Acute myeloid leukemia (AML) is a prevalent and potentially fatal hematologic malignancy with limited improvements in survival rates over the past few decades. ITGAM, encoding CD11b, is a significant integrin component in leukocytes, involved in various biological processes. However, its role in AML prognosis and immune cell infiltration remains poorly understood.

This study investigated the prognostic significance and potential function of ITGAM in AML using comprehensive bioinformatic analyses.

ITGAM expression was markedly upregulated in AML patients, correlating with advanced age (> 60 years), French-American-British (FAB) classification subtypes M4 and M5, and intermediate or poor cytogenetic risk. Gene enrichment analysis revealed that ITGAM was involved in immune system regulation and was positively associated with the infiltration of neutrophils, immature dendritic cells, and macrophages in AML. Notably, the expression of ITGAM was linked to increased infiltration of immunosuppressive subsets of these innate immune cells, which may partially explain its association with a poorer prognosis.

These findings suggest that ITGAM could serve as a valuable prognostic biomarker in AML, reflecting an adverse prognosis associated with enhanced infiltration of immunosuppressive innate immune cells.

Tumor-associated macrophages (TAMs) are crucial in hepatocellular carcinoma (HCC) progression and prognosis, making them promising immunotherapy targets. In traditional Chinese medicine (TCM), qi stagnation and blood stasis are linked to the HCC tumor microenvironment (TME), but few studies explore the effects of related TCM herbs on the TME. Calceolarioside B, a key phenylethanoid glycoside in Akebiae Fructus, has not been well studied for its pharmacological activities or molecular targets, and its role in HCC remains unclear.

This study aimed to investigate the effects of Calceolarioside B on TAMs in HCC and clarify its potential targets and regulatory mechanisms.

Murine intrahepatic transplantation HCC models and macrophage-HCC cell co-culture systems were used to investigate the effects of Calceolarioside B on M2-like TAMs polarization and infiltration, and tumor growth. Cellular thermal shift assay, small molecular pull-down assay and surface plasmon resonance were utilized to identify the potential targets regulating M2-like TAMs. Single-cell RNA sequencing and TCGA dataset analyses clarified the differential expression, prognosis, and TAMs association of the potential targets in HCC.

Calceolarioside B reduces M2-like TAMs polarization and infiltration in the TME by binding to and inhibiting matrix metallopeptidase-12 (MMP12) form both macrophages and HCC cells, thereby preventing immunosuppressive effects. Public database analysis revealed that MMP12 overexpression promoted macrophage infiltration, with MMP12+ macrophages preferentially aggregating in primary and metastatic HCC tumors.

Calceolarioside B is identified as a novel MMP12 inhibitor modulating TAMs in the TME, offering a potential TAM-targeting strategy for HCC therapy.

Hepatocellular carcinoma (HCC) is the dominant type of liver cancer and is associated with a high mortality rate. However, HCC lacks biomarkers for diagnosis and immune therapy response. Tumor-derived exosomes (TDEs) carcinogen-specific molecules have been used for screening multiple biomarkers. This study aimed to identify new biomarkers for the diagnosis of HCC and response to immune checkpoint blockade (ICB) therapy.

Analysis of differentially expressed genes (DEGs) in HCC and normal tissues was integrated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ExoCarta datasets. The expression of CCT3 was validated in samples from patients with HCC using quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry (IHC) techniques.

Exosomal CCT3 was identified as a potential biomarker with significant impact. The expression of CCT3 in different tumor stages and normal tissues adjacent to the tumors (NATs) was validated using qPCR, western blotting, and IHC. CCT3 expression significantly increased the number of activated natural killer cells in HCC, as confirmed by qPCR and IHC. CCT3 expression significantly increases the expression of immune checkpoints in HCC. HCC-derived exosomes significantly increase the enrichment of CCT3.

Exosomal CCT3 is a biomarker for diagnosis and ICB therapy of HCC via MYC pathway activation and immune infiltration.

Glioblastoma (GBM) is largely refractory to antibodies against programmed cell death 1 (anti-PD-1) therapy. Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM. This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM.

We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations. The biological functions of a novel circular RNA (circRNA) were validated both in vitro and in vivo. Mechanically, co-immunoprecipitation, RNA immunoprecipitation and pull-down assays were conducted.

Mesenchymal GBM (MES-GBM) cells, which were associated with a poor prognosis, and secreted phosphoprotein 1 (SPP1)+ myeloid-derived macrophages (SPP1+ MDMs), a unique subpopulation of MDMs with complex functions, preferentially accumulated in non-responders to anti-PD-1 therapy, indicating that MES-GBM cells and SPP1+ MDMs were the main anti-PD-1-resistant cell subpopulations. Functionally, we determined that circular RNA succinate dehydrogenase complex assembly factor 2 (circSDHAF2), which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations, facilitated the formation of a regional MES-GBM and SPP1+ MDM cell interaction loop, resulting in a spatially specific adaptive immunosuppressive microenvironment. Mechanically, we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5 (ITGA5) protein through N-glycosylation. Meanwhile, the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1+ MDMs, which in turn maintained the MES-GBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway, ultimately promoting GBM immune escape. Importantly, our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity.

This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells, MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of targeting ITGA5 to reduce anti-PD-1 resistance in GBM.

Hepatocellular carcinoma (HCC) remains a global health challenge owing to its widespread incidence and high mortality. HCC has a specific immune tolerance function because of its unique physiological structure, which limits the efficacy of chemotherapy, radiotherapy, and molecular targeting. In recent years, new immune approaches, including adoptive cell therapy, tumor vaccines, and oncolytic virus therapy, have shown great potential. As the efficacy of immunotherapy mainly depends on the spatial heterogeneity of the tumor immune microenvironment, it is necessary to elucidate the crosstalk between the composition of the liver cancer immune environment, from which potential therapeutic targets can be selected to provide more appropriate individualized treatment programs. The role of spatial heterogeneity of immune cells in the microenvironment of HCC in the progression and influence of immunotherapy on improving the treatment and prognosis of HCC were comprehensively analyzed, providing new inspiration for the subsequent clinical treatment of liver cancer.

