Angiogenesis is a complex physiological process. In recent years, the immune regulation of angiogenesis has received increasing attention, and innate immune cells, which are centred on macrophages, are thought to play important roles in vascular neogenesis and development. Various innate immune cells can act on the vasculature through a variety of mechanisms, with commonalities as well as differences and synergistic effects, which are crucial for the progression of vascular lesions. In recent years, monotherapy with antiangiogenic drugs has encountered therapeutic bottlenecks because of the short-term effect of 'vascular normalization'. The combination treatment of antiangiogenic therapy and immunotherapy breaks the traditional treatment pattern. While it has a remarkable curative effect and survival benefits, it also faces many challenges. This review focuses on innate immune cells and mainly introduces the regulatory mechanisms of monocytes, macrophages, natural killer (NK) cells, dendritic cells (DCs) and neutrophils in vascular lesions. The purpose of this paper was to elucidate the underlying mechanisms of angiogenesis and development and the current research status of innate immune cells in regulating vascular lesions in different states. This review provides a theoretical basis for addressing aberrant angiogenesis in disease processes or finding new antiangiogenic immune targets in inflammation and tumor.

Cancer therapy has been revolutionized by immune checkpoint inhibitors (ICIs) that create a new paradigm among cancer immunotherapies. These agents restore the immune system capacity to fight cancer through blocking the action of major immune checkpoint proteins that suppress immune responses such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which tumors exploit for immune escape. Another advancement is the absence of known biomarkers involves ICIs, which can further be translated into new liquid tests like liquid biopsies, indicating the immune status of the patient. Liquid biopsy is a minimally invasive method for identifying tumor-derived components such as circulating tumor cells, cell-free DNA and extracellular vesicles (EVs) from body fluids for analysis. Researchers increasingly use liquid biopsy for biomarkers discovery and patient stratification into clinical applications. Even though immunotherapy has great advances, still there are obstacles faced while using ICIs. Many patients fail to respond to the treatment because of the heterogeneous mechanisms of resistance. Immunotherapy resistance is a dynamic interplay between tumors and their surrounding stroma. To understand this variability, humanized mice models are increasingly used for mirroring human immune responses. Such models offer insight into cancer immunotherapy when human immune system is engrafted into mice, and EV and biomarker profiles are established in those models. EVs reflect differences in tumor characteristics and the immune landscape around tumors to develop personalized strategies to enhance ICI efficacy. This may improve patient prognosis, giving reason to hope for better, more effective treatments.

More and more evidence show that diabetes is closely related to osteoarthritis (OA). However, the role and mechanism of DNA damage-inducible transcript 4 protein (DDIT4) in diabetic OA (DOA) have not been clarified.

We collected OA patients and non-OA subjects who underwent total knee replacement surgery, and analyzed the DDIT4 expression in synovial samples using RT-qPCR. The cell viability of fibroblast-like synoviocytes (FLSs) was measured by CCK-8 assay. Annexin V-FITC/PI double staining was used to detect the cell apoptosis. Scratch and Transwell assays were used to determine cell migration and invasion, respectively.

The levels of cellular inflammatory factors (IL-1β, IL-6 and TNF-α), oxidative stress and glycolysis related indicators were detected by using kits. Western blot was used to determine the expression of DDIT4, Aggrecan, COL3A1, MMP3, MMP13, HK2, PFKP and PKM2 in FLSs or ATDC5 cells. The results showed that the expression level of DDIT4 was significantly reduced in the synovial samples of OA patients and primary FLSs. Functional studies showed that DDIT4 overexpression inhibited the overactivation, migration, and invasion of FLSs, as well as alleviated chondrocyte injury co-cultured with FLSs. Importantly, the expression of DDIT4 was down-regulated in patients with DOA and closely related to DOA. Further research found that high glucose (HG) promoted excessive activation, migration, and invasion of FLSs, and exacerbated the followed chondrocyte injury. Overexpression of DDIT4 alleviated HG-induced abnormal function of FLSs and injury to chondrocytes. Importantly, DDIT4 inhibited lactate synthesis, glucose uptake, LDH activity, extracellular acidification rate, oxygen consumption rate, and expression levels of glycolysis related protein (HK2, PFKP, PKM2) in HG-induced FLSs. And the glycolysis inhibitors (Cyto-B and 3BrPA) alleviated the injury of ATDC5 chondrocytes co-cultured with FLSs.

DDIT4 participates in HG-induced FLSs overactivation and inflammation response, as well as chondrocyte injury and OA progression by regulating glycolysis processes.

