Cancer seriously threatens the lives and health of people worldwide, and exosomes seem to play an important role in managing cancer effectively, which has attracted extensive attention from researchers in recent years. This study aimed to scientifically visualize exosomes research in cancer (ERC) through bibliometric analysis, reviewing the past, summarizing the present, and predicting the future, with a view to providing valuable insights for scholars and policy makers. Researches search and data collection from Web of Science Core Collection and clinical trial.gov. Calculations and visualizations were performed using Microsoft Excel, VOSviewer, Bibliometrix R-package, and CiteSpace. As of December 1, 2024, and March 8, 2025, we identified 8,001 ERC-related publications and 107 ERC-related clinical trials, with an increasing trend in annual publications. Our findings supported that China, Nanjing Medical University, and International Journal of Molecular Sciences were the most productive countries, institutions, and journals, respectively. Whiteside, Theresa L. had the most publications, while Théry, C was the most co-cited scholar. In addition, Cancer Research was the most co-cited journal. Spatial and temporal distribution of clinical trials was the same as for publications. High-frequency keywords were "extracellular vesicle," "microRNA" and "biomarker." Additional, "surface functionalization," "plant," "machine learning," "nanomaterials," "promotes metastasis," "engineered exosomes," and "macrophage-derived exosomes" were promising research topics. Our study comprehensively and visually summarized the structure, hotspots, and evolutionary trends of ERC. It would inspire subsequent studies from a macroscopic perspective and provide a basis for rational allocation of resources and identification of collaborations among researchers.

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.

Glioblastoma remain one of the deadliest malignant tumors in the central nervous system, largely due to their aggressiveness, high degree of heterogeneity, and the protective barrier of the blood-brain barrier (BBB). Conventional therapies including surgery, chemotherapy and radiotherapy often fail to improve patient prognosis due to limited drug penetration and non-specific toxicity. We then present recent advances in biomimetic nanodelivery systems, focusing on cell membrane coatings, nanoenzymes, and exosome-based carriers. By mimicking endogenous biological functions, these systems demonstrate improved immune evasion, enhanced BBB traversal, and selective drug release within the tumor microenvironment. Nevertheless, we acknowledge unresolved bottlenecks related to large-scale production, stability, and the intricacies of regulatory compliance. Looking forward, we propose an interdisciplinary roadmap that combines materials engineering, cellular biology, and clinical expertise. Through this collaborative approach, this work aims to optimize biomimetic nanodelivery for glioma therapy and ultimately improve patient outcomes.

Breast cancer (BC), which is the most common tumor in women, has greatly endangered women's lives and health. Currently, patients with BC receive comprehensive treatments, including surgery, chemotherapy, radiotherapy, endocrine therapy, and targeted therapy. According to the latest research, the development of BC is closely related to the inflammatory immune response, and the immunogenicity of BC has steadily been recognized. As such, immunotherapy is one of the promising and anticipated forms of treatment for BC. The potential values of miRNA in the diagnosis and prognosis of BC have been established, and aberrant expression of associated miRNA can either facilitate or inhibit progression of BC. In the tumor immune microenvironment (TME), miRNAs are considered to be an essential molecular mechanism by which tumor cells interact with immunocytes and immunologic factors. Aberrant expression of miRNAs results in reprogramming of tumor cells actively, which may suppress the generation and activation of immunocytes and immunologic factors, avoid tumor cells apoptosis, and ultimately result in uncontrolled proliferation and deterioration. Therefore, through activating and regulating the immunocytes related to tumors and associated immunologic factors, miRNA can contribute to the advancement of BC. In this review, we assessed the function of miRNA and associated immune system components in regulating the advancement of BC, as well as the potential and viability of using miRNA in immunotherapy for BC.

Traditional drug delivery strategies often have side effects due to uneven drug distribution leading to the subtherapeutic impacts. Ligand-modified nanoparticles offer a revolutionary approach to precise drug delivery. These modified nanoparticles can potentially target macrophages, which is crucial for defense and disease progression efficiently. Out of many classes of ligands, biomacromolecular ligands emerged as potential ligands for directing these nanoparticles to macrophages due to their consecutive receptors over the macrophage surface, assisting easy internalization and thus supporting elevated efficacy and reduced toxicity. This approach could significantly improve treatment for diseases like cancer, tuberculosis, etc. by directing drugs to macrophages and reducing side effects. By leveraging nanotechnology and biomacromolecular-based ligand-directed targeting, we can achieve more precise and effective treatments, paving the way for advancements in precision medicine.

One of the leading causes of cancer-related mortality globally is non-small cell lung cancer (NSCLC). It has become a significant public health concern due to its rising incidence rate and fatality. Tumor-associated macrophage (TAM) is important in the tumor microenvironment (TME) of NSCLC because they have an impact on the development, metastasis, and incidence of tumors. As a crucial element of the TME, TAM contributes to tumor immune evasion, facilitates tumor proliferation and metastasis, and modulates tumor angiogenesis, immunosuppression, and treatment resistance through the secretion of diverse cytokines, chemokines, and growth factors. Consequently, TAM assumes a multifaceted and intricate function in the onset, progression, and therapeutic response of NSCLC, serving as a crucial focal point for comprehending the tumor microenvironment and formulating novel therapeutic methods. The study aims to review the biological properties and potential processes of TAM in NSCLC, investigate its involvement in the clinical of NSCLC patients, and discuss its potential as a therapeutic target.

