance their stability and angiogenic signaling. Biomaterials that modulate GF activity by mimicking interactions observed in the native ECM could be designed as an effective treatment strategy.

Rho-Kinase as a Target for Cancer Therapy and Its Immunotherapeutic Potential.

Cancer immunotherapy is fast rising as a prominent new pillar of cancer treatment, harnessing the immune system to fight against numerous types of cancer. Rho-kinase (ROCK) pathway is involved in diverse cellular activities, and is therefore the target of interest in various diseases at the cellular level including cancer. Indeed, ROCK is well-known for its involvement in the tumor cell and tumor microenvironment, especially in its ability to enhance tumor cell progression, migration, metastasis, and extracellular matrix remodeling.

Fibrinolytic nanocages dissolve clots in the tumor microenvironment, improving the distribution and therapeutic efficacy of anticancer drugs.

Fibrin, one of the components of the extracellular matrix (ECM), acts as a transport barrier within the core of tumors by constricting the blood vessels and forming clots, leading to poor intratumoral distribution of anticancer drugs. Our group previously developed a microplasmin-based thrombolytic ferritin nanocage that efficiently targets and dissolves clots without causing systemic fibrinolysis or disrupting hemostatic clots. We hypothesized that the thrombolytic nanocage-mediated degradation of fibrin clots in the tumor ECM can lead to enhanced intratumoral drug delivery, especially for nanosized anticancer drugs.

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.

Caspase-cleavable peptide-doxorubicin conjugate in combination with CD47-antagonizing nanocage therapeutics for immune-mediated elimination of colorectal cancer.

Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8 T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.

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.