Tumor-derived extracellular vesicles (TDEVs) represent a heterogeneous population of extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, which are essential for tumor growth. EVs function as natural carriers of bioactive molecules, including lipids, proteins, and nucleic acids, enabling them to influence and regulate complex cellular interactions within the tumor microenvironment (TME). The TDEVs mainly have immunosuppressive functions as a result of the inhibitory signals disrupting the immune cell anti-tumor activity. They enhance tumor progression and immune evasion by inhibiting the effector function of immune cells and by altering critical processes of immune cell recruitment, polarization, and functional suppression by different signaling pathways. In this sense, TDEVs modulate the NF-κB pathway, promoting inflammation and inducing immune evasion. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling is required for TDEV-mediated immune suppression and the manifestation of tumor-supporting features. The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling, necessary for metabolic reprogramming, is orchestrated by TDEV to abrogate immune response and drive cancer cell proliferation. Finally, exosomal cargo can modulate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, activating pro-inflammatory responses that influence tumor development and immunomodulation. In this review, we take a deep dive into how TDEVs affect the immune cells by altering key signaling pathways. We also examine emerging therapeutic approaches aimed at disrupting EV-mediated pathways, offering promising avenues for the development of novel EV-based cancer immunotherapy.

Cholesterol, as a major component of cell membranes, is closely related to the metabolic regulation of cells and organisms; tumor-associated macrophages play an important push role in tumor progression. We know that tumor-associated macrophages are polarized from macrophages, and the abnormalities of cholesterol metabolism that may be induced during their polarization are worth discussing. This manuscript focuses on metabolic abnormalities in tumor-associated macrophages, and first provides a basic summary of the regulatory mechanisms of abnormal macrophage polarization. Subsequently, it comprehensively describes the features of abnormal glucose, lipid and cholesterol metabolism in TAMs as well as the different regulatory pathways. Then, the paper also discusses the link between abnormal cholesterol metabolism in TAMs and tumors, chronic diseases and aging. Finally, the paper summarizes cancer therapeutic strategies targeting cholesterol metabolism that are already in clinical trials, as well as nanomaterials capable of targeting cholesterol metabolism that are in the research stage, in the hope of providing value for the design of targeting materials. Overall, elucidating metabolic abnormalities in tumor-associated macrophages, particularly cholesterol metabolism, could provide assistance in tumor therapy and the design of targeted drugs.

Metastases are associated with poor survival in head and neck squamous cell carcinoma (HNSCC) patients and tumour-associated macrophages (TAMs) are important drivers in tumour progression and metastasis formation. Small extracellular vesicles (sEVs) are another important factor that contribute to systemic immunosuppression and pre-metastatic niche formation. Here, we investigate the effect of plasma sEVs from HNSCC patients on pre-metastatic niche formation, directly or through modulation of macrophages.

Primary macrophages were incubated with sEVs from plasma of HNSCC patients or healthy donors (HD). RNA profiles and inflammatory properties of macrophages were evaluated. Direct and indirect effects of sEVs on chemotaxis, T cell activation, proliferation and epithelial-to-mesenchymal transition (EMT) of tumour cells were investigated.

sEVs of HNSCC patients and HD induced different RNA profiles in macrophages. sEVs induced apoptosis and inhibition of T cell activation, while tumour cells were attracted by sEV-treated macrophages, but not sEVs directly. Proliferation was inhibited by both, sEVs and supernatant of EV-treated macrophages in HNSCC. Additionally, EMT in tumour cells was reversed by HNSCC sEV-treated macrophages.

sEVs from plasma of HNSCC patients transformed macrophages into metastasis-promoting TAMs and inhibited anti-tumour T cells, highlighting the potential of sEVs and TAMs as targets for therapeutic approaches.

Psoriasis and atopic dermatitis (AD) are both chronic inflammatory skin diseases. Their pathogenesis remains incompletely understood. The polarization states of macrophages, as a crucial part of the innate immune system, are influenced by various factors such as cytokines, inflammatory mediators, and epigenetics. Research has demonstrated that macrophages play a "double-edged sword" role in the pathological process of inflammatory skin diseases: they both drive inflammation progression and participate in tissue repair. This article summarizes the roles of macrophages in the inflammatory development and tissue homeostasis of psoriasis and atopic dermatitis. It explores the impact of different factors on macrophages and inflammatory skin diseases. In conclusion, understanding the classification and plasticity of macrophages is crucial for a deeper understanding of the pathogenesis of psoriasis and AD and the development of personalized treatments.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

Monocytes differentiate into macrophages (Mφs) to facilitate lung metastasis, but the monocyte-to-Mφ transition during this process is not well understood. To investigate, we performed bulk RNA sequencing on Mφs isolated from the lungs of mice bearing Lewis lung carcinoma tumors and from naive lungs. Our results showed impaired differentiation of monocytes into major histocompatibility complex (MHC) class II+ Mφs, with an upregulation of PGE2-inducible genes, including Arg1, in tumor-associated Mφs (TAMs). In vitro experiments confirmed that prostaglandin E2 (PGE2) inhibits the differentiation of MHC class II+ Mφs while promoting Arg1+ Mφs via the E prostanoid 2 (EP2) receptor, accompanied by DNA methylation. Whole-genome bisulfite sequencing revealed that PGE2-EP2 signaling drives the hypermethylation and downregulation of gene sets related to myeloid cells in non-neoplastic tissues. Our study highlights PGE2-EP2-driven DNA methylation in the monocyte-to-TAM transition, suggesting potential therapeutic avenues for lung metastasis.

