Purpose: Human amniotic fluid stem cells (hAFSCs) have shown significant regenerative potential in treating hair loss, wound healing, and tissue repair. This study aims to evaluate the effects of human amniotic fluid (hAF) on hair follicle (HF) regeneration and immune system modulation.

Materials and Methods: The hAF used was pooled, acellular, and gamma-irradiated to standardize its contents and enhance its stability. Both irradiated (FAFI) and non-irradiated (FAF) hAF were assessed for their efficacy and safety in promoting hair growth and modulating immune responses in a rat model of hair loss. The study examined HF regeneration, transition to the anagen phase, and macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype.

Results: Both FAF and FAFI treatments significantly increased HF density, with FAFI exhibiting enhanced effects. Histological analysis demonstrated improved HF regeneration, increased M2 macrophages, and reduced collagen fiber deposition in treated areas. Gamma irradiation likely improved the efficacy of FAFI by stabilizing active components and inhibiting protease activity.

Conclusions: Irradiated hAF is a safe and effective therapeutic candidate for alopecia and HF growth disorders. These findings support further evaluation of hAF in clinical trials to validate its potential for hair regeneration therapies.

Tumor-associated macrophages (TAMs) play a multifaceted role in the tumor microenvironment, notably by suppressing antitumor immune responses through immunosuppressive mechanisms. TAMs secrete a range of cytokines that simultaneously inhibit T cell function and foster a microenvironment that supports tumor progression and dissemination. Our study has delved into the intricate relationship between the metabolic reprogramming of TAMs and their impact on tumor progression. Mitochondrial metabolic reprogramming mediated by the SENP1-Sirt3 axis altered the dynamics and activity of tumor-infiltrating immune cells, including macrophages and CD8+ T lymphocytes. SENP1-Sirt3 axis increases the level of acetyl-CoA in macrophage mitochondria, which in turn promotes cholesterol biosynthesis in macrophages. The upregulation of cholesterol synthesis is a key factor in driving macrophage polarization towards the immunosuppressive M2 phenotype, which in turn supports tumor development. Notably, increased cholesterol levels contributed to a reduction in the number and activity of CD8+ T cells, which are essential for mounting an effective immune response against cancer cells. These findings suggest that targeting cholesterol biosynthesis in TAMs may be a promising strategy for cancer immunotherapy. SIGNIFICANCE: Activation of the SENP1-Sirt3 axis initiates mitochondrial metabolic reprogramming in tumor-associated macrophages (TAMs), leading to enhanced cholesterol and acetyl-CoA production, M2 macrophage polarization, and impaired CD8+ T cell anti-tumor responses.

Dipeptidyl peptidase 9 (DPP9) is an indispensable intracellular protease. Among its many molecular functions is suppression of the NLRP1 inflammasome. Inhibitors targeting all four proteases of the DPP4 family, including DPP9, can reduce tumour burden, including in mouse liver. To explore hepatocyte DPP9 in experimental hepatocellular carcinoma (HCC), we generated hepatocyte-specific DPP9-KO mice by crossing albumin-Cre mice with DPP9 floxed mice and treated sequentially with diethylnitrosamine, then with thioacetamide combined with an atherogenic high-fat diet until 28 weeks of age. DPP9-KO mice had less body, liver and subcutaneous adipose tissue mass, lower fasting plasma glucose and fewer small macroscopic liver nodules compared to DPP9-WT control mice. However, there were no differences in the total number of macroscopic liver nodules, or of microscopic tumour burden, inflammation, fibrosis or steatosis. Consistent with the known function of DPP9 to suppress NLRP1 activation, activated caspase-1 protein and inflammation markers Nfkbib, Cxcl10 and Ccl5 were elevated in DPP9-KO liver. The tumour suppressor protein p53 was increased and the autophagy proteins beclin1, LC3B and p62 were altered. In conclusion, hepatocyte-specific DPP9 gene deletion in experimental primary liver cancer improved energy metabolism and may reduce liver cancer initiation, via mechanisms that may include increased autophagy and tumour suppression.

Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Early coagulation-inflammation interaction and late in-stent restenosis undermine the efficacy of vascular stents after implantation. Targeting the interplay between inflammation and coagulation, and smooth muscle cell (SMC) proliferation, we presented a microenvironment-responsive coating designed to regulate tissue responses and vascular regeneration throughout the remodeling process. Coagulation was inhibited by incorporating anticoagulant tirofiban into the coating. MMP9-responsive nanoparticles embedded in the coating released salvianolic acid A to modulate inflammatory cell behavior and inhibit SMC dysfunction. By effectively interfering with clotting and inflammation, the coating suppressed platelet-fibrin interaction and formation of platelet-monocyte aggregates, thereby mitigating adverse effects on reendothelialization. Its ability to influence SMC proliferation and migration resulted in reduced intimal hyperplasia. Coated stents were shown to significantly regulate tissue regeneration, improve the vascular environment and even reduced the lipid content in the narrowed atherosclerotic vessels in vivo. This direct approach enhanced the vascular tissue regeneration after stent implantation, and offered promising insights for optimizing vascular stent design.

Although the neuroprotective effects of triggering receptor expressed on myeloid cell 2 (TREM2) upregulation after ischemic stroke has been demonstrated, the level change and effect of soluble TREM2 (sTREM2) derived from proteolytic cleavage of the TREM2 extracellular domain in ischemic stroke remain unknown. In our study, the level and function of sTREM2 were detected in neuron-microglia co-cultures subjected to oxygen glucose deprivation (OGD) and in the ischemic striatum of C57BL/6 J mice in a transient middle cerebral artery occlusion (tMCAO) model. sTREM2's effect on neuronal nitric oxide synthase (nNOS)-postsynaptic density protein-95 (PSD-95) interaction was determined by co-immunoprecipitation. The microglial-activated morphology in the striatum was identified by immunohistochemistry. Quantitative real-time polymerase chain reactionwas used to detect the transcriptional levels of TREM2, shorter variant TREM2, insulin-like growth factor 1, interleukin (IL)-4, and IL-13. Levels of sTREM2, generated through the cleavage of full-length TREM2 at the His157-Ser158 peptide bond, declined after OGD and tMCAO. sTREM2 reduced neuronal death after OGD and alleviated brain infarction and neurological deficits after tMCAO by disrupting the nNOS-PSD-95 interaction, promoting microglial activation, and increasing the expression of some cytokines associated with microglial polarization towards an anti-inflammatory phenotype. To the best of our knowledge, this is the first study to suggest that sTREM2 protects against transient cerebral ischemia.

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.

Multiple myeloma (MM) is a clonal hematologic malignancy characterized by low rate of complete remissions. Cytokine-induced killer (CIK) cell therapy has shown promising benefits in MM treatment. In this study, we investigated whether the pro-inflammatory cytokines secreted by macrophages could upregulate MICA/B expression and thus the cytotoxicity of CIK cells. Flow cytometry was used for phenotypic measurement and the cytotoxicity assay of CIK cells. Soluble MICA/B and macrophage-derived cytokines were measured using ELISA assay. CCK-8 assay was applied to evaluate cell viabilities. Gene expression levels were investigated using RT-qPCR. The expression of MICA/B and PD-L1 in MM cells was upregulated by pro-inflammatory cytokines. Pro-inflammatory cytokines enhanced the cytotoxicity of CIK cells against MM cells, with TNF-α exhibiting a more potent effect than IL-1β and IL-6 as it strengthened both components of the NKG2D-MICA/B axis. PD-L1 blockade promoted the cytotoxic ability of CIK cells. Mechanistically, IL-1β, IL-6, and TNF-α enhanced the transcription of MICA/B and PD-L1 genes via the PI3K/AKT, JAK/STAT3, and MKK/p38 MAPK pathways. Pro-inflammatory cytokines upregulated the expression of MICA/B and PD-L1, thereby promoting the cytotoxicity of CIK cells against MM by strengthening the NKG2D pathway, while PD-L1 blockade enhanced the cytotoxicity of CIK cells.

CRLM (Colorectal liver metastasis), a prevalent form of distant metastasis in colorectal cancer, is a leading cause of mortality in affected patients. Despite advancements in immunotherapy for colorectal cancer, clinical benefits in CRLM patients remain limited. The immunosuppressive liver microenvironment plays a pivotal role in facilitating metastatic colonization and disease progression.

We performed fecal metabolomics in ABX (antibiotic-treated) mice and single-cell RNA sequencing on hepatic tissues from four cohorts: CRC (colorectal cancer) , CRLM, LCA-fed CRC, and LCA-fed CRLM mice, to delineate intergroup immune heterogeneity. Cellular and molecular profiling across groups was conducted via Luminex multiplex assays, flow cytometry, and immunofluorescence. Integrated multi-omics analyses elucidated LCA-driven pathways modulating metastatic progression RESULTS: We demonstrated that LCA (lithocholic acid), a gut microbiota-derived metabolite, activates TGR5 in hepatic CAFs (cancer-associated fibroblasts) to upregulate CCL3 secretion. Elevated CCL3 levels subsequently recruit MDSCs (myeloid-derived suppressor cells) into metastatic niches. While MDSCs primarily suppress T-cell activation, we identified a paradoxical role of MDSC-derived CCL2 in attenuating immunosuppression via CCR2 signaling, suggesting a compensatory pro-inflammatory axis within the tumor microenvironment CONCLUSIONS: These findings suggest new immunotherapeutic strategies for the treatment of CRLM.

