The TME is a critical niche for determining the fate of cancer therapy. Tumor cells often polarize nontumor cells, including immune cells, in the TME to favor cancer growth. In pancreatic cancer, macrophages are associated with poor therapy outcomes and unfavorable survival, especially when rendered into M2 macrophages. The latter show features also found in so-called tumor-associated macrophages (TAM), which are described as protecting and propelling tumor growth. In this context, it has been understudied which pancreatic cancer chemokines contribute to macrophage polarization. To this end, we analyzed murine RAW264.7 macrophages and Panc02 and PDA6606 pancreatic cancer cells in mono- and coculture to identify release patterns of 13 chemokines. Artificial macrophage polarization confirmed prominent changes in surface receptor and chemokine secretion profiles. Strikingly, RAW264.7 cocultures with Panc02 or PDA6606 were congruent in showing elevated levels of CCL2, CCL5, CCL17, CCL20, CCL22, CXCL5, and CXCL10. Further underlining the suitability of our in vitro model, both pancreatic cancer cell lines showed similar modulation of the critical macrophage polarization markers arginase, CD206, and iNOS, as well as chemokine receptors CCR2 and CCR4. Collectively, we demonstrated that our model is suitable for testing the roles and functions of chemokines in macrophage polarization by pancreatic cancer cells.

Oncolytic adenoviruses are among the most widely utilized oncolytic viruses due to their notable anti-tumor and gene expression capabilities, and modification of ADVs to create armed adenoviruses remains a popular research direction. Nonetheless, immune suppression triggered by ADV and targeted enhancements based on this limitation have been relatively unexplored.

Flow cytometry was employed to assess immune infiltration in the tumor microenvironment following ADV therapy. Targeted novel recombinant oncolytic viruses, ADVNE and ADVPPE, were designed, and their antitumor efficacy, safety, and ability to reshape immune infiltration were evaluated in both subcutaneous tumor models in mice and in vitro experiments. Immune cell depletion assays confirmed the critical role of macrophages. The impact of HMGB1 on macrophage polarization was investigated using shRNA, qRT-PCR, ELISA, and flow cytometry. Furthermore, the importance of TLR4 and its downstream pathways was validated through immunoprecipitation, Western blotting, homozygous knockout mice, and TLR4 inhibitors.

We demonstrated that ADV limits the infiltration of effector memory/effector CD8 + T cells (TEM/TE) within the tumor microenvironment. To address this, we leveraged the strong capacity of NE or PPE to recruit TEM/TE by constructing novel recombinant oncolytic adenoviruses, ADVNE or ADVPPE, armed with NE or PPE. These recombinant viruses induce pyroptosis in colorectal cancer cells accompanied by the release of HMGB1. HMGB1 binds to TLR4 on the surface of macrophages, activating the MyD88-NFκB-NLRP3 (ASC) pathway and promoting M1 polarization of TAMs, thereby increasing TEM/TE cell infiltration and enhancing antitumor efficacy.

In summary, this study presents the development of the novel oncolytic adenoviruses ADVNE and ADVPPE with enhanced anti-tumor efficacy and provides an in-depth exploration of their specific anti-tumor mechanisms. These findings indicate promising clinical therapeutic prospects and offer new insights for advancing oncolytic adenovirus therapies.

Tumor-infiltrating myeloid cells (TIMs), which encompass tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and tumor-associated dendritic cells (TADCs), are of great importance in tumor microenvironment (TME) and are integral to both pro- and anti-tumor immunity. Nevertheless, the phenotypic heterogeneity and functional plasticity of TIMs have posed challenges in fully understanding their complexity roles within the TME. Emerging evidence suggested that the presence of TIMs is frequently linked to prevention of cancer treatment and improvement of patient outcomes and survival. Given their pivotal function in the TME, TIMs have recently been recognized as critical targets for therapeutic approaches aimed at augmenting immunostimulatory myeloid cell populations while depleting or modifying those that are immunosuppressive. This review will explore the important properties of TIMs related to immunity, angiogenesis, and metastasis. We will also document the latest therapeutic strategies targeting TIMs in preclinical and clinical settings. Our objective is to illustrate the potential of TIMs as immunological targets that may improve the outcomes of existing cancer treatments.

Triple-negative breast cancer is a particularly aggressive type of breast cancer that is closely associated with abnormal vascularization within the tumor. However, traditional anti-VEGF therapies and other treatments have limited efficacy. Tumor-associated macrophages (TAMs) induce and regulate tumor angiogenesis. In recent years, regulating TAMs polarization has become a hot topic for research with objectives to normalize tumor vasculature and improve drug delivery and the tumor microenvironment. Our previous studies have found that peritumoral electroacupuncture (EA) can regulate tumor angiogenesis, but the underlying mechanism remains unclear.

In this study, we examined the phenotype of TAMs and inflammatory factors to observe the effect of peritumoral electroacupuncture on the phenotypic polarization of TAMs. Based on this, we evaluated the structure and function of tumor vasculature. Finally, we conducted a preliminary exploration of the mechanism underlying the regulation of TAMs phenotypic polarization by peritumoral electroacupuncture.