Hepatocellular carcinoma (HCC), with high incidence and mortality rates among digestive system diseases, has become a focal point for researchers. However, the more we learn about HCC, the more apparent it becomes that our understanding is still superficial. The successes and failures of numerous studies underscore the urgent need for precision medicine in cancer treatment. A crucial aspect of preclinical research in precision medicine is the experimental model, particularly cell culture models. Among these, 3D cell culture models can effectively integrate and simulate the tumor microenvironment, closely reflecting the in vivo conditions of patients. This capability provides a solid theoretical foundation for personalized treatment approaches. In this review, we first outline the common in vitro 3D cell culture models and examine the essential elements within the tumor microenvironment, followed by insights into the current state and future developments of 3D in vitro cell models for HCC.

Streptococcus mutans, the principal pathogen associated with dental caries, impacts individuals across all age groups and geographic regions. Beyond its role in compromising oral health, a growing body of research has established a link between S. mutans and various systemic diseases, including immunoglobulin A nephropathy (IgAN), nonalcoholic steatohepatitis (NASH), infective endocarditis (IE), ulcerative colitis (UC), cerebral hemorrhage, and tumors. The pathogenic mechanisms associated with S. mutans frequently involve collagen-binding proteins (CBPs) and protein antigens (PA) present on the bacterial surface. These components facilitate intricate interactions with the host immune system, thereby potentially contributing to various pathological processes. Specifically, CBP is implicated in the deposition of IgA and complement component C3, which exhibits characteristics reminiscent of IgAN-like lesions through animal models, recent clinical studies suggest a potential involvement of S. mutans in IgAN. In addition, CBP binds to complement component C1q, effectively inhibiting the classical activation pathway of the complement system. In addition, CBP promotes the induction of host cells to produce interferon-gamma (IFN-γ). Furthermore, CBP leads to direct inhibitory effects on platelets and the activation of matrix metalloproteinase-9 (MMP-9) at sites of vascular injury. Moreover, PA enhances the ability of S. mutans to invade hepatic tissue. Through utilization of its PAc, S. mutans excessively produces kynurenine (KYNA), which promotes the development and progression of oral squamous cell carcinoma (OSCC). This article synthesizes the latest advancements in understanding the mechanisms of intricate interactions between S. mutans and various systemic conditions in humans, expanding our perspective beyond the traditional focus on dental caries.

Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract, with increasing incidence and mortality rates, posing a significant burden on human health. Its progression relies on various mechanisms, among which the tumor microenvironment and tumor-associated macrophages (TAMs) have garnered increasing attention. Macrophage infiltration in various solid tumors is associated with poor prognosis and is linked to chemotherapy resistance in many cancers. These significant biological behaviors depend on the heterogeneity of macrophages. Tumor-promoting TAMs comprise subpopulations characterized by distinct markers and unique transcriptional profiles, rendering them potential targets for anticancer therapies through either depletion or reprogramming from a pro-tumoral to an anti-tumoral state. Single-cell RNA sequencing technology has significantly enhanced our research resolution, breaking the traditional simplistic definitions of macrophage subtypes and deepening our understanding of the diversity within TAMs. However, a unified elucidation of the nomenclature and molecular characteristics associated with this diversity remains lacking. In this review, we assess the application of conventional macrophage polarization subtypes in colorectal malignancies and explore several unique subtypes defined from a single-cell omics perspective in recent years, categorizing them based on their potential functions.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Prostate cancer is one of the most common malignancies in men. The tumour microenvironment (TME) has a critical role in the initiation, progression, and metastasis of prostate cancer. TME contains various cell types, including cancer-associated fibroblasts (CAFs), endothelial cells, immune cells such as macrophages, lymphocytes B and T, natural killer (NK) cells, and other proteins such as extracellular matrix (ECM) components. The interactions and communications between these cells within the TME are crucial for the growth and response of various solid tumours, such as prostate cancer to different anticancer modalities. In this review article, we exemplify the various mechanisms by which the TME influences prostate cancer progression. The roles of different cells, cytokines, chemokines, and growth factors in modulating the immune response and prostate tumour growth will be discussed. The impact of these cells and factors and other ECM components on tumour cell invasion and metastasis will also be discussed. We explain how these interactions in TME can affect the response of prostate cancer to therapy. We also highlight the importance of understanding these interactions to develop novel therapeutic approaches for prostate cancer.

Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.

