Skeletal muscle regeneration is a complex process that depends on the interplay between immune responses and muscle stem cell (MuSC) activity. Macrophages play a crucial role in this process, exhibiting distinct polarization states-M1 (pro-inflammatory) and M2 (anti-inflammatory)-that significantly affect tissue repair outcomes. Recent advancements in nanomedicine have positioned gold nanoparticles (Au NPs) as promising tools for modulating macrophage polarization and enhancing muscle regeneration. This review examines the role of Au NPs in influencing macrophage behavior, focusing on their physicochemical properties, biocompatibility, and mechanisms of action. We discuss how Au NPs can promote M2 polarization, facilitating tissue repair through modulation of cytokine production, interaction with cell surface receptors, and activation of intracellular signaling pathways. Additionally, we highlight the benefits of Au NPs on MuSC function, angiogenesis, and extracellular matrix remodeling. Despite the potential of Au NPs in skeletal muscle regeneration, challenges remain in optimizing nanoparticle design, developing targeted delivery systems, and understanding long-term effects. Future directions should focus on personalized medicine approaches and combination therapies to enhance therapeutic efficacy. Ultimately, this review emphasizes the transformative potential of Au NPs in regenerative medicine, offering hope for improved treatments for muscle injuries and diseases.

Therapeutic strategies aiming at the tumor immune microenvironment (TIME) hold promise for glioblastoma (GBM) treatment. However, adjuvant immunotherapies targeting checkpoint inhibitors just prove effective for a selected group of GBM patients. The extensive involvement of GBM-associated macrophages highlights their potential role in tumor behavior. In-depth exploration of the impact of macrophages on the efficacy of immunotherapy is crucial for enhancing treatment outcomes. In this study, we conducted a comprehensive analysis using bulk RNA-seq, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics to explore the heterogeneity of tumor-associated macrophages (TAMs) in GBM. Flow cytometry was employed to investigate the effects of VSIG4 on TAM phenotypes, and co-culture cellular assays were performed to evaluate its contribution to GBM malignancy. Integrating 16 patient samples, we examined the immunological significance of VSIG4+S100A10+TAMs. VSIG4 expression on macrophages is significantly upregulated and correlated with the TIME, promoting the polarization of macrophages towards M2 and facilitating GBM progression. Spatial transcriptomics and human samples multiplex immunofluorescence (mIF) confirmed the co-localization of VSIG4+S100A10+TAMs with various T cells, resulting in the inhibition of T cell immune responses and a reduction in anti-tumor immunity. Our findings demonstrate for the first time that VSIG4+S100A10+TAM is an independent prognostic indicator of poor outcome for GBM and markedly accumulates in patients exhibiting non-responsiveness to anti-PD-1 immunotherapy. Targeting this specific bifunctional subgroup can potentially open up new avenues for the immunotherapy of GBM.

Colorectal cancer (CRC) is the second most common malignant tumor in the world. With its increasing incidence and younger age trend, its impact on human health has been paid more and more attention. Currently, we have a variety of chemotherapy drugs that can be used to treat colorectal cancer. However, the drug resistance of colorectal cancer has become a significant factor affecting its cure rate. Some studies have reported that exosomes are related to the occurrence of drug resistance. However, the exact mechanism is not precise. Therefore, we focused on the role of cancer associated-fibroblast-derived (CAFs-derived) exosomes in colorectal progression. It was found that cancer cells transmit information through exosome interaction and induce chemotherapy resistance by promoting epithelial-mesenchymal transition (EMT), up-regulating the Wnt/β-catenin signaling pathway, transforming growth factor-β1 (TGF-β1) pathway, promoting angiogenesis and other possible molecular mechanisms. In addition, in terms of clinical significance and therapeutic strategies, we explore the clinical relevance of CAFs-derived exosomes in colorectal cancer patients and their potential as potential biomarkers for predicting chemotherapy response. We also provide a new possible direction for overcoming chemotherapy resistance in colorectal cancer by targeting CAFs-derived exosomes.

Ovarian cancer is a malignant tumor that arises in the female reproductive system and is associated with a very high mortality rate. This is primarily due to the highly invasive nature of metastasis and recurrence. Transforming the immune environment from an immunosuppressive state to an anti-tumor state through the phenotypic transformation of tumor-associated macrophages is crucial for inhibiting the growth, metastasis, and recurrence of ovarian cancer.

A polymer micelle (RC-PH-Ms) containing paclitaxel (PTX) and honokiol (HNK) was designed based on high expression of reactive oxygen species in the tumor microenvironment. Once the micelles are actively targeted to the tumor microenvironment characterized by elevated levels of reactive oxygen species, the responsive bond is cleaved, thereby exposing the secondary targeting ligand C7R. The released PTX and HNK facilitate the transformation of relevant macrophages in the tumor microenvironment from an M2 phenotype to an M1 phenotype, which in turn inhibits tumor growth, invasion and metastasis, inhibit angiogenesis and reduce tumor recurrence.

The effects of RC-PH-Ms on modulating the immune microenvironment and inhibiting tumor growth, invasion and metastasis, vascularization and recurrence were investigated both in vivo and in vitro.

RC-PH-Ms can significantly inhibit the metastasis and recurrence of ovarian cancer, which provides a new perspective for clinical treatment.

The ability of small nucleic acids to modulate gene expression via a range of processes has been widely explored. Compared with conventional treatments, small nucleic acid therapeutics have the potential to achieve long-lasting or even curative effects via gene editing. As a result of recent technological advances, efficient small nucleic acid delivery for therapeutic and biomedical applications has been achieved, accelerating their clinical translation. Here, we review the increasing number of small nucleic acid therapeutic classes and the most common chemical modifications and delivery platforms. We also discuss the key advances in the design, development and therapeutic application of each delivery platform. Furthermore, this review presents comprehensive profiles of currently approved small nucleic acid drugs, including 11 antisense oligonucleotides (ASOs), 2 aptamers and 6 siRNA drugs, summarizing their modifications, disease-specific mechanisms of action and delivery strategies. Other candidates whose clinical trial status has been recorded and updated are also discussed. We also consider strategic issues such as important safety considerations, novel vectors and hurdles for translating academic breakthroughs to the clinic. Small nucleic acid therapeutics have produced favorable results in clinical trials and have the potential to address previously "undruggable" targets, suggesting that they could be useful for guiding the development of additional clinical candidates.

