Tumor-associated macrophages (TAMs) play a key role in facilitating a range of cancerous processes by modulating the tumor microenvironment thus being a target for cancer treatment. Astragaloside III (AS-III), a compound derived from Astragalus triterpenoid saponins, has demonstrated immunomodulatory and anticancer properties, but the underlying mechanism remains unclear. Here, we demonstrated that AS-III suppressed metastasis, angiogenesis and induced apoptosis of lung cancer in vitro and in vivo by inhibiting macrophage M2 polarization and inducing M1 phenotype transformation. This was achieved through the inhibition of the MAPK signaling pathway. Furthermore, the tumor inhibitory effects of AS-III were found to be mediated by the Akt/mTOR pathway. Overall, these results highlight the role of AS-III in modifying the TAMs in TME, offering fresh perspectives on tumor immunotherapy by means of targeting macrophage.

Cell membrane coating has emerged as a promising strategy for the surface modification of biomaterials with biological membranes, serving as a cloak that can carry more functions. The cloaked biomaterials inherit diverse intrinsic biofunctions derived from different cell sources, including enhanced biocompatibility, immunity evasion, specific targeting capacity, and immune regulation of the regenerative microenvironment. The intrinsic characteristics of biomimicry and biointerfacing have demonstrated the versatility of cell membrane coating technology on a variety of biomaterials, thus, furthering the research into a wide range of biomedical applications and clinical translation. Here, the preparation of cell membrane coatings is emphasized, and different sizes of coated biomaterials from nanoscale to macroscale as well as the engineering strategies to introduce additional biofunctions are summarized. Subsequently, the utilization of biomimetic membrane-cloaked biomaterials in biomedical applications is discussed, including drug delivery, imaging and phototherapy, cancer immunotherapy, anti-infection and detoxification, and implant modification. In conclusion, the latest advancements in clinical and preclinical studies, along with the multiple benefits of cell membrane-coated nanoparticles (NPs) in biomimetic systems, are elucidated.

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.

Breast cancer bone metastasis is a major cause of mortality in patients with advanced breast cancer. Although decreased mineral density is a known risk factor for bone metastasis, the underlying mechanisms remain poorly understood because studying the isolated effect of bone mineral density on tumor heterogeneity is challenging with conventional approaches. Moreover, mineralized biomaterials are commonly utilized for clinical bone defect repair, but how mineralized biomaterials affect the foreign body response and wound healing is unclear. Here, we investigate how bone mineral affects tumor growth and microenvironmental complexity in vivo by combining single-cell RNA-sequencing with mineral-containing or mineral-free decellularized bone matrices. We discover that the absence of bone mineral significantly influences fibroblast and immune cell heterogeneity, promoting phenotypes that increase tumor growth and alter the response to injury or disease. Importantly, we observe that the stromal response to bone mineral content depends on the murine tumor model used. While lack of bone mineral induces tumor-promoting microenvironments in both immunocompromised and immunocompetent animals, these changes are mediated by altered fibroblast phenotype in immunocompromised mice and macrophage polarization in immunocompetent mice. Collectively, our findings suggest that bone mineral density affects tumor growth by impacting microenvironmental complexity in an organism-dependent manner.

Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment, yet the roles and mechanisms of TAMs in inflammation-associated oncogenesis remain enigmatic. We report that protein canopy homolog 2 (CNPY2) functions as a novel TLR4 regulator, promoting cytokine production in macrophages. CNPY2 binds directly to TLR4. Cnpy2 deficiency reduces cell surface expression of TLR4, nuclear translocation of NFκB and cytokine production in macrophages. Macrophage-specific CNPY2 deficiency significantly decreases cytokine production in macrophages and reduces hepatocarcinogenesis in a diethylnitrosamine (DEN)-induced liver cancer model. RNA-sequencing analysis revealed Cnpy2 knockout decreased the mRNA level and cell surface expression of two VEGF receptors, Flt1 and Kdr, compared to those in WT counterparts, resulting in inhibition of macrophage tumor infiltration. Cnpy2 knockout inhibits NFκB2/p52-mediated transcription of Flt1 and Kdr in macrophages. These findings demonstrate that CNPY2 regulates macrophages in both inflammation and hepatocarcinogenesis and may serve as a therapeutic target for cancer.

N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.

The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.