In this research, a hollow mesoporous responsive nanomotor was proposed for enhanced photothermal/immunotherapy under near infrared (NIR) irradiation. HA-HMCuS/AS as the nanomotor composed of hollow mesoporous copper sulfide (HMCuS) loaded with artesunate (AS) and hyaluronic acid (HA) was utilized to induce the polarization of tumor-associated macrophages. At the beginning, ResNet18 deep learning model was utilized to predict the Brunauer-Emmett-Teller (BET) surface area of HMCuS based on the morphology data set which was obtained from our conventional research. And then, we predicted that the as-synthesized HMCuS has a large surface area, which is beneficial for drug loading. Then, upon near-infrared light irradiation, HA-HMCuS/AS exhibited significant cytotoxicity against breast cancer cells and induced tumor thermal ablation. Additionally, HA-HMCuS/AS was found to inhibit the expression of TREM2 at the tumor site, promoting the transition of M2-type macrophages to M1-type macrophages in tumor tissue and enhancing the inflammatory response at the tumor site. In addition, photothermal therapy enabled tumor cells to release tumor-associated antigen and injury-related molecular patterns, promote the maturation and metastasis of dendritic cells, and further activate the body's specific antitumor immune response. By combining photothermal therapy with immunotherapy, the HA-HMCuS nanomotor demonstrated even more robust tumor ablation and suppression effects.

Giant cell arteritis (GCA) is a prevalent artery and is strongly correlated with age. The role of CD4+ Memory T cells in giant cell arteritis has not been elucidated.

Through single-cell analysis, we focused on the CD4+ Memory T cells in giant cell arteritis. eQTL analysis and mendelian randomization analysis identified the significant genes which have a causal effect on giant cell arteritis risk. CD4+ Memory T cells were subsequently divided into gene-positive and gene-negative groups, then further single-cell analysis was conducted. Mendelian randomization of plasma proteins, blood-urine biomarkers and metabolites were also performed. Eventually, the PMA induced Jurkat cell lines were used for biological experiments to explore the specific functions of significant causal genes in CD4+ Memory T cells.

Similarity of CD4+ Memory T cells in GCA and old samples were explored. DDIT4 and ARHGAP15 were identified as significant risk genes via mendelian randomization. The CD4+ Memory T cells were then divided into DDIT4 ± or ARHGAP15 ± groups, and further single-cell analysis indicated the differences in aspects involving intercellular communication, functional pathways, protein activity, metabolism and drug sensitivity between positive and negative groups. In vitro experiments, including overexpression and knockdown, demonstrated that DDIT4 leading to a chronic, low-intensity inflammatory state in CD4+ Memory T cells, eventually promoting the development of GCA.

DDIT4 and ARHGAP15 have significant causal effects on giant cell arteritis risk. Specifically, DDIT4 exhibit pro-inflammatory effects on GCA via promotes chronic, low-intensity inflammatory in CD4+ Memory T cell.

Ischemic conditions such as hypoxia and nutrient starvation, together with interactions with stromal cells, are critical drivers of metastasis. These conditions arise deep within tumor tissues, and thus, observing nascent metastases is exceedingly challenging. We thus developed the 3MIC-an ex vivo model of the tumor microenvironment-to study the emergence of metastatic features in tumor cells in a 3-dimensional (3D) context. Here, tumor cells spontaneously create ischemic-like conditions, allowing us to study how tumor spheroids migrate, invade, and interact with stromal cells under different metabolic conditions. Consistent with previous data, we show that ischemia increases cell migration and invasion, but the 3MIC allowed us to directly observe and perturb cells while they acquire these pro-metastatic features. Interestingly, our results indicate that medium acidification is one of the strongest pro-metastatic cues and also illustrate using the 3MIC to test anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC can help dissecting the complexity of the tumor microenvironment for the direct observation and perturbation of tumor cells during the early metastatic process.

Macrophages are a critical component of the innate immune system, derived from monocytes, with significant roles in anti-inflammatory and anti-tumour activities. In the tumour microenvironment, however, macrophages are often reprogrammed into tumour-associated macrophages (TAMs), which promote tumour growth, metastasis, and therapeutic resistance.

To review recent advancements in the understanding of macrophage polarisation and reprogramming, highlighting their role in tumour progression and potential as therapeutic targets.

This is a review article synthesising findings from recent studies on macrophage polarisation and reprogramming in tumour biology.

Not applicable (review of existing literature).

Key studies were identified and summarised to explore mechanisms of macrophage polarisation and reprogramming, focusing on M1/M2 polarisation, metabolic and epigenetic changes, and pathway regulation.

Macrophage reprogramming in the tumour microenvironment involves complex mechanisms, including phenotypic and functional alterations. These processes are influenced by M1/M2 polarisation, metabolic and epigenetic reprogramming, and various signalling pathways. TAMs play a pivotal role in tumour progression, metastasis, and therapy resistance, making them prime targets for combination therapies.

Understanding the mechanisms underlying macrophage polarisation and reprogramming offers promising avenues for developing therapies to counteract tumour progression. Future research should focus on translating these insights into clinical applications for effective cancer treatment.

Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.