Introduction and importance: Most extrahepatic metastases of hepatocellular carcinoma (HCC) are to the lungs and bones, metastases to the colon are rare. In the present study, we experienced a case of metastasis to the ascending colon during repeated treatment for HCC. Case Presentation: A 63-year-old man was diagnosed with multiple HCCs (T4N0M0 stage IIIB) associated with portal vein invasion. Transcatheter arterial chemoembolization (TACE), transarterial infusion (TAI) and radiofrequency ablation (RFA) were performed, and partial response was achieved, but the main nodule at S6 lesion subsequently recurred to protrude outside of the liver. A partial hepatic S6 resection was performed for local control 1.5 years after the initial treatment. IVR was then performed again, but approximately 8 months after hepatic resection, an abdominal computed toography (CT) showed a mass lesion in the ascending colon. After a total colonoscopy and biopsy, a diagnosis of colorectal metastasis of HCC was made. A right hemicolectomy was performed for local control. The patient had a good post-operative course, but developed liver failure due to rapid growth of the tumor thrombus of the main portal vein and died of primary disease approximately 3.5 months after the colon resection. Clinical Discussion: The metastasis of HCC to the colon is an extremely rare occurrence. Conclusion: One possible reason for this rarity is that portal vein tumor thrombosis (PVTT) results in colorectal metastasis via trans-portal retrograde metastasis.

Collaboration of cancerous cells and microenvironment is the root for tumor spreading, leading to difficulty in complete metastasis blockage via mono-intervention. Herein, a triple-responsive nanoassembly is designed for orienting tumor cells and migration-driving M2 tumor associated macrophages (TAMs) in microenvironment for efficient anti-metastatic therapy. Structurally, a reactive oxygen species (ROS)-responsive crosslinked short-chain polyquaternium is synthesized to bridge graphene oxide (GO) scaffold with apolipoprotein A-I crown via borate-crosslinking, electrostatic adherence, and coordinative coupling. The protein-crowning polymeric GO nanoparticles could give multimodal shielding and triple-responsive release of doxorubicin and Snail-targeted siRNA. Tailor-made apolipoprotein A-I crown fulfills nanoparticles synergistically attacking tumor cells and M2 TAMs via binding with overexpressed scavenger receptors. The findings witness the targeted accumulation and potent cytotoxicity of the hybrid nanoparticles for M2 TAMs and tumor cells; especially, elimination of M2 TAMs in tumor microenvironment holds back Snail-enhancing transforming growth factor (TGF)-β signal pathway, which collaborates with Snail silencing in tumor cells to reverse epithelial mesenchymal transition (EMT) and metastasis-promoting niche. Collectively, the synergistic targeting therapeutic platform could provide a promising solution for metastatic tumor treatment.

Cancer cells are among the many types of cells that release exosomes, which are nanovesicles. Because of their many potential applications, exosomes have recently garnered much attention from cancer researchers. The bioactive substances that exosomes release as cargo have been the subject of several investigations. The substances in question may operate as biomarkers for diagnosis or affect apoptosis, the immune system, the development and spread of cancer, and other processes. Others have begun to look at exosomes in experimental therapeutic trials because they believe they may be useful in the treatment of cancer. This review started with a short description of exosome biogenesis and key features. Next, the potential of tumor-derived exosomes and oncosomes to influence the immune system throughout the development of cancer, as well as alter tumor microenvironments (TMEs) and pre-metastatic niche creation, was investigated. Finally, there was talk of exosomes' possible use in cancer treatment. Furthermore, there is emerging consensus about the potential application of exosomes to be biological reprogrammers of cancer cells, either as carriers of naturally occurring chemicals, including anticancer medications, or as carriers of anticancer vaccines for immunotherapy as well as boron neutron capture therapy (BNCT). We briefly review the key ideas and logic behind this intriguing therapy recommendation.

Perineural invasion (PNI) is a notorious feature of salivary adenoid cystic carcinoma (SACC) and other neurotropic tumors. The pathogenesis of PNI that involves the molecular communication between the tumor and the suffered nerve is elusive. The in vitro co-culture assays of SACC cells with dorsal root ganglia (DRG) or neural cells showed that nerve-derived CCL2 activated CCR2 expression in SACC cells, promoting the proliferation, adhesion, migration, and invasion of SACC cells via the ERK1/2/ITGβ5 pathway. Meanwhile, SACC-derived exosomes delivered ITGβ5 to promote the neurite outgrowth of neural cells or DRG. Blocking of CCL2/CCR2 axis or ITGβ5 inhibited the PNI of SACC cells in models in vitro by 3D co-culture of DRG with SACC cells and in vivo by xenografting SACC cells onto the murine sciatic nerve. High levels of ITGβ5 in tissues or plasma exosomes were significantly correlated with CCL2 and CCR2 expression in the tissues and associated with PNI and poor prognosis of SACC cases. Our findings revealed a novel reciprocal loop between neural and tumor cells driven by the CCL2/CCR2 axis and exosomal ITGβ5 during PNI of SACC. The present study may provide a prospective diagnostic and anti-PNI treatment strategy for SACC patients via targeting the nerve-tumor interactions.

Exosomes are extracellular vesicles with a diameter ranging from 40 to 160 nm. They are produced by hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells in liver tissue. The secretion of exosomes might vary in quantity and composition in reaction to multiple triggers and various stages of disease. They transport various payloads, such as proteins, DNAs, and RNAs, and enable cell interaction to regulate myriad physiological and pathological processes in liver tissue. Long non-coding RNAs (lncRNAs) are a crucial component of exosomes with an excellent capability to regulate multiple cellular activities such as differentiation, development, metabolism, proliferation, apoptosis, and activation. With the advancements in transcriptomic and genomic study methods and database management technology, the functions and mechanisms of exosomal lncRNAs in liver diseases have been well-studied. This article delves into the detailed role of exosomal lncRNAs in liver disease onset and progression, ranging from hepatocellular carcinoma (HCC) to liver fibrosis drug-induced liver damage (DILI) and steatotic liver diseases.