Colorectal cancer (CRC) is one of the most prevalent malignant neoplasms globally. Its development and metastasis are closely associated with the polarization of macrophages within the tumor microenvironment (TME). In particular, the polarization of M2-type macrophages has been demonstrated to be related to the promotion of tumor growth, migration, and angiogenesis. This study aims to investigate the role of miR-92a-3p in colon cancer-derived exosomes in regulating M2-type macrophage polarization by targeting EID2B and to elucidate the impact of this process on tumor migration and angiogenesis. MicroRNAs that were differentially expressed in plasma exosomes from CRC patients were initially identified through a search of the GEO database. The results were then verified by RT-qPCR using miR-92a-3p. The uptake of exosomes was observed via laser confocal microscopy, and the impact of miR-92a-3p on the polarization of exosomes and macrophages was examined through the use of RT-qPCR and WB. A bioinformatics analysis and a dual-luciferase reporter assay were employed to identify the downstream target of miR-92a-3p and to investigate its effect on the MAPK/ERK pathway. miR-92a-3p was upregulated in plasma exosomes of colon cancer patients and exhibited a positive correlation with lymph node metastasis. The results demonstrated that miR-92a-3p was capable of promoting M0 macrophage polarization toward the M2 phenotype, and of enhancing the migratory and invasive capacities of CRC cells, as well as their angiogenic potential in vitro. Bioinformatic analysis and experimental validation demonstrated that miR-92a-3p targeted EID2B and that this target gene was negatively correlated with M2-type macrophage polarization. The results demonstrated that miR-92a-3p promotes macrophage M2 polarization by activating the MAPK/ERK pathway. miR-92a-3p activates the MAPK/ERK pathway and induces macrophage M2 polarization by targeting EID2B, thereby promoting migration and angiogenesis in CRC. These findings offer new potential targets for the treatment of colon cancer.

Exosomes are double-membrane vesicular nanoparticles in the category of extracellular vesicles, ranging in size from 30 to 150 nm, and are released from cells through a specific multi-step exocytosis process. Exosomes have emerged as promising tools for tissue repair due to their ability to transfer bioactive molecules that promote cell proliferation, differentiation, and tissue regeneration. However, the therapeutic application of exosomes is hindered by their rapid clearance from the body and limited retention at the injury site. To overcome these challenges, hydrogels, known for their high biocompatibility and porous structure, have been explored as carriers for exosomes. Hydrogels can provide a controlled release mechanism, prolonging the retention time of exosomes at targeted tissues, thus enhancing their therapeutic efficacy. This review focuses on the combination of different exosomes with hydrogels in the context of tissue repair. We first introduce the sources and functions of exosomes, particularly those from mesenchymal stem cells, and their roles in regenerative medicine. We then examine various types of hydrogels, highlighting their ability to load and release exosomes. Several strategies for encapsulating exosomes in hydrogels are discussed, including the impact of hydrogel composition and structure on exosome delivery efficiency. Finally, we review the applications of exosomes-loaded hydrogels in the repair of different tissues, such as skin, bone, cartilage, and nerve, and explore the challenges and future directions in this field. The combination of exosomes with hydrogels offers significant promise for advancing tissue repair strategies and regenerative therapies.

Ubiquitination and deubiquitination have emerged as pivotal regulators of the development of colorectal cancer (CRC). However, the precise role of USP48 in CRC tumorigenesis is poorly understood. In this study, immunohistochemistry, protein blotting, MTT assays, plate cloning, scratch assays, transwell assays, and Hoechst 33258 staining were utilized to assess the expression level of USP48 and its involvement in CRC. The interaction between USP48 and Transforming growth factor-β activated kinase-1(TAK1) was confirmed using co-IP. Additionally, the impact of deubiquitination on downstream signaling was determined through qRT-PCR. Furthermore, the associations between USP48 and tumor-associated macrophages within the tumor microenvironment were investigated using flow cytometry. The findings of our study demonstrated that USP48 expression is downregulated in CRC patients. Through deubiquitination, USP48 interacts with and stabilizes TAK1, leading to the inhibition of TAK1-triggered NF-κB activation and effectively suppresses CRC tumorigenesis. Moreover, this study showed a positive correlation between USP48 expression and M1-type TAM polarization, revealed the potential of USP48 as a molecular target for the effective treatment of CRC in the future.

In recent years, immunotherapy has shown significant therapeutic potential in patients with advanced tumors. However, only a small number of individuals benefit, mainly due to the tumor microenvironment (TME), which provides conditions for the development of tumors. Macrophages in TME, known as tumor-associated macrophages (TAM), are mainly divided into M1 anti-tumor and M2 pro-tumor phenotypes, which play a regulatory role in various stages of tumorigenesis, promote tumorigenesis and metastasis, and cause immunotherapy resistance.

This review focuses on research strategies and preclinical/clinical research progress in translating TAM into antitumor phenotype by referring to the PubMed database for five years. These include small molecule chemotherapy drug development, metabolic regulation, gene editing, physical stimulation, nanotechnology-mediated combination therapy strategies, and chimeric antigen receptor-based immunotherapy.

It is necessary to explore the surface-specific receptors and cell signaling pathways of TAM further to improve the specificity and targeting of drugs and to strengthen research in the field of probes that can monitor changes in TAM in real time. In addition, the physical stimulation polarization strategy has the advantages of being noninvasive, economical, and stable and will have excellent clinical transformation value in the future.