The tumor microenvironment (TME) is characterized by a complex array of factors, including aerobic conditions, high glutathione (GSH) levels, acidic pH, and elevated hydrogen peroxide (H2O2) content, all of which promote cancer progression and contribute to poor prognosis. Fortunately, these challenges can be addressed using MnO2-based nanomaterials. In this study, we have designed and synthesized a Curcumin/MnO2@PLGA@4T1 cell membrane (CMP@4T1m) system aimed at remodelling the TME and enhancing sonodynamic immunotherapy for breast cancer. Through the homologous targeting ability of 4T1m, CMP@4T1m efficiently accumulates at the tumor site. Upon ultrasound irradiation, curcumin (Cur) acts as a sonosensitizer, generating cytotoxic reactive oxygen species (ROS) that induce immunogenic cell death (ICD), activate T-cell responses, and repolarize protumoral M2-like macrophages to antitumoral M1-like macrophages. In the TME, which is mildly acidic and enriched with GSH and H2O2, MnO2 not only oxidizes GSH to glutathione disulfide (GSSG) but also reacts with H2O2 and H+ to produce oxygen, alleviating hypoxia and significantly enhancing the sonodynamic immunotherapy effect. Additionally, Mn2+ generated during this process converts H2O2 into cytotoxic hydroxyl radicals (˙OH). This study thus lays the foundation for advancing cancer nanomedicine, offering a novel approach that integrates TME remodelling with sonodynamic immunotherapy.

Glioblastoma is the most aggressive primary brain tumor, with a median survival of 15 months with treatment. Standard-of-care (SOC) consists of resection, radio- and chemotherapy. Clinical trials involving PD-1 inhibition with nivolumab combined with SOC failed to increase survival. A quantitative understanding of the interactions between the tumor and its immune environment that drive treatment outcomes is currently lacking. As such, we developed a mathematical model of tumor growth that considers CD8+ T cells, pro- and antitumoral tumor-associated macrophages and microglia (TAMs), SOC, and nivolumab. Using our model, we studied five TAM-targeting strategies currently under investigation for solid tumors. Our results show that PD-1 inhibition fails due to a lack of CD8+ T cell recruitment during treatment, explained by TAM-driven immunosuppressive mechanisms. Our model predicts that while reducing TAM numbers does not improve prognosis, altering their functions to counter their protumoral properties has the potential to considerably reduce post-treatment tumor burden. In particular, restoring antitumoral TAM phagocytic activity through anti-CD47 treatment in combination with SOC was predicted to nearly eradicate the tumor. By studying time-varying efficacy with the same half-life as the anti-CD47 antibody Hu5F9-G4, our model predicts that repeated dosing of anti-CD47 provides sustained control of tumor growth. We propose that targeting TAMs by enhancing their antitumoral properties is a highly promising avenue to treat glioblastoma and warrants future clinical development. Together, our results provide proof-of-concept that mechanistic mathematical modeling can uncover the mechanisms driving treatment outcomes and explore the potential of novel treatment strategies for hard-to-treat tumors like glioblastoma.

While platinum-based chemotherapeutics have revolutionized cancer treatment, their clinical potential is limited by off-target toxicity and restricted antitumor mechanisms. Herein, we introduce a dual-locked Pt(IV) prodrug designed for tumor-specific activation, combining platinum-based chemotherapy with TLR7/8-mediated immunotherapy. The prodrug features a γ-glutamyl-caged TLR7/8 agonist as an axial ligand, enabling sequential activation by elevated glutathione (GSH) and γ-glutamyltranspeptidase (GGT) in the tumor microenvironment. Reduction of the Pt(IV) core releases cisplatin and depletes intracellular reductants, amplifying reactive oxygen species to trigger synergistic ferroptosis and apoptosis. Concurrently, GGT-cleaved axial ligand activates tumor-associated macrophages and dendritic cells, repolarizing immunosuppressive M2-like macrophages to pro-inflammatory M1-like phenotypes while recruiting effector and memory T cells. In murine models, the Pt(IV) prodrug demonstrated potent antitumor efficacy by confining immune activation to malignant tissues, eradicating primary tumors, and establishing durable protective immunity against recurrence. This spatiotemporally controlled dual-release strategy minimizes systemic toxicity while synergizing chemotherapy and immunotherapy, offering a transformative approach for targeted cancer therapy.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.