The progression of triple-negative breast cancer is shaped by both tumor cells and the surrounding tumor microenvironment (TME). Within the TME, tumor-associated macrophages (TAMs) represent a significant cell population and have emerged as a primary target for cancer therapy. As antigen-presenting cells within the innate immune system, macrophages are pivotal in tumor immunotherapy through their phagocytic functions. Due to the highly dynamic and heterogeneous nature of TAMs, re-polarizing them to the anti-tumor M1 phenotype can amplify anti-tumor effects and help mitigate the immunosuppressive TME.

In this study, we designed and constructed an ultrasound-responsive targeted nanodrug delivery system to deliver Siglec-G siRNA and Fe3O4, with perfluorohexane (PFH) at the core and mannose modified on the surface (referred to as MPFS@NDs). Siglec-G siRNA blocks the CD24/Siglec-G mediated "don't eat me" phagocytosis inhibition pathway, activating macrophages, enhancing their phagocytic function, and improving antigen presentation, subsequently triggering anti-tumor immune responses. Fe3O4 repolarizes M2-TAMs to the anti-tumor M1 phenotype. Together, these components synergistically alleviate the immunosuppressive TME, and promote T cell activation, proliferation, and recruitment to tumor tissues, effectively inhibiting the growth of primary tumors and lung metastasis.

This work suggests that activating macrophages and enhancing phagocytosis to remodel the TME could be an effective strategy for macrophage-based triple-negative breast cancer immunotherapy.

Antiangiogenic therapy can alter the tumor microenvironment (TME) and thus exert anti-tumor effects, and has the potential to increase the efficacy of conventional therapy and immunotherapy. The aim of this study was to examine current research hotspots and collaborative networks on the relationship between previous antiangiogenic therapies and the TME through bibliometric analysis.

From the Web of Science Core Collection database, all publications from inception through December 2023 were downloaded. In-depth analysis was performed by Bibliometrix packages in R. Keywords and collaborative networks were analyzed using VOSviewers and Citespace.

We obtained a total of 9027 publications. They come from 27 countries and were published in 1387 journals, with a total of 39,604 authors in the studied area. The number of publications increases dramatically from 2014 to 2023, accounting for 73.87% (6668/9027) of all publications. China and CANCERS have the highest number of publications on this topic and CANCER RESEACH is the most influential. In the last decade (2013- 2023), research has gradually shifted from studying the role of vascular endothelial growth factor in the TME to examining how antivascular therapy can contribute to the progression of cancer treatment. Furthermore, nanoparticle-based drug delivery systems and immunotherapy have been widely explored in the past five years. The findings of this study will help scientists to explore this promising field in depth by providing insight into the relationship between antiangiogenic therapy and the TME.

The relationship between the antiangiogenic therapy and the TME has been developing rapidly, but cooperation between different institutions and countries is still limited. Researchers can use this study to identify hotspots and develop trends for related research, thereby facilitating the development and cooperative exchange in this field, as well as to suggest potential future research directions.

Tumor-associated macrophages (TAMs) constitute the primary subset of immune cells within the tumor microenvironment (TME). Exhibiting both phenotypic and functional heterogeneity, TAMs play distinct roles in tumor initiation, progression, and responses to therapy in patients with cancer. In response to various immune and metabolic cues within the TME, TAMs dynamically alter their metabolic profiles to adapt. Changes in glucose, amino acid, and lipid metabolism in TAMs, as well as their interaction with oncometabolites, not only sustain their energy demands but also influence their impact on tumor immune responses. Understanding the molecular mechanisms underlying the metabolic reprogramming of TAMs and their orchestration of metabolic processes can offer insights for the development of novel cancer immunotherapies targeting TAMs. Here, we discuss how metabolism reprograms macrophages in the TME and review clinical trials aiming to normalize metabolic alterations in TAMs and alleviate TAM-mediated immune suppression and protumor activity.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the loss or low expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and progesterone receptor (PR). Due to the lack of clear therapeutic targets, paclitaxel (PTX) is often used as a first-line standard chemotherapy drug for the treatment of high-risk and locally advanced TNBC. PTX is a diterpenoid alkaloid extracted and purified from Taxus plants, functioning as an anticancer agent by inducing and promoting tubulin polymerization, inhibiting spindle formation in cancer cells, and preventing mitosis. However, its clinical application is limited by low solubility and high toxicity. Nanodrug delivery system (NDDS) is one of the feasible methods to improve the water solubility of PTX and reduce side effects. In this review, we summarize the latest advancements in PTX-targeted NDDS, as well as its combination with other codelivery therapies for TNBC treatment. NDDS includes passive targeting, active targeting, stimuli-responsive, codelivery, and multimode strategies. These systems have good prospects in improving the bioavailability of PTX, enhancing tumor targeting, reducing toxicity, controlling drug release, and reverse tumor multidrug resistance (MDR). This review provides valuable insights into the clinical development and application of PTX-targeted NDDS in the treatment of TNBC.