This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Microplastics (MPs) are pervasive in several ecosystems and have the potential to infiltrate multiple aspects of human life through ingestion, inhalation and dermal exposure, thus eliciting substantial concerns regarding their potential implications for human health. Whilst initial research has documented the effects of MPs on disease development across multiple physiological systems, MPs may also facilitate tumor progression by influencing the tumor microenvironment (TME). This evolving focus underscores the growing interest in the role of MPs in tumorigenesis and their interactions within the TME. In the present review, the relationship between MPs and the TME is comprehensively assessed, providing a detailed analysis of their interactions with tumor cells, stromal cells (including macrophages, fibroblasts and endothelial cells), the extracellular matrix and inflammatory processes. Recommendations for future research directions and strategies to address and reduce microplastic pollution are proposed.

Ferroptosis represents an emerging, iron-dependent form of cell death driven by lipid peroxidation. In recent years, it has garnered significant attention in the realm of cancer immunotherapy, particularly in studies involving immune checkpoint inhibitors. This form of cell death not only enhances our comprehension of the tumor microenvironment but is also considered a promising therapeutic strategy to address tumor resistance, investigate immune activation mechanisms, and facilitate the development of cancer vaccines. The combination of immunotherapy with ferroptosis provides innovative targets and fresh perspectives for advancing cancer treatment. Nevertheless, tumor cells appear to possess a wider array of ferroptosis evasion strategies compared to CD8+T cells, which have been conclusively shown to be more vulnerable to ferroptosis. Furthermore, ferroptosis in the TME can create a favorable environment for tumor survival and invasion. Under this premise, both inducing tumor cell ferroptosis and inhibiting T cell ferroptosis will impact antitumor immunity to some extent, and even make the final result run counter to our therapeutic purpose. This paper systematically elucidates the dual-edged sword role of ferroptosis in the antitumor process of T cells, briefly outlining the complexity of ferroptosis within the TME. It explores potential side effects associated with ferroptosis-inducing therapies and critically considers the combined application of ferroptosis-based therapies with ICIs. Furthermore, it highlights the current challenges faced by this combined therapeutic approach and points out future directions for development.

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.

Immune cells within the tumor microenvironment impact cancer progression, resistance, response to treatments. Despite remarkable outcomes for some cancer patients, immunotherapies remain unsatisfactory for others. Here, we designed an experimental setting using the Alb-R26 Met "inside-out" mouse model, faithfully recapitulating molecular features of liver cancer patients, to explore the effects of distinct anticancer targeted therapies on the tumor immune landscape. Using two treatments in clinical trials for different cancer types, Decitabine and MEK+BCL-XL blockage, we show their capability to trigger tumor regression in Alb-R26 Met mice and to superimpose distinct profiles of immune cell types and immune-checkpoints, impacting immunotherapy response. A machine learning approach processing tumor imaging and immune profile data identified a putative signature predicting tumor treatment response in mice and patients. Outcomes exemplify how the tumor immune microenvironment is differentially reshaped by distinct anticancer agents and highlight the importance of measuring its modulation during treatment to optimize oncotherapy and immunotherapy combinations.

The main challenges in current immunotherapy for triple-negative breast cancer (TNBC) lie in the immunosuppressive tumor microenvironment (TME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, resetting TAMs is a promising strategy for ameliorating the immunosuppressive TME. Here, we developed genetically engineered macrophages (GEMs) with gene-carrying adenoviruses, to maintain the M1-like phenotype and directly deliver the immune regulators interleukin-12 and CXCL9 into local tumors, thereby reversing the immunosuppressive TME. In tumor-bearing mice, GEMs demonstrated targeted enrichment in tumors and successfully reprogramed TAMs to M1-like macrophages. Moreover, GEMs significantly enhanced the accumulation, proliferation, and activation of CD8+ T cells, mature dendritic cells, and natural killer cells within tumors, while diminishing M2-like macrophages, immunosuppressive myeloid-derived suppressor cells, and regulatory T cells. This treatment efficiently suppressed tumor growth. In addition, combination therapy with GEMs and anti-programmed cell death protein 1 further improved interferon-γ+CD8+ T cell percentages and tumor inhibition efficacy in an orthotopic murine TNBC model. Therefore, this study provides a novel strategy for reversing the immunosuppressive TME and improving immunotherapeutic efficacy through live macrophage-mediated gene delivery.

Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.

Breast cancer ranks as the most prevalent cancer type impacting women globally, both in terms of incidence and mortality rates, making it a major health concern for females. There's an urgent requirement to delve into new cancer treatment methods to improve patient survival rates.