As the fourth leading cause of death from cancer and the sixth most common neoplasm in the world, hepatocellular carcinoma (HCC) is responsible for ninety percent of all primary liver cancers. There are four mechanisms that contribute to the spread of cancer: the separation of cells from the primary neoplasm, their survivability during metastasis, extravasation, and the development of secondary tumors at remote locations. In addition to its role in the development of a scaffold for cell adhesion, the extracellular matrix (ECM) also plays a role in the stimulation of signal transduction and the regulation of essential cellular mechanisms, including proliferation, migration, differentiation, and viability. The disruption of cell-ECM interactions and the ensuing separation of cells from the primary ECM trigger anoikis, a form of programmed cell death. One of the most effective factors in suppressing anoikis is ECM receptors from the integrin family. Cell migration, proliferation, and survival are primarily governed by the formation of physical connections with the cytoskeleton and the conveyance of signals between cells and the ECM via integrin receptors.

Wilms tumor (WT) is a common renal malignancy in pediatric patients. Interleukin (receptors) (IL(R)s) play significant roles in tumor biology, however, their specific involvement in WT remains inadequately understood. We employed univariate Cox regression analysis to screen for certain IL(R) genes associated with prognosis and then analyzed their expression patterns. A prognostic model was constructed based on five selected IL(R)s using the LASSO Cox regression algorithm. To further elucidate the relationship between the prognostic model and the immune microenvironment, we conducted immune-related analyses. Additionally, we performed experiments to verify the roles of IL20RA and IL19 in WT. Finally, CNV, methylation and pan-cancer analysis were performed for IL19 and IL20RA. Our analysis ultimately identified five genes associated with prognosis: IL20RA, IL19, IL24, IL11 and IL17RD. The prognostic model incorporating these five genes demonstrated robust predictive power in both training and validation cohorts. Notably, IL19 and IL20RA were found to promote epithelial-mesenchymal transition (EMT) through the STAT3/SNAIL pathway, thereby contributing to tumor progression. Furthermore, significant differences in immune function and checkpoint expression were observed between the two groups. The high-risk group exhibiting a lower TIDE score, which suggests a potentially better response to immunotherapy. This study introduces a novel IL(R)-based prognostic signature for WT, highlighting IL20RA as a potential therapeutic target. These findings offer valuable insights for future studies on WT.

Cancer is responsible for nearly one in six global fatalities, making it a major health issue worldwide. Despite advancements in early detection, surgery, and targeted therapies, effective treatment remains challenging due to the complexity and heterogeneity of the disease. A key factor in cancer progression and resistance to treatment is the tumor microenvironment (TME). It is a complex ecosystem comprising cancer cells, stromal cells, immune cells, extracellular matrix (ECM), and soluble factors like cytokines and chemokines. These components interact dynamically to influence tumor growth, metastasis, immune evasion, and treatment resistance. Cancer cells drive the formation of the TME by releasing signaling molecules, while stromal cells, such as fibroblasts and endothelial cells, support tumor metabolism, angiogenesis, and invasion. Immune cells within the TME can either suppress or promote tumor progression, depending on their activation state. Additionally, the TME can promote the growth of immunosuppressive cells that aid cancer cells in evading immune surveillance, such as regulatory T-cells and myeloid-derived suppressor cells. The TME also impedes drug delivery by creating defective blood vessels, contributing to drug resistance. Recent technological advancements have deepened our understanding of the TME, revealing its role in immune modulation, metabolism, and extracellular matrix remodeling. As a result, targeting the TME has become a promising strategy to overcome treatment resistance and improve cancer therapy outcomes.

The apelinergic system exerts multiple biological activities in human pathologies, including cancer. Overactivation of apelin/APJ, which has been detected in many malignant tumors, and the strong correlation with progression-free and overall survival, suggested the role of an oncogene for the apelin gene. Emerging evidence sheds new light on the effects of apelin on cellular functions and homeostasis in cancer cells and supports a direct role for this pathway on different hallmarks of cancer: "sustaining proliferative signaling", "resisting cell death", "activating invasion and metastasis", "inducing/accessing vasculature", "reprogramming cellular metabolism", "avoiding immune destruction" and "tumor-promoting inflammation", and "enabling replicative immortality". This article reviews the currently available literature on the intracellular processes regulated by apelin/APJ, focusing on those pathways correlated with tumor development and progression. Furthermore, the association between the activity of the apelinergic axis and the resistance of cancer cells to oncologic treatments (chemotherapy, immunotherapy, radiation) suggests apelin/APJ as a possible target to potentiate traditional therapies, as well as to develop diagnostic and prognostic applications. This issue will be also covered in the review.

Inflammation is an essential component of the immune response that protects the host against pathogens and facilitates tissue repair. Chronic inflammation is a critical factor in cancer development and progression. It affects every stage of tumor development, from initiation and promotion to invasion and metastasis. Tumors often create an inflammatory microenvironment that induces angiogenesis, immune suppression, and malignant growth. Immune cells within the tumor microenvironment interact actively with cancer cells, which drives progression through complex molecular mechanisms. Chronic inflammation is triggered by factors such as infections, obesity, and environmental toxins and is strongly linked to increased cancer risk. However, acute inflammatory responses can sometimes boost antitumor immunity; thus, inflammation presents both challenges and opportunities for therapeutic intervention. This review examines how inflammation contributes to tumor biology, emphasizing its dual role as a critical factor in tumorigenesis and as a potential therapeutic target.

Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.

Although immune checkpoint inhibition in particular has shown promise in cancer immunotherapy, it is not always efficient. Recent studies suggest that SMARCAL1 may play a role in tumor immune evasion, yet its pan-cancer role is unclear. We conducted a comprehensive analysis of SMARCAL1 using TCGA, GTEx, and CCLE databases, evaluating its expression, genetic alterations, epigenetic modifications, and their clinical correlations across 33 cancer types. Our findings indicate that SMARCAL1 is overexpressed in several cancers, such as Glioma, LUAD, KIRC, and LIHC, impacting prognosis. Elevated SMARCAL1 is linked to poor outcomes in Glioma, LUAD, and LIHC but correlates with better survival in KIRC. We also found significant associations between SMARCAL1 expression and DNA methylation in 13 cancers. Furthermore, SMARCAL1 expression correlates with immune infiltration, suggesting it as a potential therapeutic target in cancer immunotherapy. This study underscores the need for further research on SMARCAL1 to enhance immunotherapeutic strategies.