Cancer, the most common condition worldwide, ranks second in terms of the number of human deaths, surpassing cardiovascular diseases. Uncontrolled cell multiplication and resistance to cell death are the traditional features of cancer. The myriad of treatment options include surgery, chemotherapy, radiotherapy, and immunotherapy to treat this disease. Conventional chemotherapy drug delivery suffers from issues such as the risk of damage to benign cells, which can cause toxicity, and a few tumor cells withstand apoptosis, thereby increasing the likelihood of developing tolerance. The side effects of cancer chemotherapy are often more pronounced than its benefits. Regarding drugs used in cancer chemotherapy, their bioavailability and stability in the tumor microenvironment are the most important issues that need immediate addressing. Hence, an effective and reliable drug delivery system through which both rapid and precise targeting of treatment can be achieved is urgently needed. In this work, we discuss the development of various nanobased carriers in the advancement of cancer therapy-their properties, the potential of polymers for drug delivery, and recent advances in formulations. Additionally, we discuss the use of tumor metabolism-rewriting nanomedicines in strengthening antitumor immune responses and mRNA-based nanotherapeutics in inhibiting tumor progression. We also examine several issues, such as nanotoxicological studies, including their distribution, pharmacokinetics, and toxicology. Although significant attention is being given to nanotechnology, equal attention is needed in laboratories that produce nanomedicines so that they can record themselves in clinical trials. Furthermore, these medicines in clinical trials display overwhelming results with reduced side effects, as well as their ability to modify the dose of the drug.

Immunotherapy research focuses on reshaping the tumor microenvironment (TME) to enhance its antitumor immune responses, with an emphasis on understanding the impact of RNA methylation in triple-negative breast cancer (TNBC) TME regulation. This study explored the influence of various RNA methyltransferases on TME cells in TNBC and their correlation with prognosis and immunotherapy response. Using non-negative matrix factorization on single-cell RNA-sequencing data, distinct TME cell clusters were identified based on the expression of 30 RNA methyltransferases. Various analyses, including pseudotime, cell communication, transcription factor regulatory network, and gene enrichment, were conducted on these clusters. The roles of RNA methyltransferase-mediated TME clusters in prognosis and immunotherapy response were determined using TNBC bulk RNA-Seq data, and the findings were validated through immunofluorescence analysis of a tissue microarray comprising 87 samples. Spatial transcriptomic analysis further revealed the distribution of TME cell clusters. Different methyltransferase-mediated cell clusters exhibited unique metabolic, immune, transcriptional, and intercellular communication patterns. Survival analysis indicated prognostic significance in specific TME cell clusters, and immunofluorescence analysis confirmed the prognostic value of m6A_WTAP + CD8T + cells. In conclusion, our study illustrated the involvement of these cell subgroups in tumor growth and antitumor immunity modulation, providing insights into the enhancement of TNBC immunotherapy.

Metabolic rewiring of cancer cells is one of the hallmarks of cancer. As a consequence, the metabolic landscape of the tumour microenvironment (TME) differs compared to correspondent healthy tissues. Indeed, due to the accumulation of acid metabolites, such as lactate, the pH of the TME is generally acidic with a pH drop that can be as low as 5.6. Disruptions in the acid-base balance and elevated lactate levels can drive malignant progression not only through cell-intrinsic mechanisms but also by impacting the immune response. Generally, acidity and lactate dampen the anti-tumour response of both innate and adaptive immune cells favouring tumour progression and reducing the response to immunotherapy. In this review, we summarize the current knowledge on the functional, metabolic and epigenetic effects of acidity and lactate on the cells of the immune system. In particular, we focus on the role of monocarboxylate transporters (MCTs) and other solute carrier transporters (SLCs) that, by mediating the exchange of lactate (among other metabolites) and bicarbonate, participate in pH regulation and lactate transport in the cancer context. Finally, we discuss advanced approaches to target pH or lactate in the TME to enhance the anti-tumour immune response.

Immunomodulatory therapies, including immune checkpoint inhibitors, have drastically changed outcomes for certain cancer types over the last decade. Gliomas are among the cancers that have seem limited benefit from these agents, with most trials yielding negative results. The unique composition of the glioma immune microenvironment is among the culprits for this lack of efficacy. In recent years, several efforts have been made to improve understanding of the glioma immune microenvironment, aiming to pave the way for novel therapeutic interventions. In this review, we discuss some of the main components of the glioma immune microenvironment, including macrophages, myeloid-derived suppressor cells, neutrophils and microglial cells, as well as lymphocytes. We then provide a comprehensive overview of novel immunomodulatory agents that are currently in clinical development, namely oncolytic viruses, vaccines, cell-based therapies such as CAR-T cells and CAR-NK cells as well as antibodies and peptides.