Tumor-associated macrophages (TAMs), as key immune components of the TME, play a pivotal role in tumor progression by fostering an immunosuppressive environment. Programmed death 1 (PD-1), a critical immune checkpoint molecule predominantly expressed on T cells, mediates immune suppression by binding to programmed death-ligand 1 (PD-L1) on tumor cells within the tumor microenvironment (TME). Emerging evidence reveals that TAMs also express PD-1, however, the expression and functional regulatory mechanisms of PD-1 on TAM remain poorly understood.

In this study, we combined bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data to investigate the association between PD-1 expression on macrophages and patient prognosis, while also uncovering the molecular mechanisms by which PD-1 regulates macrophage function. To further investigate the role of PD-1 in macrophage activity, we established a fluorescence-labeled tumor-bearing mouse model using CT26 cells, a murine colorectal cancer cell line, to evaluate the relationship between PD-1 expression on TAMs and their phagocytic activity as well as other functions. Additionally, to mimic the TME in vitro, we cultured bone marrow-derived macrophages (BMDMs) with CT26-conditioned medium (CT26-CM).

Our results suggest that PD-1 expression on TAMs drives macrophage polarization toward an M2-like phenotype, suppresses their phagocytic activity, inhibits the synthesis of interferon-γ (IFN-γ) signaling molecules, and ultimately promotes tumor progression. Mechanistically, we demonstrated that PD-1 regulates the synthesis of IFN-γ signaling molecules and the polarization of M2-type macrophages in BMDMs through the JAK2-STAT3 signaling pathway. Overall, our study demonstrates that PD-1 expression on TAMs facilitates the formation of an immunosuppressive microenvironment, ultimately accelerating tumor progression.

Not applicable.

The study identifies GPR65 as an important determinant of B-cell acute lymphoblastic leukemia response to CAR T-cell therapy. Notably, GPR65 absence signals CAR T resistance. By emphasizing the therapeutic potential of targeting VEGFA or host macrophages, our study identifies routes to optimize CAR T-cell therapy outcomes in hematologic malignancies via tumor microenvironment manipulation.

The inflammatory response in bone tissue often triggered by LPS is a complex process. Since LPS through TLR4 and in presence of IFNγ activates osteoclast differentiation and bone resorption, therefore, suppression of osteoclastogenesis through inhibition of TLR4 vs IFNγ mediated inflammation could be a reasonable strategy for the treatment of inflammatory bone loss. Administration of anti-TLR4 (30 mg/kg) and anti-IFNγ antibodies (6.6 mg/kg) were utilized before LPS (5 mg/kg) challenge and subsequently mice were treated with mouse IL-10 (0.02 mg/kg). Then RBMCs were isolated from different groups of mice and stimulated (in vitro) with M-CSF (10 ng/ml) and RANKL (10 ng/ml) to induce bone marrow cell differentiation in presence of LPS (100 ng/ml). The involvement of RANKL and M-CSF in the regulation of bone inflammation underlines the intricate signaling pathways. Furthermore, the study sheds light on the potential therapeutic effects of exogenous IL-10 possibly through STAT3 signaling in the RBMCs. The use of antibodies against TLR4 and IFNγ, in conjugation with IL-10in LPS bone damage model, appears to downregulate the activation of NF-κB, and reduction of many pro-inflammatory cytokines regulating the inflammatory cascade in RBMC. This suggests a promising avenue for the development of treatments aimed at mitigating bone inflammation associated with bacterial infections. Therefore, inhibition of TLR4 and IFNγ could be explored as potential therapeutic agents against LPS induced bone loss.

Glioblastoma (GBM) demonstrates extensive immunomodulatory mechanisms that challenge effective therapeutic interventions. These phenomena extend well beyond the tumor microenvironment (TME) and are reflected in the circulating immunophenotype. B lymphocytes (B cells) have received limited attention in GBM studies despite their emerging importance in mediating both local and systemic immune responses. Recent findings highlight the complex regulatory interactions between B cells and other immune cell populations, including tumor-infiltrating macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and other infiltrating lymphocytes (TILs). B cells are believed to hinder the efficacy of modern immunotherapy strategies focusing on T cells.