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

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

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

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

Lung adenocarcinoma (LUAD) patients have high heterogeneity. The significance and clinical value of M2 macrophage-related genes in LUAD require further exploration. We aimed to construct a prognostic signature to predict the immunotherapy efficacy and prognosis in LUAD.

GSE26939 and GSE19188 chips were downloaded from the Gene Expression Omnibus (GEO). Weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) analysis were used to screen M2 macrophage-related prognostic genes. A signature based on M2 macrophage-related prognostic genes was established and used to predict the prognosis and immunotherapy efficacy in LUAD.

Twenty-two M2 macrophage-related genes associated with the prognosis of LUAD were confirmed using WGCNA, and then two molecular subtypes were identified with significantly different survival, gene expressions, and clinic characteristics were classified. LASSO analysis identified nine M2 macrophage-related prognostic genes to establish a risk signature, classifying patients into low- and high-risk groups. Data indicated that low-risk patients had better survival. Moreover, the signature was an independent prognostic factor for LUAD and a potential biomarker for patients receiving immunotherapy. Single-cell transcriptome analysis may provide important information on molecular subtypes and heterogeneity.

Risk signature based on M2 macrophage-related genes is a valuable tool for predicting prognosis and immunotherapy response in patients with LUAD.

Integrins, a group of transmembrane receptors, play a crucial role in mediating the interactions between cells and extracellular matrix (ECM) proteins. The intracellular signaling initiated by these cell-matrix interactions in leukocytes mediates many essential cellular processes such as survival, migration, metabolism, and other immunological functions. Macrophages, as phagocytes, participate in both proinflammatory and anti-inflammatory processes, including progression. Numerous reports have shown that the integrin-regulated secretome, comprising cytokines, chemokines, growth factors, proteases, and other bioactive molecules, is a crucial modulator of macrophage functions in tumors, significantly influencing macrophage programming and reprogramming within the tumor microenvironment (TME) in addition to driving their step-by-step entry process into tumor tissue spaces. Importantly, studies have demonstrated a pivotal role for integrin receptor-mediated secretome and associated signaling pathways in functional reprogramming from anti-tumorigenic to pro-tumorigenic phenotype in tumor-associated macrophages (TAMs). In this comprehensive review, we have provided an in-depth analysis of the latest findings of various key pathways, mediators, and signaling cascades associated with integrin-driven polarization of macrophages in tumors. This manuscript will provide an updated understanding of the modulation of inflammatory monocytes/ macrophages and TAMs by integrin-driven secretory pathways in various functions such as migration, differentiation, and their role in tumor progression, angiogenesis, and metastasis.

Platelet count and function may be closely related to survival and prognosis of stroke and cancer. However, little is known on the impact of platelet count on the patients with a history of stroke and cancer. This study aimed to examine the association between baseline platelet level and all-cause mortality in this population using a cross-sectional analysis.

Participants with a history of stroke and cancer were selected from the database of the National Health and Nutrition Examination Survey from 2007 to 2018. A maximum selected rank statistic was conducted to determine platelet cutoff with the most significant association with mortality. The association between platelet and mortality was characterized visually using restricted cubic spline (RCS). Weighted multivariable Cox regression models were performed to evaluate the association between platelet count and mortality. Time-dependent receiver operating characteristic (ROC) analysis was conducted to assess the accuracy of platelet count in predicting mortality.

Forty-three (43/113, 38.05%) stroke patients with cancer were alive at a median follow-up of 42 months (interquartile range, 23-74 months). The RCS analysis demonstrated a linear relationship between platelet and mortality (nonlinear, p = 0.352). Mortality in higher-platelet group (> 209 × 109/L, n = 57) was decreased than lower-platelet group (≤ 209 × 109/L, n = 56) (Model 1 HR 0.43, 95% CI 0.24-0.77, p = 0.005) (Model 2 HR 0.58, 95% CI 0.35-0.96, p = 0.03). Subgroup analyses showed no significant interaction between platelet and age, sex, BMI, WBC and neutrophil. The areas under time-dependent ROC curve of the 1-, 2-, 3-, 4- and 5-year survival rates were 0.54, 0.55, 0.57, 0.53, 0.59 for mortality of stroke patients with cancer.

Lower platelet count may be an independent predictor of all-cause mortality in population with a history of stroke and cancer. This result may provide valuable insights for the long-term management in stroke patients with cancer.

T cells are the central players in antitumor immunity, and effective tumor killing depends on their ability to infiltrate into the tumor microenvironment (TME) while maintaining normal cytotoxicity. However, late-stage tumors develop immunosuppressive mechanisms that impede T cell movement and induce exhaustion. Investigating T cell migration in human tumors in vivo could provide novel insights into tumor immune escape, although it remains a challenging task. In this study, we developed ReMiTT, a computational method that leverages spatial transcriptomics data to track T cell migration patterns within tumor tissue. Applying ReMiTT to multiple tumor samples, we identified potential migration trails. On these trails, chemokines that promote T-cell trafficking display an increasing trend. Additionally, we identified key genes and pathways enriched on these migration trails, including those involved in cytoskeleton rearrangement, leukocyte chemotaxis, cell adhesion, leukocyte migration, and extracellular matrix (ECM) remodeling. Furthermore, we characterized the phenotypes of T cells along these trails, showing that the migrating T cells are highly proliferative. Our findings introduce a novel approach for studying T cell migration and interactions within the tumor microenvironment (TME), offering valuable insights into tumor-immune dynamics.