Over the past few decades, immunotherapy has emerged as a powerful strategy to overcome the limitations of conventional cancer treatments. The use of extracellular vesicles, particularly exosomes, which carry cargoes capable of modulating the immune response, has been extensively explored as a potential therapeutic approach in cancer immunotherapy. Exosomes can deliver their cargo to target cells, thereby influencing their phenotype and immunomodulatory functions. They exhibit either immunosuppressive or immune-activating characteristics, depending on their internal contents. These exosomes originate from diverse cell sources, and their internal contents can vary, suggesting that there may be a delicate balance between immune suppression and stimulation when utilizing them for immunotherapy. Therefore, a thorough understanding of the molecular mechanisms underlying the role of exosomes in cancer progression is essential. This review focuses on the molecular mechanisms driving exosome function and their impact on the tumor microenvironment (TME), highlighting the intricate balance between immune suppression and activation that must be navigated in exosome-based therapies. Additionally, it underscores the challenges and ongoing efforts to optimize exosome-based immunotherapies, thereby making a significant contribution to the advancement of cancer immunotherapy research.

Herpes virus entry mediator (HVEM) is a novel costimulatory molecule which mediates stimulatory or inhibitory signals in immune responses which makes it an attractive target in cancer therapeutics. However, the role of tumor cell intrinsic HVEM on tumor biology remains largely unknown. In this study, We demonstrated that CK+HVEM+ tumor correlates with better survival using Multiplex immuno histochemistry (mIHC) in Human Lung Adenocarcinoma Tissue microarray. Next, we showed that HVEM knockdown promoted NSCLC cell invasion and metastasis in vitro whereas exhibited no effect on proliferation. Conversely, HVEM overexpression results in the opposite phenotype. Meanwhile, the conclusion were further confirmed in vivo experiment that overexpression of HVEM reduced the invasion and metastasis of NSCLC whereas no effect on tumor mass. Besides, vivo experiment showed that M1 TAMs in the HVEM overxrpression group was increased and the proportion of M2 macrophages was decreased compared to the vector group. Mechanistically, The C-terminal 228-283 amino acid segment of HVEM protein interacts with the N-terminal 1-383 amino acid segment of MPRIP protein, inhibiting its downstream glycolysis signaling pathway and suppressing NSCLC cells progression. In addition, macrophage coculture assay suggested that HVEM overexpression inhibited M2 macrophage polarization through GM-CSF/GM-CSFRα axis. In summary, our study has demonstrated that tumor cell intrinsic HVEM is a potential tumour metastasis suppressor, which may serve as a potential target for immunotherapy.

Hepatocellular carcinoma (HCC) is a major type of liver cancer and an important cause of cancer death. It has been reported that the hepatocyte death plays an important role in HCC. Ferroptosis is an iron-dependent programmed cell death characterized by the accumulation of free iron and lipid peroxidation. A series of studies have shown that ferroptosis contributes to the occurrence and development of HCC. MicroRNAs (miRNAs) are non-coding RNAs with a length of approximately 222 nt. In recent years, miRNAs have been shown to participate in regulating ferroptosis to play a vital role in HCC, but the related mechanisms are not fully understood. This review summarized the current understanding of ferroptosis, as well as the biogenesis and function of miRNAs, and focused on the role of miRNAs regulation of ferroptosis in HCC, with the hope of providing new targets and ideas for the treatment of HCC.

The tumor microenvironment (TME) is a complex and heterogeneous system containing various cells cooperating and competing with each other. Extracellular vesicles (EVs) differing in form and content are important intercellular communication mediators in the TME. Previous studies have focused on the cargoes within EVs rather than on the donors from which they originate and the recipient cells that exert their effects. Therefore, we provide here a detailed overview of the important roles of EVs in shaping tumor fate, highlighting their various mechanisms of intercellular dialog within the TME. We evaluate recent advances and also raise unresolved challenges to provide new ideas for clinical treatment strategies using EVs.

Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.

The clinical treatment of hospital-acquired persistent osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) presents two major challenges: ineffective drug delivery into deep tissues and counteracting the rapid establishment of an immunosuppressive microenvironment. Indeed, MRSA can evade immunosurveillance and undermine both innate and adaptive immune responses. Herein, the engineered nanovesicles, functioning by combining sonodynamic therapy (SDT) with immune modulation, were constructed for the precise and noninvasive removal of MRSA in deep tissue and activation of the antimicrobial immune response using a newly engineered nanovesicle. Macrophage-derived M1 phenotypic microvesicles (M1-MW) internalized vancomycin-cross-linked micelles with the acoustic sensitizer indocyanine green (ICG) (VCG micelles). The vesicles of M1-MW were grafted with PEGylated mannose, allowing for targeted accumulation at the infection site. The VCG micelles were responsive to the highly reducing environment and released ICG to generate ROS after exposure to ultrasounds. This effect was combined with the presence of vancomycin to kill MRSA. In an osteomyelitis infection model, we observed an improved survival rate and reprogramming of macrophages to a pro-inflammatory M1 phenotype. The latter promoted T-cell activation and immune defense against MRSA-camouflaged homologous cell-transferred infections. Thus, our study presents a noninvasive and efficient treatment (VCG@MMW) for deep osteomyelitis with improved bacterial clearance and reduced risk of recurrence with enhanced immune response.

The activation of astrocytes in the injured lesion induces the progression of spinal cord injury (SCI). However, adverse side-effects during systemic administration have limited applications. Exosomes (Exos) are an emerging clinical treatment method that exerts anti-inflammatory effects by reducing pro-inflammatory factors and promoting functional recovery. Exosomes exhibit great potential as carriers of traditional Chinese medicine, attributed to their high delivery efficiency to internalized and targeted accumulation in inflammatory tissues. Herein, We synthesized resveratrol loaded microglia-derived exosomes (R-MDEs) for highly efficient accumulation and infiltration in the injured spinal cord. In vitro and in vivo experiments suggested that R-MDEs effectively accumulated in A1 astrocytes, inhibited reactive oxygen species (ROS) and glial scar formation by reprogramming the metabolic astrocytes. R-MDEs achieve a synergistic therapeutic effect of immunomodulation and neuroprotection, thereby shedding new light on the application of Exos and provides great potential for SCI.