This is a focused review of available evidence regarding B cells in GBM through January 2025.

Peripheral blood reflects a systemically dampened immune response, with sustained lymphopenia, increased plasma cells, and dysfunctional memory B cells. The tumor immune landscape is enriched in cells of B-lineage. Subsets of poorly characterized B regulatory cells (Bregs) populate the TME, developing their phenotype due to their proximity to MDSCs, TAMs, and tumoral cells. The Bregs inhibit CD8+ T activity and may have potential prognostic significance.

Understanding the role of B cells, how they are recruited, and their differentiation shifted towards an immunomodulatory role could inform better therapeutic strategies and unleash their full antitumoral potential in GBM.

Tumor-associated macrophages (TAMs) contribute to tumor progression by promoting angiogenesis, remodeling the tumor extracellular matrix, inducing tumor invasion and metastasis, as well as immune evasion. Due to the high plasticity of TAMs, they can polarize into different phenotypes with distinct functions, which are primarily categorized as the pro-inflammatory, anti-tumor M1 type, and the anti-inflammatory, pro-tumor M2 type. Notably, anti-tumor macrophages not only directly phagocytize tumor cells, but also present tumor-specific antigens and activate adaptive immunity. Therefore, targeted regulation of TAMs to unleash their potential anti-tumor capabilities is crucial for improving the efficacy of cancer immunotherapy. Nanomedicine serves as a promising vehicle and can inherently interact with TAMs, hence, emerging as a new paradigm in cancer immunotherapy. Due to their controllable structures and properties, nanomedicines offer a plethora of advantages over conventional drugs, thus enhancing the balance between efficacy and toxicity. In this review, we provide an overview of the hallmarks of TAMs and discuss nanomedicines for targeting TAMs with a focus on inhibiting recruitment, depleting and reprogramming TAMs, enhancing phagocytosis, engineering macrophages, as well as targeting TAMs for tumor imaging. We also discuss the challenges and clinical potentials of nanomedicines for targeting TAMs, aiming to advance the exploitation of nanomedicine for cancer immunotherapy.

Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.

Pediatric solid tumors represent a significant subset of childhood cancers, accounting for approximately 60% of new diagnoses. Despite advancements in therapeutic strategies, survival rates remain markedly disparate between high-income and resource-limited settings, underscoring the urgent need for novel and effective treatments. Lipid metabolic reprogramming is a fundamental hallmark of cancer, driving tumor progression, therapeutic resistance, and immune evasion through enhanced fatty acid uptake, increased de novo lipid synthesis, and activated fatty acid β-oxidation (FAO). Ubiquitination, a dynamic post-translational modification mediated by the ubiquitin-proteasome system (UPS), plays a crucial role in regulating lipid metabolism by modulating the stability and activity of key metabolic enzymes and transporters involved in cholesterol and fatty acid pathways. This review comprehensively examines the complex interplay between ubiquitination and lipid metabolic reprogramming in pediatric solid tumors. It delineates the mechanisms by which ubiquitination influences cholesterol biosynthesis, uptake, efflux, and fatty acid synthesis and oxidation, thereby facilitating tumor growth and survival. Furthermore, the review identifies potential UPS-mediated therapeutic targets and explores the feasibility of integrating ubiquitination-based strategies with existing treatments. By targeting the UPS to disrupt lipid metabolism pathways, novel therapeutic avenues may emerge to enhance treatment efficacy and overcome resistance in pediatric oncology. This synthesis of current knowledge aims to provide a foundation for the development of innovative, precision medicine approaches to improve clinical outcomes for children afflicted with solid tumors.

Macrophages are crucial in the body's inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS-p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.