Immunotherapy has made significant strides in cancer treatment, particularly through immune checkpoint blockade (ICB), which has shown notable clinical benefits across various tumor types. Despite the transformative impact of ICB treatment in cancer therapy, only a minority of patients exhibit a positive response to it. In patients with solid tumors, those who respond well to ICB treatment typically demonstrate an active immune profile referred to as the "hot" (immune-inflamed) phenotype. On the other hand, non-responsive patients may exhibit a distinct "cold" (immune-desert) phenotype, differing from the features of "hot" tumors. Additionally, there is a more nuanced "excluded" immune phenotype, positioned between the "cold" and "hot" categories, known as the immune "excluded" type. Effective differentiation between "cold" and "hot" tumors, and understanding tumor intrinsic factors, immune characteristics, TME, and external factors are critical for predicting tumor response and treatment results. It is widely accepted that ICB therapy exerts a more profound effect on "hot" tumors, with limited efficacy against "cold" or "altered" tumors, necessitating combinations with other therapeutic modalities to enhance immune cell infiltration into tumor tissue and convert "cold" or "altered" tumors into "hot" ones. Therefore, aligning with the traits of "cold" and "hot" tumors, this review systematically delineates the respective immune characteristics, influencing factors, and extensively discusses varied treatment approaches and drug targets based on "cold" and "hot" tumors to assess clinical efficacy.

The stress response protein regulated in development and DNA damage response 1 (REDD1) has emerged as a key player in the pathogenesis of diabetes. Diabetes upregulates REDD1 in a variety of insulin-sensitive tissues, where the protein acts to inhibit signal transduction downstream of the insulin receptor. REDD1 functions as a cytosolic redox sensor that suppresses Akt/mTORC1 signaling to reduce energy expenditure in response to cellular stress. Whereas a transient increase in REDD1 contributes to an adaptive cellular response, chronically elevated REDD1 levels are implicated in disease progression. Recent studies highlight the remarkable benefits of both whole-body and tissue-specific REDD1 deletion in preclinical models of type 1 and type 2 diabetes. In particular, REDD1 is necessary for the development of glucose intolerance and the consequent rise in oxidative stress and inflammation. Here, we review studies that support a role for chronically elevated REDD1 levels in the development of diabetes complications, reflect on limitations of prior therapeutic approaches targeting REDD1 in patients, and discuss potential opportunities for future interventions to improve the lives of people living with diabetes. This article is part of a series of Perspectives that report on research funded by the American Diabetes Association Pathway to Stop Diabetes program.

Sugar serves as the primary energy source for mammals, with glucose metabolism facilitating energy acquisition in human cells. The proper functioning of intracellular glucose metabolism is essential for the maintenance of orderly and healthy physiological activities. Tumor cells, characterized by uncontrolled growth, exhibit dysregulated proliferation and apoptosis processes, leading to abnormal alterations in glucose metabolism. Specifically, tumor cells exhibit a shift towards aerobic glycolysis, resulting in the production of lactic acid that can be utilized as a metabolic intermediate for sustained tumor cell growth. This article provides a comprehensive overview of the enzymes involved in glucose metabolism and the alterations in gene expression that occur during tumor progression. It also examines the current research on targeting abnormal glucose metabolism processes for tumor treatment and discusses potential future directions for utilizing glucose metabolism as a therapeutic target.

In recent years, mostly spanning the past decade, the concept of immunometabolism has ushered with a novel perspective on carcinogenesis, tumor progression, and tumor response to therapy. It has become clear that the metabolic state of immune cells plays a significant role in shaping their antitumor or protumor activities within the cancer microenvironment. Consequently, the examination of tumor metabolic heterogeneity, including an exploration of immunometabolism, proves indispensable for enhancing prognostic tools and advancing the quest for personalized treatments. Here we have delved into how metabolic reprogramming profoundly influences the acquisition and maintenance of functional states, spanning from effector and cytotoxic profiles to regulatory and immunosuppressive phenotypes in both innate and adaptive immunity. These alterations wield considerable influence over tumor evolution and affect the outcome of cancer. Furthermore, we explore some of the cellular signaling mechanisms that underpin the metabolic and phenotypic flexibility of immune cells in response to external stimuli.

Cholangiocarcinoma (CCA) is a rare but highly invasive cancer, with its incidence rising in recent years. Currently, surgery remains the most definitive therapeutic option for CCA. However, similar to other malignancies, most CCA patients are not eligible for surgical intervention at the time of diagnosis. The chemotherapeutic regimen of gemcitabine combined with cisplatin is the standard treatment for advanced CCA, but its effectiveness is often hampered by therapeutic resistance. Recent research highlights the remarkable plasticity of tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). TAMs play a crucial dual role in either promoting or suppressing tumor development, depending on the factors that polarize them toward pro-tumorigenic or anti-tumorigenic phenotypes, as well as their interactions with cancer cells and other stromal components. In this review, we critically examine recent studies on TAMs in CCA, detailing the expression patterns and prognostic significance of different TAM subtypes in CCA, the mechanisms by which TAMs influence CCA progression and immune evasion, and the potential for reprogramming TAMs to enhance anticancer therapies. This review aims to provide a framework for deeper future research.