The ubiquitously expressed transmembrane protein, Herpesvirus Entry Mediator (HVEM), functions as a molecular switch, capable of both activating and inhibiting the immune response depending on its interacting ligands. HVEM-Fc is a novel recombinant fusion protein with the potential to eradicate tumor cells.

The anti-tumor efficacy of HVEM-Fc was evaluated in C57BL/6 mice-bearing lung cancer models: a syngeneic model and an orthotopic model of mouse lung cancer. Additionally, patient-derived organoids were employed in conjunction with T cell co-culture systems. To investigate the underlying mechanisms, a comprehensive array of techniques was utilized, including single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and flow cytometry. Furthermore, the anti-tumor effects of HVEM-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed. Finally, mouse immune cell depletion antibodies were used to elucidate the underlying mechanisms of action.

In vivo, 1 mg/kg HVEM-Fc demonstrated effective inhibition of tumor growth and metastasis in C57BL/6 mice bearing lung cancer model and a KP orthotopic model of mouse lung cancer. Multi-omics analysis showed that HVEM-Fc induced an immune-stimulatory microenvironment. Notably, the combination of HVEM-Fc with a PD-1 inhibitor demonstrated the most potent inhibition of tumor cell growth. In vitro, HVEM-Fc was validated to eradicate tumor cells through the activation of T cells in both non-small cell lung cancer (NSCLC) organoids and T cell co-culture models.

Our data demonstrate that HVEM-Fc exerts a strong signal that augments and prolongs T-cell activity in both murine models and human NSCLC organoid models. Moreover, the combination of HVEM-Fc with a PD-1 inhibitor yields the most effective anti-tumor outcomes.

Tumour-associated macrophages (TAMs) are critical components of the tumour microenvironment (TME), significantly influencing cancer progression and treatment resistance. This review aims to explore the innovative use of engineered bacteria to reprogram TAMs, enhancing their anti-tumour functions and improving therapeutic outcomes.

We conducted a systematic review following a predefined protocol. Multiple databases were searched to identify relevant studies on TAMs, their phenotypic plasticity, and the use of engineered bacteria for reprogramming. Inclusion and exclusion criteria were applied to select studies, and data were extracted using standardised forms. Data synthesis was performed to summarise the findings, focusing on the mechanisms and therapeutic benefits of using non-pathogenic bacteria to modify TAMs.

The review summarises the findings that engineered bacteria can selectively target TAMs, promoting a shift from the tumour-promoting M2 phenotype to the tumour-fighting M1 phenotype. This reprogramming enhances pro-inflammatory responses and anti-tumour activity within the TME. Evidence from various studies indicates significant tumour regression and improved immune responses following bacterial therapy.

Reprogramming TAMs using engineered bacteria presents a promising strategy for cancer therapy. This approach leverages the natural targeting abilities of bacteria to modify TAMs directly within the tumour, potentially improving patient outcomes and offering new insights into immune-based cancer treatments. Further research is needed to optimise these methods and assess their clinical applicability.

Metastasis is a hallmark of advanced cancer, and the liver is a common site for secondary metastasis of many tumor cells, including colorectal, pancreatic, gastric, and prostate cancers. Macrophages in the tumor microenvironment (TME) promote tumor cell metastasis through various mechanisms, including angiogenesis and immunosuppression, and play a unique role in the development of liver metastasis. Macrophages are affected by a variety of factors. Under conditions of hypoxia and increased acidity in the TME, more factors are now found to promote the polarization of macrophages to the M2 type, including exosomes and amino acids. M2-type macrophages promote tumor cell angiogenesis through a variety of mechanisms, including the secretion of factors such as VEGF, IL-1β, and TGF-β1. M2-type macrophages are subjected to multiple regulatory mechanisms. They also interact with various cells within the tumor microenvironment to co-regulate certain conditions, including the creation of an immunosuppressive microenvironment. This interaction promotes tumor cell metastasis, drug resistance, and immune escape. Based on the advent of single-cell sequencing technology, further insights into macrophage subpopulations in the tumor microenvironment may help in exploring new therapeutic targets in the future. In this paper, we will focus on how macrophages affect the TME, how tumor cells and macrophages as well as other immune cells interact with each other, and further investigate the mechanisms involved in liver metastasis of tumor cells and their potential as therapeutic targets.

Colorectal cancer is the third most prevalent cancer in the world. Early screening and detection of tumours, active surgical radical treatment, postoperative adjuvant chemotherapy, targeted therapy, and immunotherapy are performed based on pathological staging and immunohistochemistry. Even with these measures, the 5-year survival rate of colorectal cancer is only 65%, and a considerable number of patients still experience tumour recurrence or even metastasis. The KRAS G12C mutation accounts for 3 to 4% of refractory colorectal cancer (advanced or metastatic colorectal cancer), and it was once believed that KRAS did not have a drug target until the emergence of KRAS G12C inhibitors provided targeted treatment for KRAS-mutated colorectal cancer. However, KRAS G12C inhibitors only produce moderate efficacy, and resistance occurs after a short remission. The mechanism of drug resistance in tumour cells is complex and diverse, and existing research has limited understanding of it. This review aims to elucidate the clinical trial progress of KRAS G12C inhibitors in refractory colorectal cancer, the research progress of drug resistance mechanisms, and the combined treatment strategies for drug resistance.