Immune checkpoint inhibitors (ICIs) plus chemotherapy have become the standard of care for first-line treatment of advanced non-small cell lung cancer (NSCLC) with EGFR/ALK negative. However, there is no clear second-line treatment option after first-line treatment failure. To investigate the efficacy and safety of ICIs alone or in combination rechallenge treatment after first-line ICIs plus chemotherapy progression in advanced NSCLC. We retrospectively analyzed the cases of patients who received ICIs alone or in combination rechallenge treatment after first-line ICIs plus chemotherapy progression in advanced NSCLC at Hunan Cancer Hospital between January 2020 and May 2024. We evaluated the effects of continued immunotherapy on patients' objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse events after first-line treatment progression, and analyzed the relationship between outcomes and clinical characteristics. A total of 154 patients were included, with 146 patients developing resistance, 8 patients showing no progression. The ORR was 16.44%, the DCR was 68.49%, and the median PFS was 4.6 months. Patients treated with the new immune drug therapy had longer PFS than those treated with the original immunotherapy (5.0 months vs. 3.7 months, p = 0.0438). The PFS in patients receiving ICIs plus targeted therapy was significantly longer than that in patients who receiving ICIs alone, chemo-ICIs plus targeted therapy and ICIs plus chemotherapy (chemo-ICIs) (5.7 months vs. 3.6 months vs3.2 months vs. 2.9 months, p = 0.0086). Multivariate analysis showed that treatment regimen was a risk factor for immune rechallenge PFS, but there was no statistical correlation between gender, age, smoking history, pathological type, intermittent treatment or first-line drug resistance and immune rechallenge PFS. Our findings suggest that selecting ICIs plus targeted therapy may improve PFS in patients with advanced NSCLC after first-line chemo-ICIs progression. while replacement with new BSAb/PD-1 may be more beneficial to patients. However, there is a lack of large sample randomized controlled studies and evidence-based medical evidence, and more clinical studies are needed to further confirm.

Chronic pain typically lasts or recurs for more than three months and is an unpleasant sensory and emotional experience, including neuropathic pain, long-term tissue damage, tumors, and viral or bacterial infections.The unpleasantness associated with pain affects the basic life of patients and has become a truly global problem. Macrophages, a powerful immune effector cell whose functional plasticity leads to polarization into different subtypes and opposite effects in different environments, are also indispensable in the development of pain.In recent years, there has been an increasing number of studies on the effects of macrophages on pain, and there are multiple pathways that regulate macrophage polarization, including lipopolysaccharide induction and IL-4/IL-13 stimulation.In addition, pathways involving macrophages and macrophage polarization have been found to have an exacerbating or mitigating role in the progression of chronic pain, with M1 macrophages generally exacerbating pain progression and M2 macrophages mitigating pain progression.Therefore, modulating macrophage polarization holds great promise as an intervention in chronic pain. In this paper, we synthesize multiple macrophage pathways as well as mechanisms affecting their pain processes in the context of different types of chronic pain, providing new avenues for chronic pain relief.

Eliciting tumour microenvironment (TME) activation in triple-negative breast cancer (TNBC) is crucial for effective anti-tumour therapies. The aim of this study is to employ pharmaceutical approaches to precisely deliver Ganoderma polysaccharide (GPS) to tumour sites, thereby enhancing TME activation. We first established a direct link between the accumulation of GPS within tumours and its efficacy in the TME activation. Building upon this insight, we then engineered a mannose/hyaluronic acid dual-coated GPS-loaded superparamagnetic iron oxide nanocomplex (Man/HA/GPS-SPIONs) with a particle size of 33.8 ± 1.6 nm and a zeta potential of -22.4 ± 3.5 mV, capable of precise tumour accumulation through magnet-assisted targeting and internalisation by tumour-associated macrophages (TAMs) and tumour cells, facilitated by dual ligand modification. In vitro, Man/HA/GPS-SPIONs effectively induced M1 polarisation of macrophages (CD86+ cells: 38.6 ± 2.8%), curbed 4T1 cell proliferation (viability: 47.3 ± 2.9%) and heightened Th1 cytokine release. Significantly, in vivo, Man/HA/GPS-SPIONs notably suppressed tumour growth (tumour index: 0.048 ± 0.005), fostered M1 polarisation of TAMs (CD45+F4/80+CD86+ cells: 26.1 ± 7.2%), consequently bolstering intratumoural T cytotoxic cells. This enhancement was intricately tied to the efficient co-delivery of GPS and iron ions to the tumours, made possible by the Man/HA/GPS-SPIONs delivery system. The synergistic effects with paclitaxel (PTX, inhibition rate: 61.2 ± 4.3%) and PD-1 inhibitors (inhibition rate: 69.8 ± 7.6%) underscored the translational potential of this approach. By harnessing a well-conceived iron-based drug delivery strategy, this study amplifies the tumour immune modulatory potential of natural polysaccharides, offering insightful guidance for interventions in the TME and synergistic therapies.

The tumor microenvironment (TME) is a critical factor in cancer progression, driving tumor growth, immune evasion, therapeutic resistance, and metastasis. Understanding the dynamic interactions within the TME is essential for advancing cancer management. Molecular imaging provides a non-invasive, real-time, and longitudinal approach to studying the TME, with techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI), and fluorescence imaging offering complementary strengths, including high sensitivity, spatial resolution, and intraoperative precision. Recent advances in imaging probe development have enhanced the ability to target and monitor specific components of the TME, facilitating early cancer diagnosis, therapeutic monitoring, and deeper insights into tumor biology. By integrating these innovations, molecular imaging offers transformative potential for precision oncology, improving diagnostic accuracy and treatment outcomes through a comprehensive assessment of TME dynamics.