In this study, we found that peritumoral electroacupuncture could promote the phenotypic polarization of TAMs toward the M1 type, thereby reducing microvascular density in tumor tissue, increasing pericyte coverage, improving the stability of the basement membrane, promoting vascular maturation, and enhancing perfusion while reducing tissue hypoxia.

Peritumoral electroacupuncture can promote the phenotypic polarization of TAMs toward the M1 type, leading to normalization of tumor vascular structure and function. The mechanism may be related to the downregulation of glyoxalase-1 and subsequent activation of the MGO-AGEs/RAGE axis.

The metabolism of stearoyl-GPE plays a key role in the liver metastasis of gastric cancer. This investigation delves into the mechanisms underlying the intricate tumor microenvironment (TME) heterogeneity triggered by stearoyl metabolism in gastric cancer with liver metastasis (LMGC), offering novel perspectives for LMGC.

Utilizing Mendelian randomization, we determined that stearoyl metabolism significantly contributes to the progression of gastric cancer (GC). Following this, bulk transcriptome analyses and single-cell multiomics techniques to investigate the roles of stearoyl-GPE metabolism-related genes, particularly NCOA4, in regulating LMGC TME.

Our analysis highlights the crucial role of stearoyl metabolism in modulating the complex microenvironment of LMGC, particularly impacting monocyte cells. Through single-cell sequencing and spatial transcriptomics, we have identified key metabolic genes specific to stearoyl metabolism within the monocyte cell population, including NCOA4. Regarding the relationship between ferroptosis, stearoyl metabolism, and LMGC findings, it is plausible that stearoyl metabolism and LMGC pathways intersect with mechanisms involved in ferroptosis. Ferroptosis, characterized by iron-dependent lipid peroxidation, represents a regulated form of cell death. The activity of Stearoyl-CoA desaturase (SCD), a critical enzyme in stearoyl metabolism, has been associated with the modulation of lipid composition and susceptibility to ferroptosis. Furthermore, the LMGC is integral to cellular processes related to oxidative stress and lipid metabolism, both of which are significant factors in the context of ferroptosis.

This study enhances the understanding of the relationship between stearoyl metabolism and ferroptosis in promoting liver metastasis of gastric cancer and its role in the regulation of tumor heterogeneity. In addition, this study contributes to a deeper understanding of the dynamics of gastric cancer tumor microenvironment (TME) and provides a basis for the development of better interventions to combat cancer metastasis.

Triple-negative breast cancer (TNBC) is challenged by the low chemotherapy response and poor prognosis. Emerging evidence suggests that cytotoxic chemotherapy may lead to the pro-metastatic tumor microenvironment (TME) by eliciting pro-tumor extracellular vesicles (EVs) from cancer cells. However, the precise mechanisms and therapeutic approaches remain inadequately understood.

This study aims to determine whether XIAOPI formula (Chinese name XIAOPI San, XPS), a nationally sanctioned medication for mammary hyperplasia, can chemosensitize TNBC by remodeling the TME via modulating EV signaling, and exploring its underlying mechanisms.

Multiple methodologies, such as EV isolation, transmission electron microscope, flow cytometry, dual-luciferase reporter assays, co-immunoprecipitation and in vivo breast cancer xenograft, were employed to elucidate the effect and molecular mechanisms of XPS on paclitaxel-induced EV signaling (EV-dead) of TNBC.

XPS, at non-toxic concentrations, synergized with PTX to inhibit the invasion and chemoresistance of TNBC cells co-cultured with macrophages. Compared to EV-dead, XPS co-treatment-elicited EVs (EV-deadXPS) exhibited a decreased capacity to promote the invasion, chemoresistance and cancer stem cell subpopulation of the co-cultured TNBC cells. Mechanistically, XPS administration led to a reduction in CXCL1 cargo in EV-dead, and thereby attenuated its activation effect on macrophage polarization into M2 phenotype through the transcriptional downregulation of PD-L1 expression. Furthermore, XPS effectively reduced the number of EV-dead from TNBC cells by inhibiting CXCL1-mediated intraluminal vesicle (ILV) biogenesis in multivesicular bodies (MVBs). Moreover, molecular explorations revealed that XPS impaired ILV biogenesis by disrupting the RAB31/FLOT2 complex via suppressing the CXCL1/Myc signaling. Importantly, XPS significantly chemosensitized paclitaxel to inhibit TNBC growth and metastasis in vivo by suppressing EV-deadCXCL1-induced PD-L1 activation and M2 polarization of macrophages.

This pioneering study not only sheds novel light on EV-deadCXCL1 as a potential therapeutic target to suppress TNBC chemoresistance and metastasis, but also provides XPS as a promising adjuvant formula to chemosensitize TNBC by remodeling EV-deadCXCL1-mediated immunosuppressive TME.

Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) promote immune evasion, cancer cell proliferation, and metastasis. Ongoing research is focused on finding ways to prevent tumor growth by inhibiting TAM polarization, which has shown a correlation with unfavorable prognosis in clinical studies. Pancreatic adenocarcinoma up-regulated factor (PAUF) is a protein secreted from pancreatic cancer (PC) and acts as a TME modulator that affects the TME by acting on not only cancer cells but also stromal cells and immune cells. Tumor cells can evade the immune system by PAUF binding to Toll-like receptor (TLR) in monocytes, as this research shows. In this study, the examination centered around the recruitment of human monocytes by PAUF and the subsequent differentiation into macrophages. In an in vitro chemotaxis assay, PAUF induced chemotactic migration of TLR2-mediated monocytes. In addition, PAUF induced differentiation of monocytes into M2 macrophages, which was verified based on expressing surface markers and cytokines and morphological analysis. The inhibition of T cell proliferation and function was observed in differentiated M2 macrophages. To conclude, these findings indicate that PAUF functions as a promoter of cancer progression by regulating the recruitment and differentiation of macrophages within TMEs, ultimately causing immunosuppression.

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer characterized by the absence of estrogen and progesterone receptors and HER2 expression, leading to limited treatment options and a poorer prognosis. TNBC is particularly prevalent in premenopausal African-descent women and is associated with aggressive tumor behavior and higher metastatic potential. Tumor-associated macrophages (TAMs) are abundantly present within the TNBC microenvironment and play pivotal roles in promoting tumor growth, progression, and metastasis through various mechanisms, including immune suppression and enhancement of angiogenesis. This review provides an in-depth overview of TNBC, focusing on its epidemiology, its molecular characteristics, and the critical influence of TAMs. It discusses the pathological and molecular aspects that define TNBC's aggressive nature and reviews current and emerging therapeutic strategies aimed at targeting these dynamics. Special attention is given to the role of TAMs, exploring their potential as therapeutic targets due to their significant impact on tumor behavior and patient outcomes. This review aims to highlight the complexities of the TNBC landscape and to present the innovative approaches that are currently being pursued to improve therapeutic efficacy and patient survival.

Tumor-associated macrophages (TAMs) constitute the largest number of immune cells in the tumor microenvironment (TME). They play an essential role in promoting tumor progression and metastasis, which makes them a potential therapeutic target for cancer treatment. TAMs are usually divided into two categories: pro-tumoral M2-like TAMs and antitumoral M1 phenotypes at either extreme. The reprogramming of M2-like TAMs toward a tumoricidal M1 phenotype is of particular interest for the restoration of antitumor immunity in cancer immunotherapy. Notably, nanomedicines have shown great potential for cancer therapy due to their unique structures and properties. This review will briefly describe the biological features and roles of TAMs in tumor, and then discuss recent advances in nanomedicine-mediated repolarization of TAMs for cancer immunotherapy. Finally, perspectives on nanomedicine-mediated repolarization of TAMs for effective cancer immunotherapy are also presented.

Metastasis worsens prostate cancer (PCa) prognosis, with the immunosuppressive microenvironment playing a key role in bone metastasis. This study aimed to investigate how an immunosuppressive environment promotes PCa metastasis and worsens prognosis of patients with PCa.

Candidate oncogenes were identified through analysis of the Gene Expression Omnibus (GEO) database. A prognostic model was developed for the purpose of identifying target genes. A single-cell RNA sequencing data from GEO database was used to analyze the localization of target genes in the tumor microenvironment. A pan-cancer analysis was conducted to study the cancer-causing potential of target genes across different types of tumors.

Fifty-one genes were found to be differentially expressed in bone metastasis compared to non-metastatic PCa, with CKS2 identified as the most significant gene associated with poor prognosis. CKS2 was shown to be linked to an immunosuppressive microenvironment and osteoclastic bone metastases, as shown by its negative correlation with immune cell infiltration and osteoblast-related gene expression. Moreover, CKS2 was found in immunosuppressive cells and was linked to bone metastasis in PCa. It was also overexpressed in different types of tumors, making it as an oncogenic gene.

This research offers a new perspective on the potential utility of CKS2 as a therapeutic target for the prevention of metastatic PCa.

This review provides an in-depth examination of the role that tumor-associated macrophages (TAMs) play in the progression of prostate cancer (PCa), with a particular focus on the factors influencing the polarization of M1 and M2 macrophages and the implications of targeting these cells for cancer progression. The development and prognosis of PCa are significantly influenced by the behavior of macrophages within the tumor microenvironment. M1 macrophages typically exhibit anti-tumor properties by secreting pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), thereby enhancing the immune response. Conversely, M2 macrophages contribute to tumor cell migration and invasion through the production of factors like arginase-1 (Arg1) and interleukin-10 (IL-10). This review not only explores the diverse factors that affect macrophage polarization but also delves into the potential therapeutic strategies targeting macrophage polarization, including the critical roles of non-coding RNA and exosomes in regulating this process. The polarization state of macrophages is highlighted as a key determinant in PCa progression, offering a novel perspective for clinical treatment. Future research should concentrate on gaining a deeper understanding of the molecular mechanisms underlying macrophage polarization and on developing effective targeted therapeutic strategies. The exploration of the potential of combination therapies to improve treatment efficacy is also emphasized. By emphasizing the importance of macrophages as a therapeutic target in PCa, this review aims to provide valuable insights and research directions for clinicians and researchers.