Malignant tumors are complicated structures of cancer cells that are constantly in communication with their local and distant environment. Exosomes are released by tumor cells and can facilitate the cell-cell interaction within the local microenvironment and the primary tumor. In fact, exosomes are secreted by both tumor and non-tumor cells, to provide a mutual communication network between cells and their micro- and/or macro-environments. Exososmes can contain a variety of biological cargos mostly based on their originated cells. Uptake of these exosomes by their recipient cells results in the alterations that their cargo can exert. MicroRNAs are identified as one of the most critical exosomal components, considering their pivotal regulatory roles in distinct biological process, including metastasis. Release and absorbance of exosomal microRNAs is possible by various cells within the host, and can have distinct biological consequences. Therefore, in this review we will discuss the role of exosomal microRNAs derived from tumor cells and untransformed cells within their micro- and macroenvironment in cancer progression and metastasis.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), has a significantly higher risk of recurrence. However, the exact mechanism by which HBV prompts HCC recurrence remains largely unknown. In this study liver microarray test revealed significant upregulation of microtubule associated protein 1S (MAP1S) in metastatic HCC compared to control. MAP1S knockdown suppressed growth of HCCLM3 cells in vitro and in vivo. Mechanistically, HBV-encoded X protein (HBx) upregulates MAP1S, which enhances microtubule (MT) acetylation by promoting the degradation of histone deacetylase 6 (HDAC6), and facilitates the nuclear translocation of Smad complex, and thereby enhancing downstream TGF-β signaling. Smad complex, in turn, increases MAP1S, establishing a feedback loop of MAP1S/Smad/TGF-β1. Finally, survival analysis of 150 HBV-associated HCC patients demonstrated both increased MAP1S and decreased HDAC6 were significantly associated with shorter relapse-free survival. Collectively, this study reveals a unique mechanism whereby HBx-induced upregulation of MAP1S drives HBV-related HCC proliferation and migration through the MAP1S/Smad/TGF-β1 feedback loop. TEASER: MAP1S is a key link between HBV infection and a higher risk of metastatic recurrence of HCC.

Exosomes are widely recognized for their roles in numerous biological processes and as intercellular communication mediators. Human cancerous and normal cells can both produce massive amounts of exosomes. They are extensively dispersed in tumor-modeling animals' pleural effusions, ascites, and plasma from people with cancer. Tumor cells interact with host cells by releasing exosomes, which allow them to interchange various biological components. Tumor growth, invasion, metastasis, and even tumorigenesis can all be facilitated by this delicate and complex system by modifying the nearby and remote surroundings. Due to the existence of significant levels of biomolecules like microRNA, exosomes can modulate the immune system's stimulation or repression, which in turn controls tumor growth. However, the role of microRNA in exosome-mediated communication between immunological and cancer cells is still poorly understood. This study aims to get the most recent information on the "yin and yang" of exosomal microRNA in the regulation of tumor immunity and immunotherapy, which will aid current cancer treatment and diagnostic techniques.

Hepatocellular carcinoma (HCC) tissue is rich in dendritic cells, T cells, B cells, macrophages, natural killer cells and cellular stroma. Together they form the tumor microenvironment (TME), which is also rich in numerous cytokines. Tumor‑associated macrophages (TAMs) are involved in the regulation of tumor development. TAMs in HCC receive stimuli in different directions, polarize in different directions and release different cytokines to regulate the development of HCC. TAMs are mostly divided into two cell phenotypes: M1 and M2. M1 TAMs secrete pro‑inflammatory mediators, and M2 TAMs secrete a variety of anti‑inflammatory and pro‑tumorigenic substances. The TAM polarization in HCC tumors is M2. Both direct and indirect methods for TAMs to regulate the development of HCC are discussed. TAMs indirectly support HCC development by promoting peripheral angiogenesis and regulating the immune microenvironment of the TME. In terms of the direct regulation between TAMs and HCC cells, the present review mainly focuses on the molecular mechanism. TAMs are involved in both the proliferation and apoptosis of HCC cells to regulate the quantitative changes of HCC, and stimulate the related invasive migratory ability and cell stemness of HCC cells. The present review aims to identify immunotherapeutic options based on the mechanisms of TAMs in the TME of HCC.

NDRG1, the first member of the NDRG family, is a multifunctional protein associated with carcinogenesis. Its function in human cancer is currently poorly understood. The aim of this study was to explore the importance of NDRG1 in tumor immune cell infiltration and epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma.

NDRG1 expression in various cancers was analyzed using TIMER 2.0, the Human Protein Atlas (HPA), UALCAN and PrognoScan. Wound healing, Transwell, MTT and colony formation assays were performed to confirm the effects of NDRG1 on the metastasis and proliferation of HCC cells. Western blotting was used to study the effect of NDRG1 on the expression of EMT-related proteins. Signaling networks were constructed using LinkedOmics and Metascape. TIMER2.0 and TISIDB were used for comprehensive analysis of tumor-infiltrating immune cells and tumor-infiltrating lymphocytes (TILs).

NDRG1 expression was higher in HCC tissue than in normal liver tissue at both the mRNA and protein levels. Overexpression of NDRG1 is associated with poor prognosis in HCC patients. Genomic analysis suggests that NDRG1 promoter hypermethylation leads to enhanced transcription, which may be one mechanism for NDRG1 upregulation in HCC. The overexpression of NDRG1 promotes the invasion, migration, and proliferation of HCC cells and induces the expression of EMT-related proteins. Immunoinfiltration analysis suggests that NDRG1 is involved in the recruitment of immune cells.

The present study showed that NDRG1 may induce metastasis and invasion through EMT and immune cell infiltration. NDRG1 could be used as a biomarker for the diagnosis and prognosis of HCC and could be a potential therapeutic target in HCC.

Liver cancer, which most commonly manifests as hepatocellular carcinoma (HCC), is the sixth most common cancer in the world. In HCC, the immune system plays a crucial role in the growth and proliferation of tumor cells. HCC achieve immune escape through the tumor microenvironment, which significantly promotes the development of this cancer. Here, this article introduces and summarizes the functions and effects of regulatory T cells (Tregs) in the tumor microenvironment, highlighting how Tregs inhibit and regulate the functions of immune and tumor cells, cytokines, ligands and receptors, etc, thereby promoting tumor immune escape. In addition, it discusses the mechanism of CAR-T therapy for HCC and elaborate on the relationship between CAR-T and Tregs.