Numerous studies have demonstrated the significant influence of immune cells on cancer development and treatment. This study specifically examines tumor-associated macrophages (TAMs), detailing their characteristics and roles in tumorigenesis and analyzing the impact of the ratio of TAM subtypes on patient survival and prognosis. It is established that TAMs interact with immunotherapy, radiotherapy, and chemotherapy, thereby influencing the efficacy of these treatments. Emerging therapies are explored, such as the use of nanoparticles (NPs) for drug delivery to target TAMs and modify the tumor microenvironment (TME). Additionally, novel anticancer strategies like the use of chimeric antigen receptor macrophages (CAR-Ms) show promising results. Investigations into the training of macrophages using magnetic fields, plasma stimulation, and electroporation are also discussed. Finally, this study presents prospects for the combination of TAM-based therapies for enhanced cancer treatment outcomes.

Tumor-associated macrophages (TAMs) drive the protumorigenic responses and facilitate tumor progression via matrix remodeling, angiogenesis, and immunosuppression by interacting with extracellular matrix proteins via integrins. However, the expression dynamics of integrin and its correlation with TAM functional programming in the tumors remain unexplored. In this study, we examined surface integrins' role in TAM recruitment and phenotypic programming in a 4T1-induced murine breast tumor model. Our findings show that integrin α5β1 is upregulated in CD11b+Ly6Chi monocytes in the bone marrow and blood by day 10 after tumor induction. Subsequent analysis revealed elevated integrin α5β1 expression on tumor-infiltrating monocytes (Ly6ChiMHC class II [MHCII]low) and M1 TAMs (F4/80+Ly6ClowMHCIIhi), whereas integrin αvβ3 was predominantly expressed on M2 TAMs (F4/80+Ly6ClowMHCIIlow), correlating with higher CD206 and MERTK expression. Gene profiling of cells sorted from murine tumors showed that CD11b+Ly6G-F4/80+α5+ TAMs had elevated inflammatory genes (IL-6, TNF-α, and STAT1/2), whereas CD11b+Ly6G-F4/80+αv+ TAMs exhibited a protumorigenic phenotype (IL-10, Arg1, TGF-β, and STAT3/6). In vitro studies demonstrated that blocking integrin α5 and αv during macrophage differentiation from human peripheral blood monocytes reduced cell spreading and expression of CD206 and CD163 in the presence of specific matrix proteins, fibronectin, and vitronectin. Furthermore, RNA sequencing data analysis (GEO dataset: GSE195857) from bone marrow-derived monocytes and TAMs in 4T1 mammary tumors revealed differential integrin α5 and αv expression and their association with FAK and SRC kinase. In line with this, FAK inhibition during TAM polarization reduced SRC, STAT1, and STAT6 phosphorylation. In conclusion, these findings underscore the crucial role of integrins in TAM recruitment, polarization, and reprogramming in tumors.

Osteosarcoma (OS) represents one of the most common primary bone cancers affecting children and young adults. The available treatments have remained unimproved for the past decades, hampered by the poor knowledge of OS etiology/pathophysiology and the lack of innovative, predictive and biologically relevant in vitro models, that can recapitulate the 3D OS tumor microenvironment (TME). Here, we report the development and characterization of an innovative 3D model of OS, composed of OS tumor cells, immune cells (macrophages) and mesenchymal stem cells (MSCs), that formed a multicellular tissue spheroid (MCTS). This fully humanized 3D model was shown to accurately mimic the native histological features of OS, while innately leading to the polarization of macrophages towards an M2-like phenotype, highly aggressive and pro-tumor profile. Upon the exposure to immunomodulatory molecules, the MCTS were shown to be responsive by shifting macrophages polarization, and dramatically altering the TME secretome. In agreement, when treated with immunomodulatory/stimulatory nanoparticles (NPSs), we were able to revert the TME secretome towards an anti-inflammatory profile. This study establishes an advanced 3D OS model capable of shedding light on macrophages and MSCs contributions to disease progression, paving the way for the development of innovative therapeutic approaches targeting the OS TME, while providing a biologically relevant in vitro tool for the efficacy screening of novel OS therapeutic approaches.

Tumor-associated macrophages (TAMs) play a pivotal role in sculpting the tumor microenvironment and influencing cancer progression, particularly through their interactions with various forms of regulated cell death (RCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis. This review examines the interplay between TAMs and these RCD pathways, exploring the mechanisms through which they interact to promote tumor growth and advancement. We examine the underlying mechanisms of these intricate interactions, emphasizing their importance in cancer progression and treatment. Moreover, we present potential therapeutic strategies for targeting TAMs and manipulating RCD to enhance anti-tumor responses. These strategies encompass reprogramming TAMs, inhibiting their recruitment, and selectively eliminating them to enhance anti-tumor functions, alongside modulating RCD pathways to amplify immune responses. These insights offer a novel perspective on tumor biology and provide a foundation for the development of more efficacious cancer therapies.