Lung cancer (LC) is one of the most common cancer worldwide. Tumor-associated macrophages (TAMs) are important component of the tumor microenvironment (TME) and are closely related to the stages of tumor occurrence, development, and metastasis. Macrophages are plastic and can differentiate into different phenotypes and functions under the influence of different signaling pathways in TME. The classically activated (M1-like) and alternatively activated (M2-like) represent the two polarization states of macrophages. M1 macrophages exhibit anti-tumor functions, while M2 macrophages are considered to support tumor cell survival and metastasis. Macrophage polarization involves complex signaling pathways, and blocking or regulating these signaling pathways to enhance macrophages' anti-tumor effects has become a research hotspot in recent years. At the same time, there have been new discoveries regarding the modulation of TAMs towards an anti-tumor phenotype by synthetic and natural drug components. Nanotechnology can better achieve combination therapy and targeted delivery of drugs, maximizing the efficacy of the drugs while minimizing side effects. Up to now, nanomedicines targeting the delivery of various active substances for reprogramming TAMs have made significant progress. In this review, we primarily provided a comprehensive overview of the signaling crosstalk between TAMs and various cells in the LC microenvironment. Additionally, the latest advancements in novel drugs and nano-based drug delivery systems (NDDSs) that target macrophages were also reviewed. Finally, we discussed the prospects of macrophages as therapeutic targets and the barriers to clinical translation.

The interaction between cancer cells and immune cells plays critical roles in gastric cancer (GC) progression and immune evasion. Forced legumain (LGMN) is one of the characteristics correlated with poor prognosis in gastric cancer patients. However, the role of gastric-cancer-secreted LGMN (sLGMN) in modulating the tumor immune microenvironment and the biological effect on the immune evasion of gastric cancer remains unclear. In this study, we found that forced expression of sLGMN in gastric cancer serum correlates with increased M2 macrophage infiltration in GC tissues and predicted resistance to anti-PD-1 immunotherapy. Mechanistically, gastric cancer cells secrete LGMN via binding to cell surface Integrin αvβ3, then activate Integrin αvβ3/PI3K (Phosphatidylinositol-4,5-bisphosphate3-kinase)/AKT (serine/threonine kinase)/mTORC2 (mammalian target of rapamycin complex 2) signaling, promote metabolic reprogramming, and polarize macrophages from the M1 to the M2 phenotype. Either blocking LGMN, Integrin αv, or knocking out Integrin αv expression and abolishing the LGMN/Integrin αvβ3 interaction significantly inhibits metabolic reprogramming and polarizes macrophages from the M1 to the M2 phenotype. This study reveals a critical molecular crosstalk between gastric cancer cells and macrophages through the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis in promoting gastric cancer immune evasion and resistance to anti-PD-1 immunotherapy, indicating that the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis may act as a promising therapeutic target.

Tumor-associated macrophages (TAMs) represent one of the most abundant tumor-infiltrating stromal cells, and their normal function in tumor microenvironment (TME) is to suppress tumor cells by producing cytokines which trigger both direct cell cytotoxicity and antibody-mediated immune response. However, upon prolonged exposure to TME, the classical function of these so-called M1-type TAMs can be converted to another type, "M2-type," which are recruited by tumor cells so that they promote tumor growth and metastasis. This is the reason why the accumulation of TAMs in TME is correlated with poor prognosis in cancer patients. Both M1- and M2-types have high degree of plasticity, and M2-type cells can be reprogrammed to M1-type for therapeutic purposes. This characteristic introduces TAMs as promising target for developing novel cancer treatments. In addition, inhibition of M2-type cells and blocking their recruitment in TME, as well as their depletion by inducing apoptosis, are other approaches for effective immunotherapy of cancer. In this review, we summarize the potential of TAMs to be targeted for cancer immunotherapy and provide an up-to-date about novel strategies for targeting TAMs.

The high malignant degree and poor prognosis of pancreatic cancer (PC) pose severe challenges to the basic research and clinical translation of next-generation therapies. The rise of immunotherapy has improved the treatment of a variety of solid tumors, while the application in PC is highly restricted by the challenge of immunosuppressive tumor microenvironment. The latest progress of nanotechnology as drug delivery platform and immune adjuvant has improved drug delivery in a variety of disease backgrounds and enhanced tumor therapy based on immunotherapy. Based on the immune loop of PC and the status quo of clinical immunotherapy of tumors, this article discussed and critically analyzed the key transformation difficulties of immunotherapy adaptation to the treatment of PC, and then proposed the rational design strategies of new nanocarriers for drug delivery and immune regulation, especially the design of combined immunotherapy. This review also put forward prospective views on future research directions, so as to provide information for the new means of clinical treatment of PC combined with the next generation of nanotechnology and immunotherapy.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and chemotherapy is the cornerstone treatment for TNBC. Regrettably, emerging findings suggest that chemotherapy facilitates pro-metastatic changes in the tumour microenvironment. Extracellular vesicles (EVs) have been highly implicated in cancer drug resistance and metastasis. However, the effects of the EVs released from dying cancer cells on TNBC prognosis and corresponding therapeutic strategies have been poorly investigated. This study demonstrated that paclitaxel chemotherapy elicited CXCL1-enriched EVs from apoptotic TNBC cells (EV-Apo). EV-Apo promoted the chemoresistance and invasion of co-cultured TNBC cells by polarizing M2 macrophages through activating PD-L1 signalling. However, baohuoside I (BHS) remarkably sensitized the co-cultured TNBC cells to paclitaxel chemotherapy via modulating EV-Apo signalling. Mechanistically, BHS remarkably decreased C-X-C motif chemokine ligand 1 (CXCL1) cargo within EV-Apo and therefore attenuated macrophage M2 polarization by suppressing PD-L1 activation. Additionally, BHS decreased EV-Apo release by diminishing the biogenesis of intraluminal vesicles (ILVs) within multivesicular bodies (MVBs) of TNBC cells. Furthermore, BHS bound to the LEU104 residue of flotillin 2 (FLOT2) and interrupted its interaction with RAS oncogene family member 31 (RAB31), leading to the blockage of RAB31-FLOT2 complex-driven ILV biogenesis. Importantly, BHS remarkably chemosensitised paclitaxel to inhibit TNBC metastasis in vivo by suppressing EV-ApoCXCL1-induced PD-L1 activation and M2 polarization of tumour-associated macrophages (TAMs). This pioneering study sheds light on EV-ApoCXCL1 as a novel therapeutic target to chemosensitise TNBC, and presents BHS as a promising chemotherapy adjuvant to improve TNBC chemosensitivity and prognosis by disturbing EV-ApoCXCL1 biogenesis.