Exosomes are small lipid nanovesicles with a diameter of 30-150 nm. They are present in all body fluids and are actively secreted by the majority of cells through the process of exocytosis. Exosomes play an essential role in intercellular communication and act as significant molecular carriers in regulating various physiological and pathological processes, such as the emergence of drug resistance in tumors. Tumor-associated exosomes transfer drug resistance to other tumor cells by releasing substances such as multidrug resistance proteins and miRNAs through exosomes. These substances change the cell phenotype, making it resistant to drugs. Tumor-associated exosomes also play a role in impacting drug resistance in other cells, like immune cells and stromal cells. Exosomes alter the behavior and function of these cells to help tumor cells evade immune surveillance and form a tumor niche. In addition, exosomes also export substances such as tumoricidal drugs and neutralizing antibody drugs to help tumor cells resist drug therapy. In this review, we summarize the mechanisms of exosomes in promoting drug resistance by delivering cargo in the context of the tumor microenvironment (TME).

The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell-cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.

Tumor metastasis is the leading cause of cancer-related death in patients with colorectal cancer (CRC). Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-binding proteins, involved in the tumorigenesis and metastasis of various cancers. However, the molecular mechanisms of hnRNPs in CRC metastasis remain unclear. This study aims to uncover the pivotal roles and molecular mechanisms of hnRNPs in CRC metastasis. Clinical database analysis suggested that the expression of hnRNP-Associated with Lethal Yellow (RALY, an important member of hnRNPs) was strongly correlated with the aggressiveness and survival of CRC patients. Gain- and loss-of-function studies demonstrated that RALY promotes the production of exosomes by increasing the formation of multivesicular bodies (MVBs) and enhancing the fusion of MVBs with the plasma membrane. Notably, RALY directly interacts with phospholipase D2 (PLD2) to enable exosome biogenesis, and cooperates with RBM15b to control PLD2 mRNA stability in an m6A-dependent manner. RALY-mediated exosome secretion activates pro-tumor macrophages and further facilitates CRC metastasis, while rescue experiments in vivo further confirmed that RALY-mediated exosome biogenesis facilitates CRC metastasis. Collectively, our findings demonstrate that RALY promotes exosome biogenesis and facilitates colorectal cancer metastasis by upregulating PLD2 and enhancing exosome production in an m6A-dependent manner, suggesting potential therapeutic strategies for combating CRC metastasis.

Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PD-L1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type).

Extracellular vesicles (EVs) have gainedsignificant attention due totheir crucialroles invarious biological systems. This review aims to explore the functions of EVs in both in physiological and pathological states of the liver, with a specific focus on the potential mechanisms and concrete evidence of EVs in liver regeneration processes. The review begins by emphasizing the importance of EVs in maintaining liver health and their involvement in different pathological conditions, starting from the liver's own EVs. Reviewing the role of EVs in liver diseases to reveal the impact of EVs in pathological processes (e.g., hepatitis, liver fibrosis, and cirrhosis) and elucidate their signaling functions at the molecular level. Subsequently, the work concentrates on the functions of EVs in liver regeneration, revealing their key role in repair and regeneration following liver injury by carrying growth factors, nucleic acids, and other bioactive molecules. This part not only theoretically clarifies the mechanisms of EVs in liver regeneration but also experimentally demonstrates their role in promoting liver cell proliferation, inhibiting apoptosis, regulating immune responses, and fostering angiogenesis, laying the groundwork for future clinical applications. Moreover, this work provides a comprehensive analysis of the challenges faced by existing EV-based therapies in liver regeneration and offers prospects for future research directions. It highlights that despite the tremendous potential of EVs in treating liver diseases, there are still technical challenges (e.g., EV isolation and purification, dosage control, and targeted delivery). To overcome these challenges, the review suggests improvements to current technologies and the development of new methods to realize the clinical application of EVs in treating liver diseases.

Tumor-associated macrophages (TAMs) are predominantly present in the tumor microenvironment (TME) and play a crucial role in shaping the efficacy of tumor immunotherapy. These TAMs primarily exhibit a tumor-promoting M2-like phenotype, which is associated with the suppression of immune responses and facilitation of tumor progression. Interestingly, recent research has highlighted the potential of repolarizing TAMs from an M2 to a pro-inflammatory M1 status-a shift that has shown promise in impeding tumor growth and enhancing immune responsiveness. This concept is particularly intriguing as it offers a new dimension to cancer therapy by targeting the tumor microenvironment, which is a significant departure from traditional approaches that focus solely on tumor cells. However, the clinical application of TAM-modulating agents is often challenged by issues such as insufficient tumor accumulation and off-target effects, limiting their effectiveness and safety. In this regard, nanomaterials have emerged as a novel solution. They serve a dual role: as delivery vehicles that can enhance the accumulation of therapeutic agents in the tumor site and as TAM-modulators. This dual functionality of nanomaterials is a significant advancement as it addresses the key limitations of current TAM-modulating strategies and opens up new avenues for more efficient and targeted therapies. This review provides a comprehensive overview of the latest mechanisms and strategies involving nanomaterials in modulating macrophage polarization within the TME. It delves into the intricate interactions between nanomaterials and macrophages, elucidating how these interactions can be exploited to drive macrophage polarization towards a phenotype that is more conducive to anti-tumor immunity. Additionally, the review explores the burgeoning field of TAM-associated nanomedicines in combination with tumor immunotherapy. This combination approach is particularly promising as it leverages the strengths of both nanomedicine and immunotherapy, potentially leading to synergistic effects in combating cancer.

Tumor-associated macrophages of the M2 phenotype promote cancer initiation and progression. Importantly, M2 macrophage-derived exosomes play key roles in the malignancy of cancer cells. Here, we report that circTMCO3 is upregulated in ovarian cancer patients, and its high expression indicates poor survival. M2-derived exosomes promote proliferation, migration, and invasion in ovarian cancer, but these effects are abolished by knockdown of circTMCO3. Furthermore, circTMCO3 functions as a competing endogenous RNA for miR-515-5p to reduce its abundance, thus upregulating ITGA8 in ovarian cancer. miR-515-5p inhibits ovarian cancer malignancy via directly downregulating ITGA8. The decreased oncogenic activity of circTMCO3-silencing exosomes is reversed by miR-515-5p knockdown or ITGA8 overexpression. Exosomal circTMCO3 promotes ovarian cancer progression in nude mice. Thus, M2 macrophage-derived exosomes promote malignancy by delivering circTMCO3 and targeting the miR-515-5p/ITGA8 axis in ovarian cancer. Our findings not only provide mechanistic insights into ovarian cancer progression, but also suggest potential therapeutic targets.