Background and Objectives: In this study, we evaluated the impact of seven immune indexes on treatment response and survival outcomes in advanced non-small-cell lung cancer (NSCLC) patients receiving second-line and subsequent nivolumab treatment under real-life conditions. Materials and Methods: The pan-immune inflammation value (PIV), systemic immune inflammation value (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), derived neutrophil-to-lymphocyte ratio (d-NLR), and prognostic nutritional index (PNI) were calculated. All immune indexes were classified as low and high based on cut-off values. Kaplan-Meier and Cox hazard models were used for survival analysis. Results: The median follow-up was 22.0 months (6.0-96.0). The median overall survival (OS) was 30.0 months and the median progression-free survival (PFS) was 7.0 months. In the univariate analysis, comorbidity (p = 0.03) and nivolumab use for more than eight cycles (p < 0.0001) were associated with an increase in PFS, while smoking history (p < 0.005) and d-NLR (p < 0.05) were more effective regarding OS. Patients who received more than eight cycles of nivolumab had longer median PFS (4 vs. 19 months, p < 0.001) and OS (23 vs. 43 months, p < 0.001). We found longer median OS in the PLR (45.7 vs. 75.4 months; p = 0.05), PIV (53.0 vs. 66.4 months; p = 0.19), SII (50.0 vs. 71.9 vs. months, p = 0.19), and NLR (49.9 vs. 74.55 months, p = 0.10) indexes in nivolumab long-term users (high vs. low groups, respectively). In short-term users of nivolumab, only d-NLR median OS (high vs. low, 19 vs. 75.2 months, p = 0.07) was different. Complete and partial response rates to nivolumab treatment were higher in the PNI-high group (p = 0.04). Conclusions: In these real-life data, we determined that the PLR, PIV, SII, and NLR indexes were effective in the prognosis of patients who received PD1 inhibitor nivolumab for a long time, and the d-NLR index was effective in those who developed progression in a short time. We found that the PNI was effective in patients who responded well to ICI treatment.

It is reported that G protein-coupled receptor 84 (GPR84) can participate in inflammation and immune regulation to repress anti-tumor responses. However, the function of GPR84 in lung cancer (LC) and its potential molecular mechanisms are still largely unknown.

Bioinformatics and molecular experiments were employed to assess the expression of GPR84 in LC. The pathways enriched by GPR84 were analyzed by the Kyoto Encyclopedia of Genes and Genomes. Bioinformatics prediction identified the potential upstream regulatory factors of GPR84, which were verified through dual luciferase and chromatin immunoprecipitation experiments. Cell viability was measured by methyl thiazolyl tetrazolium assay. The expression levels of key proteins related to the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway such as JAK2, p-JAK2, p-STAT3, and STAT3 were detected by western blot. Macrophages were co-cultured with LC cells. Flow cytometry was employed to examine the proportion of mannose receptor-positive cells. The expression levels of M2 polarization marker genes chitinase-like protein 3, arginase-1, and found in inflammatory zone 1 were measured by quantitative reverse transcription polymerase chain reaction. We applied an enzyme-linked immunosorbent assay to determine levels of cytokines (interleukin-10 and transforming growth factor beta) to evaluate the M2 macrophage polarization.

GPR84 was highly expressed in LC and substantially enriched in the JAK-STAT pathway. GPR84 facilitated the M2 polarization of macrophages in LC. Adding the JAK-STAT pathway inhibitor weakened the promoting effect of GPR84 overexpression on M2 macrophage polarization. Furthermore, GPR84 also had an upstream regulatory factor lamin B1 (LMNB1). Knocking down LMNB1 blocked the JAK-STAT signaling pathway to repress M2 macrophage polarization in LC, while overexpression of GPR84 reversed the impact of LMNB1 knockdown on macrophage polarization.

The project suggested that the LMNB1/GPR84 axis can facilitate M2 polarization of macrophages in LC by triggering the JAK-STAT pathway. Targeting LMNB1/GPR84 or blocking the JAK-STAT pathway may be a novel approach for LC diagnosis and treatment.

Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease.

This narrative review examines the link between chronic inflammation and CA-CRC. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2000 and 2024. Studies were selected based on relevance to the role of inflammation in CA-CRC, specifically targeting molecular pathways and clinical implications. Both clinical and mechanistic studies were reviewed.

Sustained inflammation in the colon fosters a pro-tumorigenic environment, leading to the initiation and progression of CA-CRC. Prevention strategies must focus on controlling chronic inflammation, optimizing IBD management, and implementing regular screenings. Emerging therapies targeting key inflammatory pathways and immune responses, along with microbiome modulation, hold promise for reducing CA-CRC risk. Understanding these molecular mechanisms provides a path toward personalized treatment and better outcomes for patients with IBD at risk of colorectal cancer.

Neuroendocrine neoplasms (NENs) present a diagnostic challenge due to their heterogeneous nature and non-specific clinical manifestations. This study aimed to explore novel biomarkers for NENs. Serum chromogranin A (CgA) levels and a panel of 48 inflammatory cytokines were analyzed in a cohort of 84 NEN patients and 40 healthy controls using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA. Significant alterations in cytokine levels were observed in the NEN patients compared to the controls, including elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), and reduced levels of angiogenic factors like platelet-derived growth factor-BB (PDGF-BB) and tumor necrosis factor beta (TNF-β). Notably, cytokines such as growth-regulated alpha protein (GRO-α) and TNF-β demonstrated strong potential as diagnostic markers, with receiver operating characteristic (ROC) curve analyses showing high sensitivity and specificity. Additionally, a positive correlation was found between CgA levels and several inflammatory cytokines, suggesting their synergistic role in tumor progression. These findings highlight the limited reliability of CgA alone as a diagnostic marker and underscore the importance of a multi-marker approach in diagnosing and monitoring NENs. Further research on a larger cohort is necessary to validate these biomarkers and their potential clinical applications.

Tumor-associated macrophages (TAMs) promote tumor advancement in many ways, such as inducing angiogenesis and the formation of new blood vessels that provide tumors with nourishment and oxygen. TAMs also facilitate tumor invasion and metastasis by secreting enzymes that degrade the extracellular matrix and generating pro-inflammatory cytokines that enhance the migration of tumor cells. TAMs also have a role in inhibiting the immune response against malignancies. To accomplish this, they release immunosuppressive cytokines such as IL-10, and TAMs can hinder the function of T cells and natural killer cells, which play crucial roles in the immune system's ability to combat cancer. The role of TAMs in breast cancer advancement is a complex and dynamic field of research. Therefore, TAMs are a highly favorable focus for innovative breast cancer treatments. This review presents an extensive overview of the correlation between TAMs and breast cancer development as well as its role in the tumor microenvironment (TME) shedding light on their impact on tumor advancement and immune evasion mechanisms. Notably, our study provides an innovative approach to employing nanomedicine approaches for targeted TAM therapy in breast cancer, providing an in-depth overview of recent advances in this emerging field.