Metabolic reprogramming provides tumors with an energy source and biofuel to support their survival in the malignant microenvironment. Extensive research into the intrinsic oncogenic mechanisms of the tumor microenvironment (TME) has established that cancer-associated fibroblast (CAFs) and metabolic reprogramming regulates tumor progression through numerous biological activities, including tumor immunosuppression, chronic inflammation, and ecological niche remodeling. Specifically, immunosuppressive TME formation is promoted and mediators released via CAFs and multiple immune cells that collectively support chronic inflammation, thereby inducing pre-metastatic ecological niche formation, and ultimately driving a vicious cycle of tumor proliferation and metastasis. This review comprehensively explores the process of CAFs and metabolic regulation of the dynamic evolution of tumor-adapted TME, with particular focus on the mechanisms by which CAFs promote the formation of an immunosuppressive microenvironment and support metastasis. Existing findings confirm that multiple components of the TME act cooperatively to accelerate the progression of tumor events. The potential applications and challenges of targeted therapies based on CAFs in the clinical setting are further discussed in the context of advancing research related to CAFs.

Cancer incidence and mortality are increasing and impacting global life expectancy. Metabolic reprogramming in the tumor microenvironment (TME) is intimately related to tumorigenesis, progression, metastasis and drug resistance. Tumor cells drive metabolic reprogramming of other cells in the TME through metabolic induction of cytokines and metabolites, and metabolic substrate competition. Consequently, this boosts tumor cell growth by providing metabolic support and facilitating immunosuppression and angiogenesis. The metabolic interplay in the TME presents potential therapeutic targets. Here, we focus on the metabolic reprogramming of four principal cell subsets in the TME: CAFs, TAMs, TILs and TECs, and their interaction with tumor cells. We also summarize medications and therapies targeting these cells' metabolic pathways, particularly in the context of immune checkpoint blockade therapy.

Metabolic conditions such as hypoxia, nutrient starvation, and media acidification, together with interactions with stromal cells are critical drivers of metastasis. Since these conditions arise deep within tumor tissues with poor access to the bloodstream, the observation of nascent metastases in vivo is exceedingly challenging. On the other hand, conventional cell culture studies cannot capture the complex nature of metastatic processes. We thus designed and implemented an ex vivo model of the tumor microenvironment to study the emergence of metastatic features in tumor cells in their native 3-dimensional (3D) context. In this system, named 3MIC, tumor cells spontaneously create ischemic-like conditions, and it allows the direct visualization of tumor-stroma interactions with high spatial and temporal resolution. We studied how 3D tumor spheroids evolve in the 3MIC when cultured under different metabolic environments and in the presence or absence of stromal cells. Consistent with previous experimental and clinical data, we show that ischemic environments increase cell migration and invasion. Importantly, the 3MIC allowed us to directly observe the emergence of these pro-metastatic features with single-cell resolution allowing us to track how changes in tumor motility were modulated by macrophages and endothelial cells. With these tools, we determined that the acidification of the extracellular media was more important than hypoxia in the induction of pro-metastatic tumor features. We also illustrate how the 3MIC can be used to test the effects of anti-metastatic drugs on cells experiencing different metabolic conditions. Overall, the 3MIC allows us to directly observe the emergence of metastatic tumor features in a physiologically relevant model of the tumor microenvironment. This simple and cost-effective system can dissect the complexity of the tumor microenvironment to test perturbations that may prevent tumors from becoming metastatic.

Metastasis remains a pivotal characteristic of cancer and is the primary contributor to cancer-associated mortality. Despite its significance, the mechanisms governing metastasis are not fully elucidated. Contemporary findings in the domain of cancer biology have shed light on the molecular aspects of this intricate process. Tumor cells undergoing invasion engage with other cellular entities and proteins en route to their destination. Insights into these engagements have enhanced our comprehension of the principles directing the movement and adaptability of metastatic cells. The tumor microenvironment plays a pivotal role in facilitating the invasion and proliferation of cancer cells by enabling tumor cells to navigate through stromal barriers. Such attributes are influenced by genetic and epigenetic changes occurring in the tumor cells and their surrounding milieu. A profound understanding of the metastatic process's biological mechanisms is indispensable for devising efficacious therapeutic strategies. This review delves into recent developments concerning metastasis-associated genes, important signaling pathways, tumor microenvironment, metabolic processes, peripheral immunity, and mechanical forces and cancer metastasis. In addition, we combine recent advances with a particular emphasis on the prospect of developing effective interventions including the most popular cancer immunotherapies and nanotechnology to combat metastasis. We have also identified the limitations of current research on tumor metastasis, encompassing drug resistance, restricted animal models, inadequate biomarkers and early detection methods, as well as heterogeneity among others. It is anticipated that this comprehensive review will significantly contribute to the advancement of cancer metastasis research.

Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.