Tumor-associated macrophages (TAMs) play a critical role in hepatocellular carcinoma (HCC) progression and metastasis. Systematic investigation of the cross-talk between TAMs and HCC may help in searching for the critical target to guard against HCC metastasis.

Herein, we found that TREM1 highly expressed in HCC tissue by analyzing the data obtain from GEO database. Interestingly, the results indicated that TREM1 was primarily expressed by monocytes. Immune infiltration studies further validated that TREM1 expression was positively related with increased infiltration of macrophages in HCC tissues. In vitro, we observed that TREM1 knockdown significantly abrogated the effect of TAMs in promoting the metastasis and epithelial-mesenchymal transition (EMT) of HCC cells. Additionally, cytokine array detection identified CCL7 as the main responsive cytokine following with TREM1 knockdown in TAMs.

Taken together, our findings strongly suggested that high expression of TREM1 was positively associated with metastasis and poor prognosis of HCC. Furthermore, TAMs expressing TREM1 contribute to EMT-based metastasis through secreting CCL7. These results provide a novel insight into the potential development of targeting the TREM1/CCL7 pathway for preventing metastatic HCC.

The lungs are the largest surface of the body and the most important organ in the respiratory system, which are constantly exposed to the external environment. Tissue Resident Macrophages in lung constitutes the important defense against external pathogens. Macrophages connects the innate and adaptive immune system, and also plays important roles in carcinogenesis and cancer immunotherapy. Lung cancer is the leading cause of cancer-related death worldwide, with an overall five-year survival rate of only 21%. Macrophages that infiltrate or aggregate in lung tumor microenvironment are defined as tumor-associated macrophages (TAMs). TAMs are the main components of immune cells in the lung tumor microenvironment. The differentiation and maturation process of TAMs can be roughly divided into two different types: classical activation pathway produces M1 tumor-associated macrophages, and bypass activation pathway produces M2 tumor-associated macrophages. Studies have found that TAMs are related to tumor invasion, metastasis, and treatment resistance, and show potential as a new target for tumor immunotherapy. Therefore, the biological function of macrophages in lung and the role of TAMs in the occurrence, development, and treatment of lung cancer are discussed in this paper.

Tumor‑associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor‑promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage‑based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM‑targeting therapeutic strategies and discussed the obstacles and perspectives of TAM‑targeting therapies for cancers.

Prostate cancer (PCa) is the second most common malignancy among men globally. The Fu-Zheng-Yi-Liu (FZYL) Formula has been widely utilized in the treatment of PCa. This study investigates whether the FZYL Formula can inhibit PCa by targeting the TAMs/CCL5 pathway. We conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their interaction. Results showed that the FZYL Formula significantly reduced the proliferation, colony formation, subpopulations of PCSCs, and sphere-formation efficacy of PCa cells, even in the presence of TAM co-culture. Additionally, the Formula markedly decreased the migration, invasion, and epithelial-mesenchymal transition (EMT) of PCa cells induced by TAMs. The FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion, with minimal cytotoxicity observed. Mechanistic studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula, as the addition of exogenous CCL5 partially reversed the formula's inhibitory effects on PCSCs self-renewal in the co-culture system. Importantly, the Formula also significantly inhibited the growth of PCa xenografts, bone metastasis, and PCSCs activity in vivo by targeting the TAMs/CCL5 pathway. Overall, this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

Tenosynovial giant cell tumor (TGCT) is a monoarticular fibrohistiocytic benign or locally aggressive soft tissue tumor that originates from the synovium of joints, bursae, and tendon sheaths. It has an inflammatory neoplastic nature, with a clinical presentation ranging from pain, swelling, stiffness, and limited range of movement to joint instability and blockage. Its uncommon incidence leads to a poorly understood pathogenesis. Localized forms of TGCT (LTGCT) can cause significant morbidity, interfere with daily patient activities, and decrease the patient's quality of life in challenging cases. This study aimed to investigate the immunohistochemical expression of PPARγ (peroxisome proliferator-activated receptor gamma) and P53 in LTGCT to understand the disease better and offer potential therapeutic targets.