Lactation is associated with long-term reduced risk of breast cancer. However, there is a transient increased risk of breast cancer in the 5 to 10 years postpartum and this is associated with a high incidence of metastasis and mortality. Breastmilk is a physiological fluid secreted by the mammary glands intimately connected with breast cells and the microenvironment that may affect postpartum breast cancer development and progression. This study aims to investigate the effect of breastmilk on interactions between breast cancer cells and macrophages in vitro.

Human breastmilk from healthy donors (n = 7) was pooled and incubated with breast cancer (MCF-7 and MDA-MB-231) and macrophage (RAW264.7) cell lines to assess cell proliferation, viability, migration, and expression of key genes associated with epithelial-mesenchymal transition (EMT) and macrophage phenotype. Indirect co-culture studies assessed the effect of breastmilk on interactions between breast cancer cells and macrophages.

Breastmilk increased the proliferation and viability of breast cancer cells, reduced EMT markers, and reduced cell migration in MDA-MB-231 cells. Breastmilk decreased mRNA expression of interleukin 1B (IL1B) and interleukin 10 (IL10) in macrophages. Reduced EMT marker expression was observed in breast cancer cells co-cultured with macrophages pre-treated with breastmilk. Macrophages co-cultured with breast cancer cells pre-treated with breastmilk exhibited increased expression of a pro-inflammatory cytokine tumor necrosis factor A (TNFA) and pro-inflammatory nitric oxide synthase 2 (NOS2), and reduced expression of cytokines IL10 and transforming growth factor B1 (TGFB1) which are associated with the alternatively-activated macrophage phenotype.

Breastmilk has the potential to promote breast cancer proliferation, however, it can also reduce breast cancer progression through inhibition of breast cancer cell migration and regulation of macrophage polarisation. These findings suggest that breastmilk has potential to shape the tumour microenvironment in postpartum breast cancer.

Salivary gland adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC) and oral squamous cell carcinoma (OSCC) occurs within the head and neck region. So far immune check point inhibitors failed in ACC. Gipie (CCDC88B) is a microtubule linker protein that activates immune cells. Gipie expressions found in head and neck cancer cells. We hypothesised that the presence of Gipie diminishes anti-tumour reactivity of immune cells towards head and neck cancer.

To determine the effect of Gipie in oral and salivary gland cancer cells, Gipie was silenced in cancer cells in cancer-immune cells co-culture models and we performed 3D Z series confocal imaging, annexin V and immune activation flow cytometry, proteome profiler and discovery phase proteomics.

ACC cells morphed into pseudonormal morphology in immune co-culture models. Silencing Gipie in ACC cells showed significant increase of apoptotic cells and activated natural killer cells, and lowering of regulatory T cells. Other salivary and oral cancer cells showed negligible effect of Gipie. Proteome profiler and proteomics assay confirmed Gipie affecting proliferation mechanism and immune activated proteins in ACC immune co-culture models.

Overall, we conclude that the presence of Gipie has a confounding role during the ACC-immune cell interaction.

Cancer vaccines based on single-source (exogenous or endogenous) tumor-associated antigens (TAAs) are often challenged by the insufficient T cell response and the immunosuppressive tumor microenvironment (TME). Herein, a dual TAAs-boosted nanovaccine based on cancer cell (4T1) membrane-cloaked, CO-immobilized Prussian blue nanoparticles (4T1-PB-CO NPs) is developed and coupled with anti-interleukin (IL)-10 therapy to maximize the efficacy of antitumor immunotherapy. 4T1 cell membrane not only endows NPs with tumor targeting ability, but also serves as exogenous TAAs to trigger CD4+ T cell response and M1-phenotype polarization of tumor-associated macrophages. Under near-infrared light irradiation, 4T1-PB-CO NPs release CO to induce immunogenic cell death (ICD) of tumor cells, thus generating endogenous TAAs to activate CD8+ T cell response. Meanwhile, ICD triggers release of damage-associated molecular patterns, which can promote DC maturation to amplify the antitumor T cell response. When combined with anti-IL-10 that reverses the immunosuppressive TME, 4T1-PB-CO NPs efficiently suppress the primary tumors and produce an abscopal effect to inhibit distant tumors in a breast tumor-bearing mouse model. Such a two-pronged cancer vaccine represents a promising paradigm for robust antitumor immunotherapy.

Immune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs the toll-like receptor (TLR)-mediated activation of myeloid antigen-presenting cells, promoting the expansion of myeloid-derived suppressor cells, and suppressing tumor-reactive cytotoxic T cell function.

The aim of this study was to develop a dual-action lipid nanoparticle (dual-LNP) coloaded with VISTA-specific siRNA and TLR9 agonist CpG oligonucleotide. We used three murine preclinical tumor models, melanoma YUMM1.7, melanoma B16F10, and colon carcinoma MC38 to assess the functional synergy of the two cargoes of the dual LNP and therapeutic efficacy.

The dual-LNP synergistically augmented antitumor immune responses and rejected large established tumors whereas LNPs containing VISTA siRNA or CpG alone were ineffective. In comparison with therapies using the soluble CpG and a VISTA-specific monoclonal antibody, the dual-LNP demonstrated superior therapeutic efficacy yet with reduced systemic inflammatory cytokine production. In three murine models, the dual-LNP treatment achieved a high cure rate. Tumor rejection was associated with influx of immune cells to tumor tissues, augmented dendritic cell activation, production of proinflammatory cytokines, and improved function of cytotoxic T cells.