Stable infiltration of myeloid cells, especially tumor-associated M2 macrophages, acts as one of the essential features of the tumor immune microenvironment by promoting the malignant progression of hepatocellular carcinoma (HCC). However, the factors affecting the infiltration of M2 macrophages are not fully understood. In this study, we found the molecular subtypes of HCC with the worst prognosis are characterized by immune disorders dominated by myeloid cell infiltration. Myeloid cell nuclear differentiation antigen (MNDA) was significantly elevated in the most aggressive subtype and exhibited a positively correlation with M2 infiltration and HCC metastasis. Moreover, MNDA functioned as an independent prognostic predictor and has a good synergistic effect with some existing prognostic clinical indicators. We further confirmed that MNDA was primarily expressed in tumor M2 macrophages and contributed to the enhancement of its polarization by upregulating the expression of the M2 polarization enhancers. Furthermore, MNDA could drive the secretion of M2 macrophage-derived pro-metastasis proteins to accelerate HCC cells metastasis both in vivo and in vitro. In summary, MNDA exerts a protumor role by promoting M2 macrophages polarization and HCC metastasis, and can serve as a potential biomarker and therapeutic target for HCC.

Fibroblast activation protein (FAP) has been indicated to express in cancer-associated fibroblasts (CAFs) in most cancers. This work was dedicated to exploring FAP's effects on hepatocellular carcinoma (HCC). The data were extracted from The Cancer Genome Atlas, Gene Expression Omnibus, ImmPort, and Reactome databases. The correlation between FAP and HCC patients' prognosis was explored via survival analysis. The qRT-PCR and western blot analysis were used to analyze the FAP mRNA and protein expression levels, respectively. The cell proliferation and apoptosis were determined using the cell counting kit-8 assay kit and Annexin V-FITC/PI apoptosis kit, respectively. The HCC patients with FAP overexpression displayed a worse prognosis. The FAP expression was positively associated with the infiltration levels of tumor purity, B cell, CD8 + T cell, CD4 + T cell, macrophage, neutrophil, and dendritic cell. The optimal nine immune related genes were screened between two groups (FAP high vs. low). Moreover, we identified 24 energy metabolism related genes (FAP high vs. low) and these 24 genes were highly expressed in the high FAP expression group. The FAP expression had a significant positive correlation with the expression of PD-1, CTLA4, PDL-1, and PDL-2. The FAP overexpression promoted proliferation and migration while inhibiting the apoptosis of HCC cells. The FAP overexpression promoted the progression of HCC by regulating the immunity to affect the prognosis of HCC patients, thereby serving as a poor prognostic marker for HCC patients.

Exosomes assume a pivotal role as essential mediators of intercellular communication within tumor microenvironments. Within this context, long noncoding RNAs (LncRNAs) have been observed to be preferentially sorted into exosomes, thus exerting regulatory control over the initiation and progression of cancer through diverse mechanisms.

Exosomes were successfully isolated from cholangiocarcinoma (CCA) CTCs organoid and healthy human serum. Notably, the LncRNA titin-antisense RNA1 (TTN-AS1) exhibited a conspicuous up-regulation within CCA CTCs organoid derived exosomes. Furthermore, a significant elevation of TTN-AS1 expression was observed in tumor tissues, as well as in blood and serum exosomes from patients afflicted with CCA. Importantly, this hightened TTN-AS1 expression in serum exosomes of CCA patients manifested a strong correlation with both lymph node metastasis and TNM staging. Remarkably, both CCA CTCs organoid-derived exosomes and CCA cells-derived exosomes featuring pronounced TTN-AS1 expression demonstrated the capability to the proliferation and migratory potential of CCA cells. Validation of these outcomes was conducted in vivo experiments.

In conclusion, our study elucidating that CCA CTCs-derived exosomes possess the capacity to bolster the metastasis tendencies of CCA cells by transporting TTN-AS1. These observations underscore the potential of TTN-AS1 within CTCs-derived exosomes to serve as a promising biomarker for the diagnosis and therapeutic management of CCA.

Exosomes, which are tiny particles released by cells, have the ability to transport various molecules, including proteins, lipids, and genetic material containing non-coding RNAs (ncRNAs). They are associated with processes like cancer metastasis, immunity, and tissue repair. Clinical trials have shown exosomes to be effective in treating cancer, inflammation, and chronic diseases. Mesenchymal stem cells (MSCs) and dendritic cells (DCs) are common sources of exosome production. Exosomes have therapeutic potential due to their ability to deliver cargo, modulate the immune system, and promote tissue regeneration. Bioengineered exosomes could revolutionize disease treatment. However, more research is needed to understand exosomes in tumor growth and develop new therapies. This paper provides an overview of exosome research, focusing on cancer and exosome-based therapies including chemotherapy, radiotherapy, and vaccines. It explores exosomes as a drug delivery system for cancer therapy, highlighting their advantages. The article discusses using exosomes for various therapeutic agents, including drugs, antigens, and RNAs. It also examines challenges with engineered exosomes. Analyzing exosomes for clinical purposes faces limitations in sensitivity, specificity, and purification. On the other hand, Nanotechnology offers solutions to overcome these challenges and unlock exosome potential in healthcare. Overall, the article emphasizes the potential of exosomes for personalized and targeted cancer therapy, while acknowledging the need for further research.

Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.

Jianpi Yangzheng decoction (JPYZ) possesses a potential anti-tumor activity in gastric cancer. However, potential effect of JPYZ on regulating tumor-associated macrophage (TAM)-derived exosomes to affect gastric cancer is still unclear.

We aimed to clarify the role of tumor-associated macrophage derived exosomes (TAM-exos) in invasive and metastasis of gastric cancer and the mechanism of JPYZ regulate TAM-exos against gastric cancer.

Flow cytometry was performed to demonstrate whether JPYZ involved in TAM polarization. After JPYZ treatment, TAM conditioned medium (TAM-CM)/TAM-exos were co-cultured with gastric cancer cells and were detected by wound healing and transwell assay. Transcriptome sequencing and bioinformatics analysis predicted the exosomal miRNA after JPYZ intervention in TAM. miRNA mimic and inhibitor were used to verify the effect of miRNA in exosomes on gastric cancer cells. Q-PCR and luciferase reporter assay were employed to clarify the targeting relationship between miRNA and target gene. Western blot assay detected the expression levels of epithelial-mesenchymal transition (EMT) markers and related signaling pathways proteins.