Cancer vaccines are promising therapeutic approaches to enhance specific T-cell immunity against most solid tumors. By stimulating anti-tumor immunity, clearing minimal residual disease, and minimizing adverse effects, these vaccines target tumor cells and are effective when combined with immune checkpoint blockade or other immunotherapies. However, the development of tumor cell-based vaccines faces quality issues due to poor immunogenicity, tumor heterogeneity, a suppressive tumor immune microenvironment, and ineffective delivery methods. In contrast, extracellular vesicles (EVs), naturally released by cells, are considered the ideal drug carriers and vaccine platforms. EVs offer highly organ-specific targeting, induce broader and more effective immune responses, and demonstrate superior tissue delivery ability. The development of EV vaccines is crucial for advancing cancer immunotherapy. Compared to cell-based vaccines, EV vaccines produced under Good Manufacturing Practices (GMP) offer advantages such as high safety, ease of preservation and transport, and a wide range of sources. This review summarizes the latest research findings on EV vaccine and potential applications in this field. It also highlights novel neoantigens for the development of EV vaccines against cancer.

Melanoma is the most aggressive type of skin cancers. Traditional chemotherapy and radiotherapy have limited effectiveness and can lead to systemic side effects. Photodynamic therapy (PDT) is a photoresponsive cancer therapy based on photosensitizers to generate reactive oxygen species (ROS) to eradicate tumor cells. Our previous study showed that exosomes derived from human γδ-T cells (γδ-T exosomes) could control Epstein-Barr virus-associated tumors. Here, we combined γδ-T exosomes and PDT for targeted photoimmunotherapy by membrane fusion of γδ-T exosomes and Chlorin e6 (Ce6)-loaded liposomes. The functional surface proteins, such as CCR5 and PD-1, on the hybrid exosomes mediated the specific binding of hybrid exosomes toward melanoma tissues. The cytolytic molecules, such as granzyme A, granzyme B, perforin, and granulysin from γδ-T exosomes, induced specific apoptosis of cancer cells without harming normal cells. In response to light irradiation, ROS generation inside melanoma cells synergized with cytolytic molecules to induce apoptosis and promote immunogenic cancer cell death (ICD). The subsequently released damage-associated molecular patterns (DAMPs) could stimulate human dendritic cell maturation and induce melanoma antigen-specific CD4+ and CD8+ T-cell responses, thereby enhancing antitumor immunity. This study provides a promising strategy by combining γδ-T exosomes and PDT for photoimmunotherapy, thereby expanding the clinical applications of γδ-T exosome therapy for cancer patients.

Glioma is the most common primary intracranial malignant tumor in adults, with a poor prognosis. Exosomes released by tumor cells play a crucial role in tumor development, metastasis, angiogenesis, and other biological processes. Despite this significance, the precise molecular mechanisms governing exosome secretion and their impact on tumor progression remain incompletely understood. While Choline Kinase Alpha (CHKA) has been implicated in promoting various types of tumors, its specific role in glioma pathogenesis remains unclear. Our study initially demonstrates that CHKA enhances the proliferation, migration, and invasion abilities of glioma cells. Interestingly, CHKA also stimulates the release of exosomes from glioma cells. Mechanistically, reduced CHKA expression hampers exosome secretion by elevating autophagy levels in gliomas, whereas counteracting the autophagy elevation resulting from CHKA downregulation restores the release of exosomes. Notably, exosomes derived from glioma cells with normal CHKA expression exhibit a greater capacity to promote glioma progression compared to those derived from cells with low CHKA expression. Overall, our findings suggest that CHKA modulates exosome secretion via an autophagy-dependent pathway, thereby facilitating the proliferation, migration, and invasion of glioma cells.

Mitophagy serves as a mitochondrial quality control mechanism to maintain the homeostasis of mitochondria and the intracellular environment. Studies have shown that there is a close relationship between mitophagy and apoptosis. Sestrin2 (Sesn2) is a highly conserved class of stress-inducible proteins that play important roles in reducing oxidative stress damage, inflammation, and apoptosis. However, the potential mechanism of how Sesn2 regulates mitophagy and apoptosis in severe acute pancreatitis (SAP) remains unclear. In the study, RAW264.7 (macrophage cell Line) cellular inflammation model established by lipopolysaccharide (LPS) treatment as well as LPS and CAE-induced SAP mouse model (wild-type and Sen2 Knockout mouse) were used. Our study showed that LPS stimulation significantly increased the level of Sesn2 in RAW264.7 cells, Sesn2 increased mitochondrial membrane potential, decreased inflammation levels, mitochondrial superoxide levels and apoptosis, and also promoted monocyte macrophages toward the M2 anti-inflammatory phenotype, suggesting a protective effect of Sesn2 on mitochondria. Further, Sesn2 increased mitophagy and decreased apoptosis via modulating the PINK1-Parkin signaling. Meanwhile, knockout of Sesn2 exacerbated pancreatic, mitochondrial damage and inflammation in a mouse model of SAP. In addition, the protective effect of Sesn2 against SAP was shown to be associated with mitophagy conducted by the PINK1-Parkin pathway via inhibiting apoptosis. These findings reveal that Sesn2 in balancing mitochondrial autophagy and apoptosis by modulating the PINK1-Parkin signaling may present a new therapeutic strategy for the treatment of SAP.

Peptides exhibit various biological activities, including biorecognition, cell targeting, and tumor penetration, and can stimulate immune cells to elicit immune responses for tumor immunotherapy. Peptide self-assemblies and peptide-functionalized nanocarriers can reduce the effect of various biological barriers and the degradation by peptidases, enhancing the efficiency of peptide delivery and improving antitumor immune responses. To date, the design and development of peptides with various functionalities have been extensively reviewed for enhanced chemotherapy; however, peptide-mediated tumor immunotherapy using peptides acting on different immune cells, to the knowledge, has not yet been summarized. Thus, this work provides a review of this emerging subject of research, focusing on immunomodulatory anticancer peptides. This review introduces the role of peptides in the immunomodulation of innate and adaptive immune cells, followed by a link between peptides in the innate and adaptive immune systems. The peptides are discussed in detail, following a classification according to their effects on different innate and adaptive immune cells, as well as immune checkpoints. Subsequently, two delivery strategies for peptides as drugs are presented: peptide self-assemblies and peptide-functionalized nanocarriers. The concluding remarks regarding the challenges and potential solutions of peptides for tumor immunotherapy are presented.