Immunotherapy has gained recognition as a promising area of research in the treatment of breast cancer, with targeted immune checkpoint therapies demonstrating the potential to yield sustained clinical responses and improve overall survival rates. Presently, the predominant immune checkpoints identified on breast cancer cells include CD47, CD24, PD-L1, MHC-I, and STC-1, among others. Nevertheless, the specific roles of these various immune checkpoints in breast carcinogenesis, metastasis, and immune evasion have yet to be comprehensively elucidated. We conducted a comprehensive review of the existing literature pertaining to breast cancer and immune checkpoint inhibitors, providing a summary of findings and an outlook on future research directions.

This article reviews the advancements in research concerning each immune checkpoint in breast cancer and their contributions to immune evasion, while also synthesizing immunotherapy strategies informed by these mechanisms. Furthermore, it anticipates future research priorities, thereby providing a theoretical foundation to guide immunotherapy as a potential interventional approach for breast cancer treatment.

Knowledge of immune checkpoints will drive the creation of novel cancer therapies, and future breast cancer research will increasingly emphasize personalized treatments tailored to patients' specific tumor characteristics.

This study aims to integrate multi-omic and clinical data concerning disulfidptosis-related genes (DRGs) to facilitate molecular typing and prognosis in colorectal cancer (CRC). Public databases provided CRC transcriptome and clinical data, enabling differential expression, genomic analyses, pathway enrichment, survival analysis, and subtyping based on the expression levels of 15 DRGs identified in published studies. Differentially expressed genes (DEGs) between subtypes were identified to create a disulfidptosis prognostic model using LASSO and Cox regression analyses. This model was evaluated by comparing risk scores, survival curves, cellular infiltration, and drug sensitivity between high- and low-risk groups. Analyses revealed differential expression, mutations, and copy number variations (CNV) in DRGs in CRC. Survival analysis demonstrated significant prognostic differences among DRG expression subtypes. GSVA and ssGSEA highlighted DRGs' regulatory roles in CRC. DEGs identified between DRG expression subtypes led to the classification into subtypes A and B. A disulfidptosis prognostic model, including genes VSIG4, SCG2, INHBB, DDC, CXCL13, KLK10, CXCL10, and CCL11A, was developed to stratify patients into high- and low-risk groups. This model displayed strong predictive capability (AUC = 0.700) and calibration. The risk score was also strongly associated with immune cell infiltration, stromal cell score, and stem cell index in the CRC tumor microenvironment. Drug sensitivity analysis indicated that high-risk samples were more responsive to most medications. We established a robust disulfidptosis prognostic model for CRC through comprehensive multi-omics analysis. Our findings provide valuable insights into the role of DRGs in CRC progression and disease management, presenting an important resource for further research.

The silent killer epithelial ovarian cancer (EOC) is a lethal malignancy with high mortality rate and often diagnosed at an advanced stage. Traditional chemotherapy for EOC remains unsatisfactory as the tumor microenvironment (TME) is complicated and contains multiple factors such as tumor associated macrophages (TAMs). Therefore, a drug delivery system which codelivery chemotherapy drug and immune modulator for EOC treatment is urgently needed.

Follicle-stimulating hormone peptide-conjugated paclitaxel and ginsenoside Rh2 codelivery liposomes (FSH@PTX-Rh2-Lips) were prepared in this study. FSH was decorated on the liposomal surface to enhance cellar uptake, PTX was used to kill cancer cells, and Rh2 was added to induce macrophages repolarization as well as a member material. The targeting, anti-tumor effect and impact on macrophage repolarization of FSH@PTX-Rh2-Lips were evaluated in vitro and in vivo.

With the ideal physicochemical properties, FSH@PTX-Rh2-Lips displayed increased cellular uptake, strong cytotoxicity to ID8 cells, inhibitory effect of tumor cell metastasis, and ability to induce macrophage repolarization from M2 to M1 in vitro. The tumor-bearing mice model suggested FSH@PTX-Rh2-Lips showed significant effect on antitumor and tumor recurrence, and the mechanism of FSH@PTX-Rh2-Lips in treatment of EOC was related to inhibiting tumor growth and inducing macrophage repolarization.

FSH@PTX-Rh2-Lips with function of affecting TAMs repolarization and altering the TME were successfully prepared and might offer an effective therapeutic strategy against EOC.