The study is cross-sectional, in which 27 LTGCT cases were collected from the Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt. Solitary and multiple LTGCT cases retrieved between January 2018 and December 2022 were included, and immunohistochemically stained with anti-PPARγ and P53 antibodies. The TGCT samples were excluded if they were insufficient for sectioning, processing, and interpretation, over-fixed, had process artifacts, or were of the diffuse TGCT type. Scoring of stain expression was performed by ImageJ (National Institutes of Health, Bethesda, MD) analysis using the threshold method and was expressed in percent area/high power field. Clinicopathological correlations were analyzed.

All the 27 collected LTGCT cases were located in the small joints of patients' hands. Cases with solitary LGTCTs constituted 55.6% (n = 15), while 44.4% (n = 12) had multiple LTGCTs related to one affected site/case (e.g., multiple tumors in one finger). PPARγ was expressed in the cytoplasm of mononuclear and multinucleated tumor cells and foamy histiocytes, while P53 expression was mainly in mononuclear cells' nuclei. PPARγ significantly correlated with P53 expression (r = 0.9 and P = 0.000). PPARγ (r = 0.4 and P = 0.02) and P53 (r = 0.5 and P = 0.01) were positively correlated with tumor size. Only P53 expression was positively correlated with tumor multiplicity (r = 0.4 and P = 0.03). Using the receiver operating characteristic curve test, the P53 cutoff score detecting the multiplicity of TGCTs was ≥20.5%, with a 75% sensitivity and 80% specificity.

PPARγ and P53 have a significant role in LTGCT growth, while P53 plays a role in tumor multiplicity. They can be possible targets in LTGCTs unfit for excision.

Endometriosis is an estrogen-dependent inflammatory disease, defined by the presence of functional endometrial tissue outside of the uterine cavity. This disease is one of the main gynecological diseases, affecting around 10%-15% women and girls of reproductive age, being a common gynecologic disorder. Although endometriosis is a benign disease, it shares several characteristics with invasive cancer. Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer, representing an earlier stage of neoplastic processes. This is particularly true for women with clear cell carcinoma, low-grade serous carcinoma and endometrioid. However, the carcinogenic pathways between both pathologies remain poorly understood. Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers (EAOCs) via pathways associated with oxidative stress, inflammation, and hyperestrogenism. This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis, specifically focusing on the complex relationship between the immune response to endometriosis and cancer, including the molecular mechanisms and their ramifications. Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored.

Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo.

It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities.

Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis.

Cell Cycle-Associated Protein 1 (CAPRIN1) play an important role in cell proliferation, oxidative stress, and inflammatory response. Nonetheless, its role in tumor immunity and ferroptosis is largely unknown in gastrointestinal cancer patients.

Through comprehensive bioinformatics, we investigate CAPRIN1 expression patterns and its role in diagnosis, functional signaling pathways, tumor immune infiltration and ferroptosis of different gastrointestinal cancer subtypes. Besides, immunohistochemistry (IHC) and immune blot were used to validate our esophagus cancer clinical data. The ferroptotic features of CAPRIN1 in vitro were assessed through knockdown assays in esophagus cancer cells.

CAPRIN1 expression was significantly upregulated, correlated with poor prognosis, and served as an independent risk factor for most gastrointestinal cancer. Moreover, CAPRIN1 overexpression positively correlated with gene markers of most infiltrating immune cells, and immune checkpoints. CAPRIN1 knockdown significantly decreased the protein level of major histocompatibility complex class I molecules. We also identified a link between CAPRIN1 and ferroptosis-related genes in gastrointestinal cancer. Knockdown of CAPRIN1 significantly increased the production of lipid reactive oxygen species and malondialdehyde. Inhibition of CAPRIN1 expression promoted ferroptotic cell death induced by RAS-selective lethal 3 and erastin in human esophagus cancer cells.

Collectively, our results demonstrate that CAPRIN1 is aberrantly expressed in gastrointestinal cancer, is associated with poor prognosis, and could potentially influence immune infiltration and ferroptosis.

Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide. Different treatment approaches are typically employed based on the stage of NSCLC. Common clinical treatment methods include surgical resection, drug therapy, and radiation therapy. However, with the introduction and utilization of immune checkpoint inhibitors, cancer treatment has entered a new era, completely revolutionizing the treatment landscape for various cancers and significantly improving overall patient survival. Concurrently, treatment resistance often poses a critical challenge, with many patients experiencing disease progression following an initial response due to treatment resistance. Increasing evidence suggests that the tumor microenvironment (TME) plays a pivotal role in treatment resistance. Tumor-associated macrophages (TAMs) within the TME can promote treatment resistance in NSCLC by secreting various cytokines activating signaling pathways, and interacting with other immune cells. Therefore, this article will focus on elucidating the key mechanisms of TAMs in treatment resistance and analyze how targeting TAMs can reduce the levels of treatment resistance in NSCLC, providing a comprehensive understanding of the principles and approaches to overcome treatment resistance in NSCLC.

Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleep-breathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. PDAC is characterized by a complex tumor microenvironment (TME), that plays a pivotal role in disease progression and resistance to therapy. Investigating the spatial distribution and interaction of TME cells with the tumor is the basis for understanding the mechanisms underlying disease progression and represents a current challenge in PDAC research. Imaging mass cytometry (IMC) is the major multiplex imaging technology for the spatial analysis of tumor heterogeneity. However, there is a dearth of reports of multiplexed IMC panels for different preclinical mouse models, including pancreatic cancer. We addressed this gap by utilizing two preclinical models of PDAC: the genetically engineered, bearing KRAS-TP53 mutations in pancreatic cells, and the orthotopic, and developed a 28-marker panel for single-cell IMC analysis to assess the abundance, distribution and phenotypes of cells involved in PDAC progression and their reciprocal functional interactions. Herein, we provide an unprecedented definition of the distribution of TME cells in PDAC and compare the diversity between transplanted and genetic disease models. The results obtained represent an important and customizable tool for unraveling the complexities of PDAC and deciphering the mechanisms behind therapy resistance.

The extracellular matrix (ECM) plays critical roles in cytoskeletal support, biomechanical transduction and biochemical signal transformation. Tumor-associated macrophage (TAM) function is regulated by matrix stiffness in solid tumors and is often associated with poor prognosis. ECM stiffness-induced mechanical cues can activate cell membrane mechanoreceptors and corresponding mechanotransducers in the cytoplasm, modulating the phenotype of TAMs. Currently, tuning TAM polarization through matrix stiffness-induced mechanical stimulation has received increasing attention, whereas its effect on TAM fate has rarely been summarized. A better understanding of the relationship between matrix stiffness and macrophage function will contribute to the development of new strategies for cancer therapy. In this review, we first introduced the overall relationship between macrophage polarization and matrix stiffness, analyzed the changes in mechanoreceptors and mechanotransducers mediated by matrix stiffness on macrophage function and tumor progression, and finally summarized the effects of targeting ECM stiffness on tumor prognosis to provide insight into this new field.

We have witnessed in the last decade new milestones in the treatment of various resistant cancers with new immunotherapeutic modalities. These advances have resulted in significant objective durable clinical responses in a subset of cancer patients. These findings strongly suggested that immunotherapy should be considered for the treatment of all subsets of cancer patients. Accordingly, the mechanisms underlying resistance to immunotherapy must be explored and develop new means to target these resistant factors. One of the pivotal resistance mechanisms in the tumor microenvironment (TME) is the high infiltration of tumor-associated macrophages (TAMs) that are highly immunosuppressive and responsible, in large part, of cancer immune evasion. Thus, various approaches have been investigated to target the TAMs to restore the anti-tumor immune response. One approach is to polarize the M2 TAMS to the M1 phenotype that participates in the activation of the anti-tumor response. In this review, we discuss the various and differential properties of the M1 and M2 phenotypes, the molecular signaling pathways that participate in the polarization, and various approaches used to target the polarization of the M2 TAMs into the M1 anti-tumor phenotype. These approaches include inhibitors of histone deacetylases, PI3K inhibitors, STAT3 inhibitors, TLR agonists, and metabolic reprogramming. Clearly, due to the distinct features of various cancers and their heterogeneities, a single approach outlined above might only be effective against some cancers and not others. In addition, targeting by itself may not be efficacious unless used in combination with other therapeutic modalities.

Breast cancer (BRCA) is a highly heterogeneous systemic disease. It is ranked first globally in the incidence of new cancer cases and has emerged as the primary cause of cancer-related death among females. Among the distinct subtypes of BRCA, triple-positive breast cancer (TPBC) has been associated with increased metastasis and invasiveness, exhibiting greater resistance to endocrine therapy involving trastuzumab. It is now understood that invasion, metastasis, and treatment resistance associated with BRCA progression are not exclusively due to breast tumor cells but are from the intricate interplay between BRCA and its tumor microenvironment (TME). Accordingly, understanding the pathogenesis and evolution of the TPBC microenvironment demands a comprehensive approach. Moreover, addressing BRCA treatment necessitates a holistic consideration of the TME, bearing significant implications for identifying novel targets for anticancer interventions. This review expounds on the relationship between critical cellular components and factors in the TPBC microenvironment and the inception, advancement, and therapeutic resistance of breast cancer to provide perspectives on the latest research on TPBC.

Bone metastasis occurs in nearly 70% of patients with metastatic prostate cancer (PCa), and represents the leading cause of death in patients with PCa. Emerging evidence has demonstrated the potential activities of icariin in modulating bone metabolism and remodelling the tumor microenvironment (TME). However, whether icariin could inhibit PCa bone metastasis and destruction by modulating the TME as well as the underlying mechanisms remains unclear.

This study investigated whether icariin could inhibit PCa bone metastasis and destruction by modulating the bone TME as well as the underlying mechanisms.