Ovarian cancer (OC) remains the most lethal gynecological malignancy, primarily due to its late-stage diagnosis, frequent recurrence, and resistance to conventional chemotherapy. A critical factor contributing to OC's aggressiveness is the tumor microenvironment (TME), particularly the presence and polarization of tumor-associated macrophages (TAMs). TAMs, often skewed toward an immunosuppressive M2-like phenotype, facilitate tumor growth, angiogenesis, metastasis, and resistance to therapy. This comprehensive review delves into the multifaceted regulation of macrophage polarization in OC, highlighting key molecular pathways such as PTEN loss, Wnt/β-catenin signaling, NF-κB, Myc, STAT3, and JNK, among others. Additionally, it explores the role of chemokines, non-coding RNAs, and various proteins in modulating TAM phenotypes. Emerging evidence underscores the significance of extracellular vesicles (EVs) and ovarian cancer stem cells (CSCs) in promoting M2 polarization, thereby enhancing tumor progression and therapy resistance. The review also identifies critical biomarkers associated with macrophage polarization, including CD163, LILRB1, MUC2, and others, which hold prognostic and therapeutic potential. Therapeutic strategies targeting TAMs are extensively discussed, encompassing oncolytic viruses, engineered EVs, immunotherapies, nanoparticles, targeted therapies, and natural products. These approaches aim to reprogram TAMs from a pro-tumorigenic M2 state to an anti-tumorigenic M1 phenotype, thereby enhancing immune responses and overcoming resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Furthermore, the review addresses the interplay between macrophage polarization and therapy resistance, emphasizing the need for novel interventions to modulate the TME effectively. By synthesizing current knowledge on macrophage polarization in ovarian cancer, this study underscores the potential of targeting TAMs to improve clinical outcomes and personalize treatment strategies for OC patients. Continued research in this domain is essential to develop robust therapeutic frameworks that can mitigate the immunosuppressive TME and enhance the efficacy of existing and novel cancer therapies.

Background: Glutathione peroxidase 4 (GPX4), an important factor regulating redox homeostasis, plays an important role in tumor microenvironment and progression. However, the role of GPX4 in gastric cancer (GC) is unclear. Methods: Spectral flow cytometry and multiplex immunohistochemistry were employed to assess the correlation between GPX4 expression and immune cell infiltration. Metabolomics analysis of conditioned media from GPX4 knockdown NUGC3 cells identified metabolic alterations. Additionally, both in vitro and in vivo functional studies were conducted to elucidate the mechanistic role of GPX4 in regulating the tumor microenvironment and progression. Results: Knockdown of GPX4 in GC cells inhibited tumor growth, enhanced CD8+ T cell infiltration, and suppressed the polarization of tumor-associated macrophages (TAMs) toward the pro-tumor M2 phenotype. Multiplex immunohistochemistry revealed a positive correlation between GPX4 expression and M2 macrophage infiltration in clinical samples from patients with GC. Metabolomics revealed that GPX4 knockdown regulate kynurenine metabolism pathway. Furthermore, mechanistic studies reveal that GPX4 silencing elevates lipid peroxidation, triggering the conversion of KYNU ubiquitin chain modifications from K48 to K63. Such ubiquitination remodeling stabilizes KYNU expression (a key kynurenine-metabolizing enzyme), reduces kynurenine accumulation, and ultimately reprograms TAM polarization to enhance antitumor immunity. We also identified that the K96 and K163 sites are important for KYNU's modification by K48 and K63 ubiquitin chains. Conclusion: Our study not only affirm the role of GPx4 in GC progression but also highlight it as a promising target for reshaping the immune microenvironment.

Macrophages are integral components of the innate immune system, present in nearly all tissues and organs throughout the body. They exhibit a high degree of plasticity and heterogeneity, participating in immune responses to maintain immune homeostasis. When the immune system loses tolerance, macrophages rapidly proliferate and polarize in response to various signaling pathways within a disrupted microenvironment. The direction of macrophage polarization can be regulated by a variety of factors, including transcription factors, non-coding RNAs, and metabolic reprogramming. Autoimmune diseases arise from the immune system's activation against host cells, with macrophage polarization playing a critical role in the pathogenesis of numerous chronic inflammatory and autoimmune conditions, such as rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura, and type 1 diabetes. Consequently, elucidating the molecular mechanisms underlying macrophage development and function presents opportunities for the development of novel therapeutic targets. This review outlines the functions of macrophage polarization in prevalent autoimmune diseases and the underlying mechanisms involved. Furthermore, we discuss the immunotherapeutic potential of targeting macrophage polarization and highlight the characteristics and recent advancements of promising therapeutic targets. Our aim is to inspire further strategies to restore macrophage balance in preventing and treating autoimmune diseases.

Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear.

Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment.

Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased AhR nuclear translocation and higher expression of IL4I1 and the M2 macrophage marker CD206 in the lungs was observed. The IL4I1/AhR axis exacerbated allergic symptoms in AR mice, fostering allergic inflammation within the nasal mucosa and lungs.

The IL4I1/AhR axis is activated within the mononuclear phagocyte system of patients with AR. This activation facilitates the polarization of mononuclear cells into M2 macrophages, which further aggravates EMT in epithelial cells and exacerbates inflammation in AR. This study may provide novel strategies for the precise treatment of AR.