We firstly demonstrated that TAM-CM intervened by JPYZ significantly inhibited the invasion and migration of gastric cancer. Furthermore, exosomes in TAM supernatants play a key role in migration of gastric cancer. Meanwhile, transcriptome sequencing and q-PCR revealed that miR-513b-5p expression was significantly reduced in TAM-exos intervened by JPYZ. And miR-513b-5p in TAM aggravated TAM-exos mediated invasion and migration of gastric cancer cells, the inhibitor of miR-513b-5p reversed TAM-exos mediated promotion. Bioinformatics analysis and luciferase reporter assay confirmed that PTEN was a direct target of miR-513b-5p in gastric cancer. MiR-513b-5p inhibited PTEN to activate AKT/mTOR signaling pathway thus promoting gastric cancer invasion and metastasis in vivo and in vitro. Importantly, JPYZ inhibited TAM derived exosomal miR-513b-5p, and alleviated AKT/mTOR activation by PTEN depended manner in gastric cancer.

TAM-exos containing miR-513b-5p lead to gastric cancer invasion and migration. Our findings clarify a novel TAM-exos mechanism of JPYZ for inhibiting gastric cancer progression.

Extracellular vesicles are nanoscale vesicles that can be secreted by all cell types, are intracellular in origin and have the same composition as their parent cells, play a key role in intercellular communication in organismal health and disease, and are now often used as biomarkers of disease and therapeutic agents in biomedical research. When injected locally or systemically, they have the ability to provide a variety of therapeutic effects, for example, regeneration of skin damage or restoration of cardiac function. However, direct injection of extracellular vesicles may result in their rapid clearance from the injection site.In order to maintain the biological activity of extracellular vesicles and to control the release of effective concentrations for better therapeutic efficacy during long-term disease treatment, the design of an optimized drug delivery system is necessary and different systems for the continuous delivery of extracellular vesicles have been developed. This paper first provides an overview of the biogenesis, composition and physiological function of extracellular vesicles, followed by a review of different strategies for extracellular vesicle isolation and methods for engineering extracellular vesicles. In addition, this paper reviews the latest extracellular vesicle delivery platforms such as micro-nanoparticles, injectable hydrogels, microneedles and scaffold patches. At the same time, the research progress and key cases of extracellular vesicle delivery systems in the field of biomedical therapeutics are described. Finally, the challenges and future trends of extracellular vesicle delivery are discussed.

This study aimed to investigate the effects of nanoparticles on macrophage polarization and their subsequent influence on post-tumorigenic behavior. Initially, seven different nanoparticles were applied to macrophages, and Zn-Ni-FeO (100 nm) and palladium nanoparticles (PdNPs, ∼25 nm) were found to induce M1-polarization in macrophages. A co-culture experiment was then conducted to examine the effects of macrophages on MCF-7 breast cancer micro-tissues. The M2-macrophages promoted tumor proliferation, while M1- and PdNPs-induced macrophages showed anti-tumor effects by suppressing cell proliferation. To reveal the mechanisms of effect, exosomes isolated from M1 (M1-Exo), M0 (M0-Exo), M2 (M2-Exo), and PdNPs-induced (PdNPs-Exo) macrophages were applied to the heterotypic tumor micro-tissues including MCF-7, human umbilical vein endothelial cells (HUVECs), and primary human dermal fibroblasts (phDFs). M2-Exo was seen to promote the migration of cancer cells and induce epithelial-mesenchymal transition (EMT), while M1-Exo suppressed these behaviors. PdNPs-Exo was effective in suppressing the aggressive nature of breast cancer cells similar to M1-Exo, moreover, the efficacy of 5-fluorouracil (5-FU) was increased in combination with PdNPs-Exo in both MCF-7 and heterotypic micro-tissues. In conclusion, PdNPs-Exo has potential anti-tumor effects, can be used as a combination therapy to enhance the efficacy of anti-cancer drugs, as well as innovative implants for breast cancer treatment.

Hepatocellular carcinoma (HCC) remains a global health challenge. Novel treatment modalities are urgently needed to extend the overall survival of patients. The liver plays an immunomodulatory function due to its unique physiological structural characteristics. Therefore, following surgical resection and radiotherapy, immunotherapy regimens have shown great potential in the treatment of hepatocellular carcinoma. Adoptive cell immunotherapy is rapidly developing in the treatment of hepatocellular carcinoma. In this review, we summarize the latest research on adoptive immunotherapy for hepatocellular carcinoma. The focus is on chimeric antigen receptor (CAR)-T cells and T cell receptor (TCR) engineered T cells. Then tumour-infiltrating lymphocytes (TILs), natural killer (NK) cells, cytokine-induced killer (CIK) cells, and macrophages are briefly discussed. The main overview of the application and challenges of adoptive immunotherapy in hepatocellular carcinoma. It aims to provide the reader with a comprehensive understanding of the current status of HCC adoptive immunotherapy and offers some strategies. We hope to provide new ideas for the clinical treatment of hepatocellular carcinoma.

Despite remarkable advancements in cancer immunotherapy, the overall response rate to anti-programmed cell death-1 (anti-PD-1) therapy in hepatocellular carcinoma (HCC) patients remains low. Our previous study has demonstrated the critical role of CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) as a regulator of HCC development and progression. However, the possible impact of CacyBP on the tumor immune microenvironment has not yet been clarified.

The expressions of CacyBP and Myd88 in HCC cell lines and tissues was detected by bioinformatics analysis, real-time quantitative PCR, western blotting and immunohistochemistry. The interaction between CacyBP and Myd88 was measured using co-immunoprecipitation and immunofluorescence. In vitro and in vivo assays were used to investigate the regulation of CacyBP on tumor-associated macrophages (TAMs).

We identified that CacyBP was positively correlated with Myd88, a master regulator of innate immunity, and Myd88 was a novel binding substrate downstream of CacyBP in HCC. Additionally, CacyBP protected Myd88 from Siah-1-mediated proteasome-dependent degradation by competitively binding to its Toll/interleukin-1 receptor (TIR) domain. Inhibition of CacyBP-Myd88 signaling subsequently diminished HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter and reduced its transcription and secretion in HCC cells. Moreover, by using in vitro and in vivo strategies, we demonstrated that depletion of CacyBP impaired the infiltration of TAMs and the immunosuppressive state of the tumor microenvironment, further sensitizing HCC-bearing anti-PD-1 therapy.