Factors associated with outcomes of chimeric antigen receptor (CAR)-T cell therapy in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have not been fully elucidated. We explored the impact of the prelymphodepletion (pre-LD) lymphocyte to monocyte ratio (LMR) and its ratio to lactate dehydrogenase (LDH) (LMR/LDH) on the efficacy and prognosis of 60 patients with R/R DLBCL undergoing CAR-T cell therapy. The optimal cutoff values for pre-LD LMR and LMR/LDH were 3.583 and 0.0103, respectively. The overall response rate (ORR)s were higher in patients with high pre-LD LMR or LMR/LDH than those with low pre-LD LMR or LMR/LDH (ORR, 100% vs. 65.79%, P = 0.006 and 96.15% vs. 38.24%, P < 0.0001, respectively). Pre-LD LMR/LDH was an independent factor associated with ORR (P = 0.010, odds ratio = 18.757; 95% confidence interval [CI] 2.046-171.975) by multivariate logistic regression analysis. Patients with high pre-LD LMR/LDH had significantly longer progression-free survival (PFS) (median PFS, 29.73 vs. 2.47 months, P < 0.0001) and overall survival (OS) (median OS, not reached vs. 7.4 months, P = 0.0002) than those with low pre-LD LMR/LDH. Multivariate Cox regression analysis showed that pre-LD LMR/LDH and ORR were independent factors affecting PFS (P = 0.030, hazard ratio [HR] = 2.561; 95% CI 1.093-5.999 and P = 0.024, HR = 2.202; 95% CI 1.22-4.369, respectively); pre-LD LMR/LDH was an independent factor affecting OS (P = 0.029, HR = 3.331; 95% CI 1.131-9.807). In conclusion, the pre-LD LMR/LDH was an independent factor associated with ORR and an independent prognostic factor in patients with R/R DLBCL undergoing CAR-T cell therapy.

Osteosarcoma is a highly malignant bone tumor that is resistant to radiotherapy and is associated with poor treatment outcomes and prognoses. Understanding the mechanisms of radioresistance and finding strategies to enhance the radiosensitivity is crucial for improving clinical efficacy. The aim of this review was to address the approaches for enhancing the efficacy of radiotherapy in osteosarcoma, thereby improving patient outcomes. Specifically, we have focused on the mechanisms of radiosensitization and the relationship between drugs that enhance radiosensitivity and cancer. These mechanisms involve a delay in DNA damage repair, promotion of apoptosis, inhibition of angiogenesis, and regulation of the tumor microenvironment. In addition, we have summarized the effects of these drugs on the proliferation, migration, invasion and apoptosis of osteosarcoma cell lines. Finally, we have discussed the therapeutic effects and adverse reactions of these drugs in other cancers, providing valuable guidance for clinical treatment strategies tailored to patients with osteosarcoma.

Approximately half of melanoma patients relapse or fail to respond to current standards of care, highlighting the need for new treatment options. Engineering T-cells with chimeric antigen receptors (CARs) has revolutionized the treatment of hematological malignancies but has been clinically less effective in solid tumors. We therefore sought to engineer alternative immune cell types to inhibit melanoma progression. Engineering macrophages with CARs has emerged as a promising approach to overcome some of the challenges faced by CAR-T cells; however, whether these engineered macrophages can effectively inhibit melanoma growth is unknown. To determine whether CAR-macrophages (CAR-Ms) specifically target and kill melanoma cells, we engineered CAR-Ms targeting chondroitin sulfate proteoglycan 4 (CSPG4), an antigen expressed in melanoma. CSPG4-targeting CAR-Ms exhibited specific phagocytosis of CSPG4-expressing melanoma cells. We developed 3D approaches to show that CSPG4-targeting CAR-Ms efficiently infiltrated melanoma spheroids. Furthermore, combining CSPG4-targeting CAR-Ms with strategies inhibiting CD47/SIRPα "don't eat me" signaling synergistically enhanced CAR-M-mediated phagocytosis and robustly inhibited melanoma spheroid growth in 3D. Importantly, CSPG4-targeting CAR-Ms inhibited melanoma tumor growth in mouse models. These results suggest engineering macrophages against melanoma antigens is a promising solid tumor immunotherapy approach for treating melanoma.

STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with Ki = 3.5 μM binding affinity, we obtained AK-068 with Ki = 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50 values of as low as 1 nM while showing minimal effect on other STAT members up to 10 μM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization.