Macrophages are pivotal immune cells involved in maintaining immune homeostasis and defending against pathogens. They exhibit significant plasticity and heterogeneity, enabling polarization into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to distinct microenvironmental cues. The process of macrophage polarization is tightly regulated by complex signaling pathways and transcriptional networks. This review explores the factors influencing macrophage polarization, the associated signaling pathways, and their roles in the pathogenesis of lung diseases, including fibrosis, cancer, and chronic inflammatory conditions. By summarizing recent advances, we aim to provide insights into the immunoregulatory functions of macrophages and their therapeutic potential. Based on our review, it is believed that targeting macrophage polarization emerges as a promising approach for developing effective treatments for lung diseases, balancing inflammation and repair while mitigating disease progression.

The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation-dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A (Ldha) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane-derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification-based tumor immunotherapy.

The tumour microenvironment (TME) is a highly structured ecosystem that surrounds a tumour and plays a crucial role in tumorigenesis. As one of the most abundant cell types in the TME, tumour-associated-macrophages (TAMs) can promote disease progression and resistance to therapy. Syndecan-3 (SDC3) is a cell-surface heparan sulphate proteoglycan expressed by TAMs, although its functional relevance in these cells remains unknown. Here, we demonstrated that pro-inflammatory cytokines drive the expression of SDC3 on the cell surface of macrophages. Genetic ablation of SDC3 in macrophages led to aberrant proliferation, adhesion and expression of CD40 and CD86 surface markers. Moreover, SDC3 defective macrophages exhibited distinctive gene expression patterns, leading to impaired tumour cell phagocytosis and increased tumour cell proliferation. Mechanistically, a decrease in the secretion of pro-inflammatory cytokines was observed in SDC3 KO macrophages, concomitant with impaired T cell effector functions. Additionally, a higher angiogenic capacity was observed in endothelial cells when co-cultured with macrophages deficient for SDC3, possibly mediated through an increased release of VEGFA, PECAM-1 and IL-8 by SDC3 KO cells. Collectively, we have identified SDC3 as a modulator of macrophage functions aiming at supporting a pro-inflammatory and anti-tumour phenotype in these cells.

Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.

Objectives: Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-7 (IL-7), designed to enhance anti-tumor immunity and synergize with immune checkpoint inhibitors. Methods: VVL-GL7 was constructed through CRISPR/Cas9-mediated knockout of TK and A49 genes, combined with the simultaneous insertion of dual cytokine-encoding cassettes. Anti-tumor efficacy was evaluated in vitro and in vivo using C57BL/6 mouse and Syrian hamster pancreatic cancer models. Comprehensive immune profiling evaluated CD8+ T-cell and macrophage infiltration dynamics while simultaneously assessing memory T-cell differentiation patterns using flow cytometry. Preclinical combination studies of VVL-GL7 and the PD-1 immune checkpoint inhibitor were systematically evaluated in a syngeneic pancreatic cancer model. Results: VVL-GL7 exhibited potent oncolytic activity, inducing significant tumor regression in both preclinical models. VVL-GL7 therapy significantly augmented CD8+ T-cell and macrophage infiltration within the tumor microenvironment, while concomitantly driving memory T-cell differentiation. The synergistic effects of VVL-GL7 and the PD-1 blockade further improved therapeutic outcomes, resulting in significantly higher tumor remission rates compared to monotherapy and achieving complete tumor regression in pancreatic cancer models. Conclusions: VVL-GL7 reprograms the immunosuppressive tumor microenvironment and synergizes with anti-PD-1 antibodies to overcome resistance in pancreatic cancer.

Regulatory T cells (Tregs) are the main immunosuppressive cells in tumor immune microenvironment (TIME). However, systemic Treg depletion is not favored due to the crucial role of Tregs in the maintenance of immune homeostasis and prevention of autoimmunity. Recently, CCR8 has been identified as a key chemokine receptor expressed on tumor-infiltrating Tregs and targeted blockade of CCR8 exerts anticancer effect in several cancer types, but whether this pathway is involved in the progression of hepatocellular carcinoma (HCC) remains unclear.

We determined the involvement of CCR8+ Tregs in HCC using human HCC tissues and TCGA database, and examined the anticancer effect and the underlying molecular mechanisms of the CCR8 antagonist, IPG0521m, which was developed in house, in murine liver cancer model with flow cytometry, bulk and single-cell RNA sequencing and Real-Time PCR.