Latexin (LXN) is a secreted protein with a molecular weight of 29 KD, which is considered a tumor suppressor and plays an important role in the inflammatory immune response. LXN is highly expressed in macrophages and regulates macrophage polarity and tumor immune escape, demonstrating excellent clinical potential. However, its mechanism is still unclear. In this study, a macrophage-T cell co-culture system is established to clarify the secretion of macrophage LXN into the extracellular through exosomes. The results indicate that LXN in macrophage-derived exosomes is functional, that is, LXN-enriched exosome inhibits CD4+T cell differentiation into Treg cells in vitro and in vivo, and exhibits good tumor suppressive effects. Based on this discovery, a biomimetic nanoparticle loaded with LXN protein (MØ@LXN-NPS) is designed and synthesized. Furthermore, the MØ@LXN-NPS shows excellent performance in both in vivo and in vitro, especially in enhancing tumor immune surveillance by inhibiting Treg cells in tumor microenvironment, thus exhibiting excellent anti-tumor activity. This study provides a demonstration for the transition of biomolecules from functional research to engineering applications. The excellent performance of MØ@LXN-NPS in tumor immune regulation suggests that the engineered biomimetic nanomedicine has good clinical application prospects.

Cancer immunotherapy, which leverages immune system components to treat malignancies, has emerged as a cornerstone of contemporary therapeutic strategies. Yet, critical concerns about the efficacy and safety of cancer immunotherapies remain formidable. Nanotechnology, especially polymeric nanoparticles (PNPs), offers unparalleled flexibility in manipulation-from the chemical composition and physical properties to the precision control of nanoassemblies. PNPs provide an optimal platform to amplify the potency and minimize systematic toxicity in a broad spectrum of immunotherapeutic modalities. In this comprehensive review, the basics of polymer chemistry, and state-of-the-art designs of PNPs from a physicochemical standpoint for cancer immunotherapy, encompassing therapeutic cancer vaccines, in situ vaccination, adoptive T-cell therapies, tumor-infiltrating immune cell-targeted therapies, therapeutic antibodies, and cytokine therapies are delineated. Each immunotherapy necessitates distinctively tailored design strategies in polymeric nanoplatforms. The extensive applications of PNPs, and investigation of their mechanisms of action for enhanced efficacy are particularly focused on. The safety profiles of PNPs and clinical research progress are discussed. Additionally, forthcoming developments and emergent trends of polymeric nano-immunotherapeutics poised to transform cancer treatment paradigms into clinics are explored.

Alpha fetoprotein(AFP) overexpression connecting with macrophage dysfunction remain poorly defined. In this study, explore AFP regulates macrophage immunomodulation in hepatocellular carcinoma(HCC) through comprehensive in vitro and in vivo studies.

Immunohistochemical and immunofluorescence staining was used to analyze the relativity of AFP and cellular membrane CD47 expression in clinical 30 HCC tissues, and the expression of AFP and CD47 in HCC cells. The intelligent living-cell high-throughput imaging analyzer was applied to dynamically track and image of macrophages to phagocytize HCC cells. The effect of AFP on regulating the level of CD47 in cellular membrane and growth of tumor in vivo was performed by animal experiment. The association of AFP and CD47 in HCC cells was detected by single cell analysis.

The present results indicated that AFP upregulated the localization of CD47 on the HCC cell surface. CD47 overexpression stimulates HCC to escape immune surveillance by transmitting "don't eat me" signals to macrophages, lead to inhibit macrophage to phagocytize HCC cells. Mechanistically, the results demonstrated that AFP enhanced CD47 membrane translocation by interacting with Hu-Antigen R(HuR), an RNA-binding protein that regulates mRNA stability and translation. AFP alters the subcellular distribution of HuR, increasing its cytoplasmic accumulation and binding to CD47 transcript.

AFP enhanced CD47 membrane translocation by interacting with HuR. These findings proved that AFP could inhibit macrophage to phagocytize HCC cells by upregulating the localization of CD47 on the HCC cell surface. Combination of AFP with CD47 blockade may be a potential therapeutic strategy for HCC treatment.

Exosome-based cancer immunotherapy is advancing quickly on the concept of artificially activating the immune system to combat cancer. They can mechanistically change the tumor microenvironment, increase immune responses, and function as efficient drug delivery vehicles because of their inherent bioactivity, low toxicity, and immunogenicity. Accurate identification of the mechanisms of action of exosomes in tumor environments, along with optimization of their isolation, purification, and characterization methods, is necessary to increase clinical applications. Exosomes can be modified through cargo loading and surface modification to enhance their therapeutic applications, either before or after the donor cells' isolation. These engineered exosomes can directly target tumor cells at the tumor site or indirectly activate innate and adaptive immune responses in the tumor microenvironment. This approach is particularly effective when combined with traditional cancer immunotherapy techniques such as vaccines, immune checkpoints, and CAR-T cells. It can improve anti-tumor responses, induce long-term immunity, and address the limitations of traditional therapies, such as poor penetration in solid tumors and immunosuppressive environments. This review aims to provide a comprehensive and detailed overview of the direct role of engineered exosomes as drug delivery systems and their immunomodulatory effects on tumors as an indirect approach to fighting cancer. Additionally, it will discuss novel immunotherapy options.