Repolarizing M2-like tumor associated macrophages (TAMs) into M1 phenotype by blocking CSF-1/CSF-1R signaling pathway represents a promising strategy to remodel the tumor immune microenvironment. Therefore, the discovery of novel potent CSF-1R inhibitors is of great significance for colorectal cancer immunotherapy. In this work, a series of novel CSF-1R inhibitors were designed and synthesized through rational molecular hybridization strategy and step by step structural optimization based on PLX3397 and BLZ945. Among these derivatives, compound III-1 was strongly bound to CSF-1R and showed potent CSF-1R inhibitory activity. It also effectively inhibited the activation of intracellular CSF-1R pathway and its downstream signaling events. Mechanically, III-1 efficiently repolarized M2-like TAMs into M1-phenotype, and inhibited the proliferation and promoted apoptosis of tumor cells through immunoregulation. More importantly, III-1 showed demonstrated efficacy against patient-derived colorectal cancer organoids and exhibited stronger anticolorectal cancer efficacy in vivo compared to PLX3397, highlighting its potential in the immunotherapy of colorectal cancer.

The nuanced roles of neuropilin (NRP) isoforms, NRP1 and NRP2, have attracted considerable scientific interest regarding cancer progression. Their differential expressions across various cancer types are specific to NRP isoforms which are shown in a cancer type-dependent manner. It accounts for the different mechanisms involved, driven by a co-expression of gene-sets associated with overexpressed NRP1 or NRP2. Their different expressions on tumour-associated macrophages (TAMs) with disparate markers are associated with the heterogenous tumour microenvironment (TME) through their plasticity and pro-tumorigenic activities.

Single-cell RNA sequencing (scRNA-seq) analyses were performed on tumours from clear cell Renal Cell Carcinoma (ccRCC) and skin cutaneous melanoma (SKCM) which exhibit the highest expressions of NRP1 and NRP2, respectively. Datasets were processed using established bioinformatics pipelines, including clustering algorithms, to determine cellular heterogeneity and quantify NRP isoform expression within distinct macrophage populations. Using differential gene expression analysis (DEGA) alongside co-enrichment studies, we explored gene-sets associated with NRP1 or NRP2 overexpression in TAMs.

Our analysis revealed a marked upregulation of NRP1 in TAMs isolated from ccRCC and elevated NRP2 expression in SKCM-derived TAMs. Both NRP1+ and NRP2+ macrophages showed an M2-like polarisation characterised by immune suppression and extracellular matrix degradation. Coupled with the previously uncharacterised NRP isoform specific- subpopulations within these cancers identified by DEGA, co-enrichment analyses demonstrated that the upregulation of gene-sets associated with NRP1 is associated with angiogenesis and tumour progression through VEGF signalling, while gene-sets with NRP2 showed dual functionality in the TME-dependent manner. Their distinct roles in regulating macrophage plasticity, tumour invasion, and metastasis were highlighted.

These findings underscore distinct isoform-specific mechanisms by which NRP1 and NRP2 contribute to TAM-mediated cancer progression. This study aims to establish a foundation for future research, leading to biological experiments with focused gene-sets derived from our findings. This approach can contribute to the development of immunomodulatory strategies targeting specific NRP isoforms in macrophages, tailored to individual cancer types and abnormal expressions of those gene markers, potentially offering a more effective therapeutic approach compared to broad-spectrum NRP inhibition strategies.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

Thermoelectric therapy has been emerging as a promising and versatile strategy for targeting malignant tumors treatment. However, the lack of effective time-space controlled triggering of thermoelectric effect in vivo limits the application of thermoelectric therapy. Here a magnetically triggered thermoelectric heterojunction (CuFe2O4/SrTiO3, CFO/STO) for synergistic thermoelectric/chemodynamic/immuno-therapy is developed. The efficient magnetothermal nanoagent (CFO) is synthesized using the hydrothermal method, and thermoelectric nanomaterials (STO) are grown on its surface to create the heterojunction. To enhance oral delivery efficiency, a fusion membrane (M) of Staphylococcus aureus and macrophage cell membranes are coated the CFO/STO heterojunction, enabling effective targeting of orthotopic colorectal cancer. Once the CFO/STO@M reaches the tumor region, in vitro alternating magnetic field (AMF) stimulation activates the catalytic treatment through a magnetic-thermo-electric energy cascade conversion effect. Additionally, the immunogenic death of tumor cells, down-regulating vascular endothelial growth factor and heat shock protein HSP70, increasing expression of endothelial cell adhesion molecule (ICAM-1/VCAM-1), and M1 polarization of macrophages contribute to tumor immunotherapy. Overall, the magnetically triggered thermoelectric heterojunction based on CFO/STO@M shows remarkable antitumor capability in female mice, offering a promising approach to broaden both the scope of application and the effectiveness of catalytic therapy.