Remarkable increase in CCR8+ Tregs was observed in human HCC tissues. Treatment of syngeneic liver cancer model with IPG0521m resulted in dramatic inhibition of tumor growth, associated with increased CD8+ T cells in tumor tissues. Bulk RNA sequencing analysis indicated that IPG0521m treatment resulted in remarkable increase in antitumor immunity. Furthermore, single-cell RNA sequencing analysis demonstrated that IPG0521m treatment resulted in a switch of Tregs from high immunosuppression to low immunosuppression phenotype, associated with elevated CD8+ T and NK cell proliferation and cytotoxicity, and decreased myeloid-derived suppressor cells and tumor-associated macrophages in the tumor tissues.

IPG0521m inhibited liver cancer growth via reducing the immunosuppressive function of Tregs, thereby boosting anti-cancer immunity. Our study paves the way for the clinical study of CCR8 antagonist in HCC and other cancers.

Macrophage differentiation, phenotype, and function have been assessed extensively in vitro by predominantly deriving human macrophages from peripheral blood. It is accepted that there are differences between macrophages isolated from different human tissues; however, the importance of anatomical source for in vitro differentiation and characterization is less clear. Here, phenotype and function were evaluated between human macrophages derived from bone marrow or peripheral blood. Macrophages were differentiated by adherence of heterogenous cell populations or CD14 isolation and polarized with IFNγ and LPS or IL-4 and IL-13 for 48 hours before evaluation of phenotype and phagocytic capacity. The presence of stromal cells in bone marrow heterogenous cultures resulted in a reduction in macrophage purity compared to peripheral blood, which was negated after CD14 isolation. Phenotypically, monocyte-derived macrophages (MDMs) derived from peripheral blood and bone marrow resulted in similar expression of classical and polarized macrophages markers, including CD14, HLA-DR, CD38, and CD40 (increased after IFNγ/LPS), and CD11b and CD206 (elevated after IL-4/IL-13). Functionally, these cells also showed similar levels of Fc-independent and Fc-dependent phagocytosis, although there was a nonsignificant reduction of Fc-dependent phagocytosis in the bone marrow derived macrophages after IFNγ/LPS stimulation. In summary, we have identified that human MDMs differentiated from peripheral blood and bone marrow showed similar characteristics and functionality, suggesting that isolating cells from different anatomical niches does not affect macrophage differentiation after CD14 isolation. Consequently, due to high yield and ready availability peripheral blood derived macrophages are still the most suitable source.

The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.

Tumor-associated macrophages (TAMs) play crucial roles in development and progression of malignant diseases. Notably, CD163+ TAMs likely perform specific pro-tumorigenic functions, suggesting that this subset may serve as both prognostic biomarkers and targets for future anti-cancer therapy. We conducted a scoping review to map the current knowledge on the prognostic role of CD163+ TAMs in the five most lethal cancers worldwide: Lung, colorectal, gastric, liver, and breast cancer. For all cancer types, most studies showed that high tumoral presence of CD163+ cells was associated with poor patient outcome, and this association was more frequently observed when CD163+ cells were measured at the tumor periphery compared to more central parts of the tumor. These results support that CD163+ TAMs represent a biomarker of poor patient outcome across a variety of solid tumors, and highlight the relevance of further investigations of CD163+ TAMs as targets of future immunotherapies.

Angiogenesis, as a core marker of cancer survival and growth, is integral to the processes of tumour growth, invasion and metastasis. In recent years, targeted angiogenesis treatment strategies have gradually become an important direction in cancer treatment. Single-cell sequencing technology can provide new insights into targeted angiogenesis by providing a deeper understanding of the heterogeneity of tumour endothelial cells and exploring the interactions between endothelial cells and surrounding cells in the tumour microenvironment. Here, we systematically review the research progress in endothelial cell pathophysiology and its endothelial‒mesenchymal transition and illustrate the heterogeneity of endothelial cells from a single-cell perspective. Finally, we examine the contributions of different cell types within the tumour microenvironment in relation to tumour angiogenesis, as well as the latest progress and strategies in targeted angiogenesis therapy, hoping to provide useful insights into the clinical application of antiangiogenic treatment. Furthermore, a summary of the present progress in the development of potential angiogenesis inhibitors and the ongoing clinical trials for combination therapies is provided. KEY POINTS: Angiogenesis plays a key role in tumour progression, invasion and metastasis, so strategies targeting angiogenesis are gradually becoming an important direction in cancer therapy. Interactions between endothelial cells and stromal cells and immune cells in the tumour microenvironment are significant in angiogenesis. The application of antiangiogenic immunotherapy and nanotechnology in antiangiogenic therapy provides a vital strategy for prolonging the survival of cancer patients.