Our studies show the dual-LNP ensured codelivery of its synergistic cargoes to tumor-infiltrating myeloid cells, leading to simultaneous silencing of VISTA and stimulation of TLR9. As a result, the dual-LNP drove a highly potent antitumor immune response that rejected large aggressive tumors, thus may be a promising therapeutic platform for treating immune-cold tumors.

Renal cell carcinoma (RCC) is one of the most common tumors that afflicts the urinary system, accounting for 90-95% of kidney cancer cases. Although its incidence has increased over the past decades, its pathogenesis is still unclear. Tumor-associated macrophages (TAMs) are the most prominent immune cells in the tumor microenvironment (TME), comprising more than 50% of the tumor volume. By interacting with cancer cells, TAMs can be polarized into two distinct phenotypes, M1-type and M2-type TAMs. In the TME, M2-type TAMs, which are known to promote tumorigenesis, are more abundant than M1-type TAMs, which are known to suppress tumor growth. This ratio of M1 to M2 TAMs can create an immunosuppressive environment that contributes to tumor cell progression and survival. This review focused on the role of TAMs in RCC, including their polarization, impacts on tumor proliferation, angiogenesis, invasion, migration, drug resistance, and immunosuppression. In addition, we discussed the potential of targeting TAMs for clinical therapy in RCC. A deeper understanding of the molecular biology of TAMs is essential for exploring innovative therapeutic strategies for the treatment of RCC.

This study intended to determine the molecular subtypes of liver hepatocellular carcinoma (LIHC) on the strength of anoikis-related genes (ARGs) and to assess their prognostic value and prospective relationship with immune cell infiltration and cancer-associated fibroblasts (CAFs). Univariate Cox regression analysis yielded 66 prognosis-related ARGs and classified LIHC into two distinct subtypes, with subtype A demonstrating overexpression of most prognosis-related ARGs and a significant survival disadvantage. Furthermore, a reliable prediction model was developed using ARGs to evaluate the risk of LIHC patients. This model served as an independent prognostic indicator and a quantitative tool for clinical prognostic prediction. Additionally, subtype-specific differences in immune cell infiltration were observed, and the risk score was potentially linked to immune-related characteristics. Moreover, the study identified a significant association between CAF score and LIHC prognosis, with a low CAF score indicating a favorable patient prognosis. In conclusion, this study reveals the molecular mechanisms underlying the development and progression of LIHC and identifies potential therapeutic targets for the disease.

Hepatocellular carcinoma is one of the most common cancers worldwide. Despite progress in treatment, recurrence after radical treatment is common, and the prognosis remains poor for patients with advanced disease. Therefore, there is a need to identify prognostic and predictive factors for the response to therapy or more intensive surveillance or treatment. Because the tumor microenvironment plays a crucial role in the development of cancer and metastasis, it is a crucial need to understand processes that are involved in carcinogenesis. Within the microenvironment, several immune cells with different roles are present. One of the most important of these is tumor-associated macrophages. These cells may exert either antitumor or protumor roles. Several studies have suggested that tumor-associated macrophages can be used as prognostic markers. Furthermore, they may be involved in resistance to immunotherapy or systemic treatment. As they play an important role in cancer development, tumor-associated macrophages are also a good target for therapy. In this review, we briefly summarize recent progress on knowledge regarding the basic molecular characteristics, impact on prognosis and potential clinical implications of tumor-associated macrophages in hepatocellular carcinoma.

Tumor vaccines, an important part of immunotherapy, prevent cancer or kill existing tumor cells by activating or restoring the body's own immune system. Currently, various formulations of tumor vaccines have been developed, including cell vaccines, tumor cell membrane vaccines, tumor DNA vaccines, tumor mRNA vaccines, tumor polypeptide vaccines, virus-vectored tumor vaccines, and tumor-in-situ vaccines. There are also multiple delivery systems for tumor vaccines, such as liposomes, cell membrane vesicles, viruses, exosomes, and emulsions. In addition, to decrease the risk of tumor immune escape and immune tolerance that may exist with a single tumor vaccine, combination therapy of tumor vaccines with radiotherapy, chemotherapy, immune checkpoint inhibitors, cytokines, CAR-T therapy, or photoimmunotherapy is an effective strategy. Given the critical role of tumor vaccines in immunotherapy, here, we look back to the history of tumor vaccines, and we discuss the antigens, adjuvants, formulations, delivery systems, mechanisms, combination therapy, and future directions of tumor vaccines.

Immunotherapy has largely failed in ovarian carcinoma (OC), likely due to that the vast tumor heterogeneity and variation in immune response have hampered clinical trial outcomes. Tumor-immune microenvironment (TIME) profiling may aid in stratification of OC tumors for guiding treatment selection. Here, we used Digital Spatial Profiling combined with image analysis to characterize regions of spatially distinct TIME phenotypes in OC to assess whether immune infiltration pattern can predict presence of immuno-oncology targets. Tumors with diffuse immune infiltration and increased tumor-immune spatial interactions had higher presence of IDO1, PD-L1, PD-1 and Tim-3, while focal immune niches had more CD163 macrophages and a preliminary worse outcome. Immune exclusion was associated with presence of Tregs and Fibronectin. High-grade serous OC showed an overall stronger immune response and presence of multiple targetable checkpoints. Low-grade serous OC was associated with diffuse infiltration and a high expression of STING, while endometrioid OC had higher presence of CTLA-4. Mucinous and clear cell OC were dominated by focal immune clusters and immune-excluded regions, with mucinous tumors displaying T-cell rich immune niches.