Melanoma is one of the tumor types with the highest risk of brain metastasis. However, the biology of melanoma brain metastasis and the role of the brain immune microenvironment in treatment responses are not yet fully understood. Using preclinical models and single-cell transcriptomics, we have identified a mechanism that enhances antitumor immunity in melanoma brain metastasis. We show that activation of the Rela/Nuclear Factor κB (NF-κB) pathway in microglia promotes melanoma brain metastasis. Targeting this pathway elicits microglia reprogramming toward a proinflammatory phenotype, which enhances antitumor immunity and reduces brain metastatic burden. Furthermore, we found that proinflammatory microglial markers in melanoma brain metastasis are associated with improved responses to immune checkpoint inhibitors in patients and targeting Rela/NF-κB pathway in mice improves responses to these therapies in the brain, suggesting a strategy to enhance antitumor immunity and responses to immune checkpoint inhibitors in patients with melanoma brain metastasis.

Cancer-associated myeloid cells due to their plasticity play dual roles in both promoting and inhibiting tumor progression. Myeloid cells with immunosuppressive properties play a critical role in anti-cancer immune regulation. Cells of different origin, such as tumor associated macrophages (TAMs), tumor associated neutrophils (TANs), myeloid derived suppressor cells (also called MDSCs) and eosinophils are often expanded in cancer patients and significantly influence their survival, but also the outcome of anti-cancer therapies. For this reason, the variety of preclinical and clinical studies to modulate the activity of these cells have been conducted, however without successful outcome to date. In this review, pro-tumor activity of myeloid cells, myeloid cell-specific therapeutic targets, in vivo studies on myeloid cell re-polarization and the impact of myeloid cells on immunotherapies/genetic engineering are addressed. This paper also summarizes ongoing clinical trials and the concept of chimeric antigen receptor macrophage (CAR-M) therapies, and suggests future research perspectives, offering new opportunities in the development of novel clinical treatment strategies.

Interactions between acute myeloid leukemia (AML) and the bone marrow microenvironment (BMME) are critical to leukemia progression and chemoresistance. In the solid tumor microenvironment, altered metabolite levels contribute to cancer progression. We performed a metabolomic analysis of AML patient bone marrow serum, revealing increased metabolites compared to age- and sex-matched controls. The most highly elevated metabolite in the AML BMME was lactate. Lactate signaling in solid tumors induces immunosuppressive tumor-associated macrophages and correlates with poor prognosis. This has not yet been studied in the leukemic BMME. Herein, we describe the role of lactate in the polarization of leukemia-associated macrophages (LAMs). Using a murine AML model of blast crisis chronic myelogenous leukemia (bcCML), we characterize the suppressive phenotype of LAMs by surface markers, transcriptomics, and cytokine profiling. Then, mice genetically lacking GPR81, the extracellular lactate receptor, were used to demonstrate GPR81 signaling as a mechanism of both the polarization of LAMs and the direct support of leukemia cells. Furthermore, elevated lactate diminished the function of hematopoietic progenitors and reduced stromal support for normal hematopoiesis. We report microenvironmental lactate as a mechanism of AML-induced immunosuppression and leukemic progression, thus identifying GPR81 signaling as an exciting and novel therapeutic target for treating this devastating disease.

Macrophages are key tumor microenvironment (TME) regulators, exhibiting remarkable plasticity that enables them to either suppress or promote cancer progression. Emerging evidence highlights the critical role of macrophage-derived long non-coding RNAs (lncRNAs) in shaping tumor immunity, influencing macrophage polarization, immune evasion, angiogenesis, metastasis, and therapy resistance. This review comprehensively elucidates the functional roles of M1- and M2-associated lncRNAs, detailing their molecular mechanisms and impact on cancer pathogenesis. In summary, elucidating the roles of lncRNAs derived from macrophages in cancer progression offers new avenues for therapeutic strategies, significantly improving patient outcomes in the fight against the disease. Further research into the functional significance of these lncRNAs and the development of targeted therapies is essential to harness their potential fully in clinical applications. We further explore their potential as biomarkers for cancer prognosis and therapeutic targets for modulating macrophage activity to enhance anti-cancer immunity. Targeting macrophage-derived lncRNAs represents a promising avenue for precision oncology, offering novel strategies to reshape the TME and improve cancer treatment outcomes.

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.