Our findings suggest that targeting CacyBP may be a novel treatment strategy for improving the efficacy of anti-PD-1 immunotherapy in HCC.

M2 type tumor-associated macrophages, an essential component of the tumor microenvironment (TME), have been proved to contribute to tumor metastasis. Dauricine (Dau) has recently received widespread attention due to its multiple targets and low price. However, the effect of Dau on macrophage polarization of TME remains unclear. In this study, we investigated the effect of Dau on prostate cancer (PCa) metastasis and specifically its correlation to macrophage polarization. Our results showed that Dau efficiently suppressed M2 polarization of macrophages induced by interleukin (IL) -4 and IL-13. Mechanistically, Dau inhibited the activity of PI3K/AKT signaling pathway, which subsequently suppressed macrophage differentiation to M2 type. Importantly, our study indicated that Dau decreased the release of chitinase 3-like protein 1 (CHI3L1) from M2 macrophages, which ultimately inhibited the M2 macrophage-mediated progression of PCa cells in vitro and in vivo. Taken together, our data demonstrated that Dau suppressed M2 polarization of macrophages via downregulation of the PI3K/AKT signaling pathway, in turn, preventing proliferation, epithelial-mesenchymal transition, migration, and invasion of PCa cells. Thus, this study reveals a previously unrecognized function of Dau in inhibition of PCa progression via intervention in M2 polarization of macrophages.

Hepatocellular carcinoma (HCC) is a prevailing cancer affecting human health. M2 macrophages are essential in mediating immune responses in tumors. This study investigated the action of M2 macrophages in immune escape of HCC.

Mitotic spindle positioning (MISP), IQ motif containing GTPase activating protein 1 (IQGAP1) and programmed cell death-1 (PD-L1) levels in primary HCC/tumor-adjacent tissues were determined by Western blot, followed by correlation analysis. M2 macrophage and CD3+CD8+T cell percentages were estimated by flow cytometry. Hep3B and HepG2 cells were treated with M2 macrophage conditioned medium (M2-CM) and M2 macrophage-derived extracellular vesicles (M2-EVs) and/or co-cultured with CD8+T cells, followed by assessment of cell viability and apoptosis. TNF-α and INF-γ levels were measured by ELISA. MISP and IQGAP1 overexpression plasmids were transfected into HCC cells to explore their role in immune escape. The interactions among MISP, IQGAP1, STAT3, and PD-L1 were analyzed by co-immunoprecipitation. The mechanism of M2-EVs in HCC immune escape was verified in nude mice.

MISP/IQGAP1/PD-L1 were upregulated in HCC tissues. MISP negatively-correlated with IQGAP1/PD-L1 and IQGAP1 positively-correlated with PD-L1. M2 macrophages were reduced but CD8+T cells were increased in HCC tissues with high MISP expression. M2-CM or M2-EVs inhibited the killing ability of CD8+T cells, increased HCC cell viability, impeded HCC cell apoptosis, induced CD8+T cell apoptosis, downregulated TNF-α and INF-γ, and upregulated PD-L1. M2-EVs facilitated HCC cell immune escape by potentiating IQGAP1 nuclear translocation and activating STAT3 phosphorylation through MISP downregulation. In vivo experiments further verified the action of M2-EVs through MISP.

M2-EVs promote HCC cell immune escape by upregulating PD-L1 through the MISP/IQGAP1/STAT3 axis.

The aim of this study was to reveal the key genes associated with macrophage polarization in liver cancer.

Data were downloaded from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas databases (TCGA). R package Seurat 4.0 was used to preprocess the downloaded single-cell sequencing data, principal component analysis, and clustering. R package SingleR was used to annotate cell types and calculate macrophage polarization scores. Spearman correlation analysis was performed to obtain key genes highly correlated with macrophage polarization in liver cancer. The Tumor IMmune Estimation Resource algorithm was used to analyze the correlation between genes and the infiltration level of macrophages. Finally, the prognostic model was constructed based on 6 macrophage polarization-related genes by multivariate Cox regression analysis. Kaplan-Meier curves and receiver operating characteristic curves validated the prognostic value of the prognostic model.

Two thousand highly variable genes were obtained after the normalization of single-cell profiles. In all, 16 principal components and 15 cell clusters were obtained. Monocytes and macrophages were the main immune cells in the microenvironment of liver cancer tissues. Macrophage polarization scores showed that cluster 5 had the highest degree of polarization. Spearman analysis yielded that a total of 6 key genes associated with macrophage polarization (CD53, TGFBI, S100A4, pyruvate kinase M, LSP1, SPP1), and Tumor IMmune Estimation Resource analysis showed that 6 key genes were significantly positively correlated with macrophage infiltration levels. The model constructed by 6 key genes could effectively evaluate the prognosis of patients with liver cancer.

The key genes associated with macrophage polarization, namely CD53, TGFBI, S100A4, pyruvate kinase M, LSP1, and SPP1, may be potential therapeutic targets for liver cancer.

N-glycosylation has been revealed to be tightly associated with cancer metastasis. As a key transferase that catalyzes the formation of β1,4 N-acetylglucosamine (β1,4GlcNAc) branches on the mannose core of N-glycans, N-acetylglucosaminyltransferase IVa (GnT-IVa) has been reported to be involved in hepatocellular carcinoma (HCC) metastasis by forming N-glycans; however, the underlying mechanisms are largely unknown. In the current study, we found that GnT-IVa was upregulated in HCC tissues and positively correlated with worse outcomes in HCC patients. We found that GnT-IVa could promote tumor growth in mice; notably, this effect was attenuated after mutating the enzymatic site (D445A) of GnT-IVa, suggesting that GnT-IVa regulated HCC progression by forming β1,4GlcNAc branches. To mechanistically investigate the role of GnT-IVa in HCC, we conducted GSEA and GO functional analysis as well as in vitro experiments. The results showed that GnT-IVa could enhance HCC cell migration, invasion and adhesion ability and increase β1,4GlcNAc branch glycans on integrin β1 (ITGB1), a tumor-associated glycoprotein that is closely involved in cell motility by interacting with vimentin. Interruption of β1,4GlcNAc branch glycan modification on ITGB1 could suppress the interaction of ITGB1 with vimentin and inhibit cell motility. These results revealed that GnT-IVa could promote HCC cell motility by affecting the biological functions of ITGB1 through N-glycosylation. In summary, our results revealed that GnT-IVa is highly expressed in HCC and can form β1,4GlcNAc branches on ITGB1, which are essential for interactions with vimentin to promote HCC cell motility. These findings not only proposed a novel mechanism for GnT-IVa in HCC progression but also revealed the significance of N-glycosylation on ITGB1 during the process, which may provide a novel target for future HCC therapy.