Macrophages are pivotal in the body's defense and response to inflammation. They are present in significant numbers and are widely implicated in various diseases, including cancer. While molecular and histological techniques have advanced our understanding of macrophage biology, their precise function within the cancerous microenvironments remains underexplored. Enhancing our knowledge of macrophages and the dynamics of their extracellular vesicles (EVs) in cancer development can potentially improve therapeutic management. Notably, macrophages have also been harnessed to deliver drugs. Noninvasive in vivo molecular imaging of macrophages is crucial for investigating intricate cellular processes, comprehending the underlying mechanisms of diseases, tracking cells and EVs' migration, and devising macrophage-dependent drug-delivery systems in living organisms. Thus, in vivo imaging of macrophages has become an indispensable tool in biomedical research. The integration of multimodal imaging approaches and the continued development of novel contrast agents hold promise for overcoming current limitations and expanding the applications of macrophage imaging. This study comprehensively reviews several methods for labeling macrophages and various imaging modalities, assessing the merits and drawbacks of each approach. The review concludes by offering insights into the applicability of molecular imaging techniques for real time monitoring of macrophages in preclinical and clinical scenarios.

Biological carriers have emerged as significant tools to deliver radionuclides in nuclear medicine, providing a meaningful perspective for tumor imaging and treatment. Various radionuclide-labeled biological carriers have been developed to meet the needs of biomedical applications. This review introduces the principles of radionuclide-mediated imaging and therapy and the selected criteria of them, as well as a comprehensive description of the characteristics and functions of representative biological carriers including bacteria, cells, viruses, and their biological derivatives, emphasizing the labeled strategies of biological carriers combined with radionuclides. Subsequently, we in-depth introduce the application of radionuclide-labeled biological carriers in tumor imaging and treatment, including the imaging of the behaviors of biological carriers in vivo and tumor metastasis and the tumor treatment by radionuclide therapy, plus other strategies and radiation-induced photodynamic therapy. Finally, the challenges and prospects of radionuclide-labeled biological carriers are discussed to improve the shortcomings of this innovative platform and promote clinical transformation in the field of medical imaging.

Melanoma is an aggressive type of skin cancer that arises from melanocytes, the cells responsible for producing skin pigment. In contrast to non-melanoma skin cancers like basal cell carcinoma and squamous cell carcinoma, melanoma is more invasive. Melanoma was distinguished by its rapid progression, high metastatic potential, and significant resistance to conventional therapies. Although it accounted for a small proportion of skin cancer cases, melanoma accounts for the majority of deaths caused by skin cancer due to its ability to invade deep tissues, adapt to diverse microenvironments, and evade immune responses. These unique features highlighted the challenges of treating melanoma and underscored the importance of advanced tools, such as single-cell sequencing, to unravel its biology and develop personalized therapeutic strategies. Thus, we conducted a single-cell analysis of the cellular composition within melanoma tumor tissues and further subdivided melanoma cells into subpopulations. Through analyzing metabolic pathways, stemness genes, and transcription factors (TFs) among cells in different phases (G1, G2/M, and S) as well as between primary and metastatic foci cells, we investigated the specific mechanisms underlying melanoma metastasis. We also revisited the cellular stemness and temporal trajectories of melanoma cell subpopulations, identifying the core subpopulation as C0 SOD3 + Melanoma cells. Our findings revealed a close relationship between the pivotal C0 SOD3 + Melanoma cells subpopulation and oxidative pathways in metastatic tumor tissues. Additionally, we analyzed prognostically relevant differentially expressed genes (DEGs) within the C0 SOD3 + Melanoma cells subpopulation and built a predictive model associated with melanoma outcomes. We selected the gene IGF1 with the highest coefficient (coef) value for further analysis, and experimentally validated its essential function in the proliferation and invasive metastasis of melanoma. In immune infiltration analysis, we discovered the critical roles played by M1/M2 macrophages in melanoma progression and immune evasion. Furthermore, the development and progression of malignant melanoma were closely associated with various forms of programmed cell death (PCD), including apoptosis, autophagic cell death, ferroptosis, and pyroptosis. Melanoma cells often resisted cell death mechanisms, maintaining their growth by inhibiting apoptosis and evading autophagic cell death. Meanwhile, the induction of ferroptosis and pyroptosis was thought to trigger immune responses that helped suppress melanoma dissemination. A deeper understanding of the relationship between melanoma and PCD pathways provided a critical foundation for developing novel targeted therapies, with the potential to enhance melanoma treatment efficacy. These findings contributed to the development of novel prognostic models for melanoma and shed light on research directions concerning melanoma metastasis mechanisms and therapeutic targets.

Diabetic wounds present a significant challenge in regenerative medicine due to impaired healing, characterized by prolonged inflammation and deficient tissue repair, primarily caused by a skewed pro-inflammatory macrophage phenotype. This study investigates the therapeutic potential of interleukin-10 (IL-10) chemically modified mRNA (modRNA)-enriched human adipose-derived multipotent stromal cells (hADSCs) in a well-established murine model of diabetic wounds. The modRNAs used in this study were chemically modified using N1-methylpseudouridine-5'-triphosphate (m1Ψ) by substituting uridine-5-triphosphate. In vitro experiments demonstrated that IL-10 modRNA-transfected hADSCs effectively modulated macrophage polarization towards an anti-inflammatory phenotype. In vivo experiments with a well-established murine model demonstrated that transplantation of hADSCsmodIL-10 on postoperative day 5 (POD5) significantly improved wound healing outcomes, including accelerated wound closure, enhanced re-epithelialization, promoted M2 polarization, improved collagen deposition, and increased neovascularization. This study concludes that IL-10 modRNA-enriched hADSCs offer a promising therapeutic approach for diabetic wound healing, with the timing of IL-10 administration playing a crucial role in its effectiveness. These cells modulate macrophage polarization and promote tissue repair, demonstrating their potential for improving the management of diabetic wounds.

Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early proinflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to proresolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. In this study, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast-derived exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet they also accelerated timely switching from M1 to M2 phenotypes. Exosome inhibition dysregulated macrophage responses, resulting in aberrant inflammation and impaired healing, whereas provision of exogenous fibroblast-derived exosomes corrected defects. Topical application of fibroblast-derived exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.

The emergence of monkeypox has become a global health threat after the COVID-19 pandemic. Due to the lack of available specifically treatment against MPV, developing an available vaccine is thus the most prospective and urgent strategy. Herein, a programmable macrophage vesicle based bionic self-adjuvanting vaccine (AM@AEvs-PB) is first developed for defending against monkeypox virus (MPV). Based on MPV-related antigen-stimulated macrophage-derived vesicles, the nanovaccine is constructed by loading the mature virion (MV)-related intracellular protein (A29L/M1R) and simultaneously modifying with the enveloped virion (EV) antigen (B6R), enabling them to effectively promote antigen presentation and enhance adaptive immune through self-adjuvant strategy. Owing to the synergistic properties of bionic vaccine coloaded MV and EV protein in defensing MPV, the activation ratio of antigen-presenting cells is nearly four times than that of single antigen in the same dose, resulting in stronger immunity in host. Notably, intramuscular injection uptake of AM@AEvs-PB demonstrated vigorous immune-protective effects in the mouse challenge attempt, offering a promising strategy for pre-clinical monkeypox vaccine development.

Oxysterols are compounds generated through oxidative reactions involving cholesterol and other steroid molecules. They play a crucial role in the tumor immune microenvironment by interacting with molecules such as the cell membrane receptor EBI2 and nuclear receptors like LXR and PXR. This interaction regulates immune cell signaling pathways, affecting proliferation, apoptosis, migration, and invasion in tumor-related processes. Activating these receptors alters the function and behavior of immune cells-such as macrophages, T cells, and dendritic cells-within the tumor microenvironment, thus promoting or inhibiting tumor development. Certain oxidized steroids can increase both the number and activation of infiltrating T cells, synergizing with anti-PD-1 to enhance anti-tumor efficacy. An in-depth study of the biological mechanisms of oxidized sterols will not only enhance our understanding of the complexity of the tumor immune microenvironment but may also reveal new therapeutic targets, providing innovative strategies for tumor immunotherapy.

Interferon-induced protein 35 (IFI35), an immunomodulator, is highly expressed in tumor cells, yet its role in enhancing tumor vaccine efficacy remains unclear. In this study, an adenovirus (Ad) vaccine encoding dual targets, IFI35 and carbonic anhydrase IX (CAIX), was developed for renal carcinoma treatment. Co-immunization with Ad-IFI35/CAIX effectively inhibited tumor growth in a subcutaneous model and significantly increased the infiltration of CD8+ T cells and dendritic cells (DCs). Furthermore, Ad-IFI35/CAIX administration induced strong cytotoxic T lymphocyte (CTL) responses and expanded multifunctional CD8+ T cell populations. Depletion of CD8+ T cells abolished the vaccine's tumor regression effects, confirming that its therapeutic effect relies on CD8+ T cell-mediated immunity. In addition, Ad-IFI35/CAIX treatment enhanced the induction of memory CTL responses, effectively suppressing the growth of tumors implanted contralaterally. The Ad-IFI35/CAIX vaccine also elicited a strong CD8+ T cell-mediated immunity against tumor metastasis and growth in lung metastasis and orthotopic renal carcinoma models. These results indicate that the Ad vaccine dual targeting IFI35 and CAIX is a potential strategy for renal carcinoma treatment.

Tumor immunity has garnered increasing attention in cancer treatment and progression. However, there is still a challenge in understanding the mechanisms of specific molecules affecting the clinical prognosis and tumor microenvironment (TME).

Here, we applied the ESTIMATE algorithm to calculate the immune and stromal scores in 504 HNSC cases from TCGA. Patients were grouped according to the median value of the immune and stromal. Clinicopathological characteristics and differentially expressed genes (DEG) were analyzed. Subsequently, LASSO, COX regression, survival analysis, and clinicopathological characteristics were conducted. Subsequently, SLC2A3 was determined as a predictive factor that high expression of SLC2A3 at the mRNA and protein levels predicted a worse clinical prognosis. GSEA25099 was utilized for external validation of immune infiltration, while tissue PCR, IHC, and Western Blot were used to confirm the expression levels of SLC2A3.

A series of immune-infiltration analyses showed that SLC2A3 expression was negatively correlated with CD8+ T cells, significantly affecting the survival prognosis of HNSC. In the GSEA analysis, the high expression of SLC2A3 was mainly enriched for immune-related biological processes. Meanwhile, high expression of SLC2A3 possessed higher TIDE scores and was also strongly positively correlated with a series of immune checkpoints affecting survival prognosis, thus causing greater susceptibility to immune escape.

Conclusively, SLC2A3 is a potential oncogene and factor of HNSC development, notably by an altered state of the immune microenvironment, immune-suppressive regulation, and immune escape.

Immunotherapy, a monumental advancement in antitumor therapy, still yields limited clinical benefits owing to its unguaranteed efficacy and safety. Therapeutic systems derived from cellular, bacterial and viral sources possess inherent properties that are conducive to antitumor immunotherapy. However, crude biomimetic systems have restricted functionality and may produce undesired toxicity. With advances in biotechnology, various toolkits are available to add or subtract certain properties of living organisms to create flexible therapeutic platforms. This review elaborates on the creation of bioengineered systems, via gene editing, synthetic biology and surface engineering, to enhance immunotherapy. The modifying strategies of the systems are discussed, including equipment for navigation and recognition systems to improve therapeutic precision, the introduction of controllable components to control the duration and intensity of treatment, the addition of immunomodulatory components to amplify immune activation, and the removal of toxicity factors to ensure biosafety. Finally, we summarize the advantages of bioengineered immunotherapeutic systems and possible directions for their clinical translation.