Electro-hyperthermia therapy (EHT) has been known to cause temperature-dependent cell death and enhance the effects of conventional antitumor treatments, such as chemotherapy and radiotherapy. Furthermore, EHT modulates the innate and adaptive immune systems. Mistletoe is one of the most broadly studied complementary and alternative therapeutic agents for cancer treatment due to its ability to stimulate the immune systems. This study aimed to investigate the effects of EHT and mistletoe therapy combination on immune responses. Tumors induced by B16-BL6 melanoma cells were treated twice with modulated EHT (mEHT) (43°C for 10 or 20 min) and with intravenous injection of a Korean mistletoe extract (KME). We examined the level of interferon (IFN)-γ, granzyme, interleukin (IL)-2, IL-10, and tumor-specific antibodies using enzyme-linked immunosorbent assay methods to further study the immunological responses in the combination of mEHT and KME. Additionally, cytotoxic T lymphocyte (CTL) activity is investigated. In this study, we revealed a significant anti-tumor immunological activity elevation in tumor-bearing mice by combined mEHT and KME therapy. Specifically, the combination of mEHT and KME treatment was effective in inhibiting tumor growth in mice. The combination treatment elicited CTL immune response and increased IFN-γ and granzyme secretion. Particularly, the co-treatment appeared to efficiently suppress the immune signal related to tumor-associated macrophage differentiation. Importantly, tumor cell-specific antibodies could be induced in mice after mEHT-treated tumor cell immunization, which represent a promising cancer vaccine strategy. Thus, our results indicate the therapeutic actions of KME as a feasible partner of mEHT, suggesting its potential candidate for cancer immunotherapy. Abbreviations: APC, Antigen-presenting cell; CTL, Cytotoxic T lymphocyte; EHT, Electro-hyperthermia therapy; ELISA, Enzyme-linked immunosorbent assay; HSP, Heat shock protein; KME, Korean mistletoe extract; NK, Natural killer; PBS, Phosphate-buffered saline; QOL, Quality of life; RF, Radio-frequency; TAM, Tumor-associated macrophage.

Immunotherapy has improved the survival rate of patients with head and neck squamous cell carcinoma (HNSCC), but less than 20 % of them have a durable response to these treatments. Excessive local recurrence and lymph node metastasis ultimately lead to death, making the 5-year survival rate of HNSCC still not optimistic. Cell metabolism has become a key determinant of the viability and function of cancer cells and immune cells. In order to maintain the enormous anabolic demand, tumor cells choose a specialized metabolism different from non-transformed somatic cells, leading to changes in the tumor microenvironment (TME). In recent years, our understanding of immune cell metabolism and cancer cell metabolism has gradually increased, and we have begun to explore the interaction between cancer cell metabolism and immune cell metabolism in a way which is meaningful for treatment. Understanding the different metabolic requirements of different cells that constitute the immune response to HNSCC is beneficial for revealing metabolic heterogeneity and plasticity, thereby enhancing the effect of immunotherapy. In this review, we have concluded that the relevant metabolic processes that affect the function of immune cells in HNSCC TME and proposed our own opinions and prospects on how to use metabolic intervention to enhance anti-tumor immune responses.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

The current therapy cannot meet the needs of glioblastoma (GBM). V-domain immunoglobulin suppressor of T-cell activation (VISTA) is significantly up-regulated in GBM patients; however, its therapeutic potential in GBM is still unclear.

Flow cytometry was used to detect the expression of VISTA and the co-expression pattern of VISTA and programmed death receptor 1 (PD-1) on brain infiltrating lymphocytes of GBM mice. Monoclonal antibody therapy was used to evaluate the therapeutic effect of α-VISTA monotherapy and α-VISTA combined with α-PD-1 on GBM mice. Transcriptome analysis, flow cytometry, and immunofluorescence were used to detect changes of immune microenvironment in mouse brain tumours. Immunofluorescence and TCGA data analysis were used to further validate the combined treatment strategy on patient data.

Compared with normal mice, the frequency of VISTA expression and co-expression of VISTA and PD-1 on tumour-infiltrating lymphocytes (TILs) in tumour-bearing mice was increased. Anti-VISTA monotherapy significantly up-regulated multiple immune stimulation-related pathways and moderately prolonged mouse survival time. Blocking the immune checkpoint VISTA and PD-1 significantly prolonged the survival time of mice and cured about 80% of the mice; CD8+ T cells played an important role in this process. In addition, we found that the expression of VISTA and PD-1 was significantly up-regulated in GBM patients by immunofluorescence, and patients with high expression of VISTA and PD-1 were associated with poor overall survival. This combination of blocking the immune checkpoint VISTA and PD-1 may achieve clinical transformation in GBM.

The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.