Hepatocellular carcinoma (HCC) is an inflammation-associated tumor involved in immune tolerance and evasion in the immune microenvironment. Immunotherapy can enhance the immune response of the body, break immune tolerance, and then recognize and kill tumor cells. The polarization homeostasis of M1 and M2 macrophages in tumor microenvironment (TME) is involved in the occurrence and development of tumors and has been considered a hot topic in tumor research. Programmed cell death ligand 1 (PD-L1) plays an important role in the polarity of TAM and affects the prognosis of HCC patients as a target of immunotherapy. To this end, efforts were hereby made to further explore the application value of PD-L1, M1 macrophages (CD86), and M2 macrophages (CD206) in the prognosis assessment of HCC, their correlation with immune cell infiltration in HCC tissues, and their bioenrichment function.

The gene expression omnibus (GEO) and the Cancer Genome Atlas (TCGA) database were used to analyze the expression of PD-L1, CD86, and CD206 in different tumor tissues. The correlation between the expression of PD-L1, CD86, and CD206 and the infiltration of immune cells was analyzed using the Tumor Immune Estimation Resource (TIMER). The tissue specimens and clinicopathological data of hepatocellular carcinoma patients having undergone surgical treatment in our hospital were collected. Immunohistochemistry was used to verify the expression of PD-L1, CD86, and CD206, and analyze the relationship with clinicopathological features and prognosis of patients. Besides, nomogram was constructed to predict the overall survival (OS) of patients at 3 and 5 years. Finally, the protein-protein interaction network information was analyzed using STRING database, and GO analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis were performed to study the biological functions of PD-L1, CD86, and CD206.

Bioinformatics analysis found that PD-L1, CD86, and CD206 were underexpressed in various tumor tissues including liver cancer, while the present immunohistochemical detection found that PD-L1, CD86, and CD206 were overexpressed in liver cancer tissues. Expressions of PD-L1, CD86, and CD206 were positively correlated with the infiltration level of immune cells in liver cancer, while the expression of PD-L1 was positively correlated with the degree of tumor differentiation. Meanwhile, the expression level of CD206 was positively correlated with gender and preoperative hepatitis, and patients with high expression of PD-L1 or low expression of CD86 had poor prognosis. AJCC stage, preoperative hepatitis, and the expression levels of PD-L1 and CD86 in cancer tissues were independent risk factors affecting survival of patients after radical hepatoma surgery. KEGG pathway enrichment analysis showed that PD-L1 was significantly enriched in T cell aggregation and lymphocyte aggregation, and might be involved in the formation of T cell antigen receptor CD3 complex and cell membrane. Besides, CD86 was significantly enriched in positive regulation of cell adhesion, regulation of mononuclear cell proliferation, regulation of leukocyte proliferation, and transduction of T cell receptor signaling pathway, while CD206 was significantly enriched in type 2 immune response, cellular response to LPS, cellular response to LPS, and involvement in cellular response to LPS.

In conclusion, these results suggest that PD-L1, CD86, and CD206 may be involved not only in the occurrence and development of HCC, but also in immune regulation, indicating the potential role of PD-L1 and CD86 as potential biomarkers and new therapeutic targets for prognosis assessment of liver cancer.

Background: Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with late diagnosis; therefore, the identification of new early biomarkers could help reduce mortality. Efferocytosis, a process in which one cell engulfs another cell, including macrophages, dendritic cells, NK cells, etc., plays a complex role in tumorigenesis, sometimes promoting and sometimes inhibiting tumor development. However, the role of efferocytosis-related genes (ERGs) in HCC progression has been poorly studied, and their regulatory effects in HCC immunotherapy and drug targeting have not been reported. Methods: We downloaded efferocytosis-related genes from the Genecards database and screened for ERGs that showed significant expression changes between HCC and normal tissues and were associated with HCC prognosis. Machine learning algorithms were used to study prognostic gene features. CIBERSORT and pRRophetic R packages were used to evaluate the immune environment of HCC subtypes and predict treatment response. CCK-8 experiments conducted on HCC cells were used to assess the reliability of drug sensitivity prediction. Results: We constructed a prognostic prediction model composed of six genes, and the ROC curve showed good predictive accuracy of the risk model. In addition, two ERG-related subgroups in HCC showed significant differences in tumor immune landscape, immune response, and prognostic stratification. The CCK-8 experiment conducted on HCC cells confirmed the reliability of drug sensitivity prediction. Conclusion: Our study emphasizes the importance of efferocytosis in HCC progression. The risk model based on efferocytosis-related genes developed in our study provides a novel precision medicine approach for HCC patients, allowing clinicians to customize treatment plans based on unique patient characteristics. The results of our investigation carry noteworthy implications for the development of individualized treatment approaches involving immunotherapy and chemotherapy, thereby potentially facilitating the realization of personalized and more efficacious therapeutic interventions for HCC.

Esophageal cancer is a prevalent tumor of the digestive tract worldwide. The detection rate of early-stage esophageal cancer is very low, and most patients are diagnosed with metastasis. Metastasis of esophageal cancer mainly includes direct diffusion metastasis, hematogenous metastasis, and lymphatic metastasis. This article reviews the metabolic process of esophageal cancer metastasis and the mechanisms by which M2 macrophages, CAF, regulatory T cells, and their released cytokines, including chemokines, interleukins, and growth factors, form an immune barrier to the anti-tumor immune response mediated by CD8+ T cells, impeding their ability to kill tumor cells during tumor immune escape. The effect of Ferroptosis on the metastasis of esophageal cancer is briefly mentioned. Moreover, the paper also summarizes common drugs and research directions in chemotherapy, immunotherapy, and targeted therapy for advanced metastatic esophageal cancer. This review aims to serve as a foundation for further investigations into the mechanism and management of esophageal cancer metastasis.