Tumor metastasis regulated by multiple complicated pathways is closely related to variations in the tumor microenvironment. Exosomes can regulate the tumor microenvironment through various mechanisms. Exosomes derived from tumor cells carry a variety of substances, including long non-coding RNAs (lncRNAs), play important roles in intercellular communication and act as critical determinants influencing tumor metastasis. In this review, we elaborate on several pivotal processes through which lncRNAs regulate tumor metastasis, including the regulation of epithelial‒mesenchymal transition, promotion of angiogenesis and lymphangiogenesis, enhancement of the stemness of tumor cells, and evasion of immune clearance. Additionally, we comprehensively summarized a diverse array of potential tumor-derived exosomal lncRNA biomarkers to facilitate accurate diagnosis and prognosis in a clinical setting.

Tenosynovial giant cell tumor is a non-malignant primary locally aggressive articular disease that affects the synovium of joints, tendon sheaths, and bursae. It is characterized by a translocation t (1;2), leading to the overexpression of CSF1 in the tumor microenvironment. CSF1 induces the recruitment of non-malignant cells, mainly macrophages, followed by the differentiation and polarization of these cells into the M2 phenotype. Surgery, particularly total synovectomy, remains the cornerstone of TGCT management. However, recurrence rates vary, reaching 40 to 60% in diffuse disease, often resulting in progressive joint dysfunction, pain, and potential need for joint replacement or limb amputation. Systemic therapy is recommended in recurrent TGCT in patients not amenable to additional surgery. Targeting the CSF1/CSF1R axis has successfully improved tumor responses and enhanced symptomatic function. In this review, we aim to explore contemporary paradigms in inoperable TGCT patients, with a focus on the physiopathology, clinical efficacy, and safety of CSF1 or CSF1R inhibitors.

The malignant interaction between tumor cells and immune cells is one of the important reasons for the rapid progression and refractoriness of glioblastoma (GBM). As an essential metabolic center of M2 macrophages, the inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the reduction of M2 macrophages. Nevertheless, the restriction of the blood-brain barrier (BBB) and non-specific cell targeting hinder the application of PERK inhibitors in GBM. Herein, the optimal NP-M-M2pep is developed successfully, which has shown the capacity of BBB penetration and specific targeting of M2 microglia. In addition to inhibiting the polarization of M2 microglia, the administration of iPERK@NP-M-M2pep reprogrammed M2 microglia into M1 ones in vitro via PERK/HIF-1α/glycolysis pathway. Efficient brain accumulation of nanoparticles is achieved after tail vein injection, with effective inhibition of GBM progression after one course of treatment. The glioma-associated microglia and macrophages (GAM) with M2 type are induced to M1 and the immunosuppressive TME is remodeled by upregulating immunostimulatory cells and downregulating immunosuppressive cells. In summary, the biomimetic membrane vesicles (BMVs) specifically delivered iPERK to GAMs offer an inspiring strategy to reprogram microglia polarization, re-educate immunosuppressive TME, and inhibit the progression of GBM.

Tumor-associated macrophages (TAMs) are commonly considered accomplices in tumorigenesis and tumor development. However, the precise mechanism by which tumor cells prompt TAMs to aid in evading immune surveillance remains to be further investigated. Here, it is elucidated that tumor-secreted galectin-1 (Gal1) conferred immunosuppressive properties to TAMs. Specifically, patient specimens and a public database is first used to analyze the clinical relevance of Gal1 in hepatocellular carcinoma (HCC). Then, it is demonstrated that TAMs functioned as a critical mediator in the Gal1-induced progression of HCC and the establishment of an immunosuppressive tumor microenvironment. Furthermore, RNA-sequencing determined that Gal1 promoted the upregulation of chemokine (C-C motif) ligand 20 (CCL20) in TAMs via activating the PI3K/AKT/NF-κB pathway. Employing an anti-CCL20 neutralizing antibody and Foxp3DTR mice, it is demonstrated that CCR6+Foxp3+ regulatory T cells (Tregs) recruited by Gal1-induced TAMs contributed to reduced infiltration and dysfunctional state of CD8+ T cells, subsequently facilitating tumor progression. Targeting Gal1 dampened the secretion of CCL20 and inhibits the recruitment of Tregs, thereby activating anti-tumor immunity and ameliorating anti-PD-1 resistance. Together, this findings revealed that Gal1-induced TAMs recruited Tregs through the CCL20-CCR6 axis. Inhibition of Gal1 improves the effectiveness of anti-PD1 therapy, shedding important new light on the combination immunotherapy of HCC.