Osteoclasts were induced from mouse bone marrow-derived macrophages (BMMs) or Raw264.7 cells. PCa cells were cultured in the conditional medium (CM) of macrophages in vitro or co-injected with macrophages in vivo to simulate their coexistence in the TME. Multiple molecular biology experiments and the mouse RM1-Luc PCa bone metastasis model were used to explore the inhibitory activity and mechanism of icariin on PCa metastasis and bone destruction.

Icariin treatment significantly suppressed PCa growth, bone metastasis and destruction as well as osteoclastogenesis in vivo. Furthermore, icariin remarkably inhibited osteoclast differentiation, even in the presence of the CM of tumor-associated macrophages (TAMs), while exhibiting no obvious effect on osteoblasts. Moreover, icariin suppressed the M2 phenotype polarization of Raw264.7-derived TAMs and transcriptionally attenuated their CC motif chemokine ligand 5 (CCL5) expression and secretion via inhibiting SPI1. Additionally, CCL5 induced the differentiation and chemotaxis of osteoclast precursor cells by binding with its receptor CCR5. The clinicopathological analysis further verified the positive correlation between the TAM/CCL5/CCR5 axis and osteoclastogenesis within the TME of PCa patients. More importantly, icariin remarkably suppressed PCa metastasis-induced bone destruction in vivo by inhibiting osteoclastogenesis via downregulating the TAM/CCL5 pathway.

Altogether, these results not only implicate icariin as a promising candidate immunomodulator for PCa bone metastasis and destruction but also shed novel insight into targeting TAM/CCL5-mediated osteoclastogenesis as a potential treatment strategy for osteolytic bone metastasis. This study helps to advance the understanding of the crosstalk between bone TME and bone homeostasis.

To build a prognostic and immunotherapeutic response prediction model for liver cancer based on marker genes of tumor-associated endothelial cell (TEC).

Single cell sequencing data from Gene Expression Omnibus (GEO) liver cancer patients were utilized to identify TEC subpopulations. Models were built from transcriptomic and clinical data of TCGA liver cancer patients. The GSE76427 and ICGC databases were used as independent validation sets. Time-dependent receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used to verify the ability of the model to predict survival. XCELL, TIMER, QUANTISEQ, CIBERSORT, CIBERSORT-ABS, and ssGSEA were applied to evaluate tumor immune cell infiltration. The TIDE score was used to predict the effect of immunotherapy. Immune blockade checkpoint gene, tumor mutational load and GSVA enrichment analyses were further explored. The expression levels of candidate genes were measured and validated by real-time PCR between liver cancer tissues and adjacent nontumor liver tissues.

Eighty-seven genes were identified as marker genes for TECs. IGFBP3, RHOC, S100A16, FSCN1, and CLEC3B were included in the constructed prognostic model. Time-dependent ROC curve values were higher than 0.700 in both the model and validation groups. The low risk group exhibited high immune cell infiltration and function than the higher risk group. The TIDE score indicated that the low-risk group benefited more from immunotherapy than the high-risk group. The risk score and multiple immune blockade checkpoint genes and immune-related pathways were strongly correlated.

Novel signatures of TEC marker genes showed a powerful ability to predict prognosis and immunotherapy response in patients with liver cancer.

Tumor-associated macrophages (TAMs) are the most critical effector cells of innate immunity and the most abundant tumor-infiltrating immune cells. They play a key role in the clearance of apoptotic bodies, regulation of inflammation, and tissue repair to maintain homeostasis in vivo. With the progression of triple-negative breast cancer（TNBC）, TAMs are "subverted" from tumor-promoting immune cells to tumor-promoting immune suppressor cells, which play a significant role in tumor development and are considered potential targets for cancer therapy. Here, we explored how macrophages, as the most important part of the TNBC ecosystem, are "subverted" to drive cancer evolution and the uniqueness of TAMs in TNBC progression and metastasis. Similarly, we discuss the rationale and available evidence for TAMs as potential targets for TNBC therapy.

Tumor-associated macrophages (TAMs) are the main immune cells in the tumor microenvironment (TME) of endometrial cancer (EC). TAMs recruitment and polarization in EC is regulated by the TME of EC, culminating in a predominantly M2-like macrophage infiltration. TAMs promote lymphatic angiogenesis through cytokine secretion, aid immune escape of EC cells by synergizing with other immune cells, and contribute to the development of EC through secretion of exosomes so as to promoting EC development. EC is a hormone- and metabolism-dependent cancer, and TAMs promote EC through interactions on estrogen receptor (ER) and metabolic factors such as the metabolism of glucose, lipids, and amino acids. In addition, we have explored the predictive significance of some TAM-related indicators for EC prognosis, and TAMs show remarkable promise as a target for EC immunotherapy.

Immunotherapy has developed rapidly in solid tumors, especially in the areas of blocking inhibitory immune checkpoints and adoptive T-cell transfer for immune regulation. Many patients benefit from immunotherapy. However, the response rate of immunotherapy in the overall population are relatively low, which depends on the characteristics of the tumor and individualized patient differences. Moreover, the occurrence of drug resistance and adverse reactions largely limit the development of immunotherapy. Recently, the emergence of nanodrug delivery systems (NDDS) seems to improve the efficacy of immunotherapy by encapsulating drug carriers in nanoparticles to precisely reach the tumor site with high stability and biocompatibility, prolonging the drug cycle of action and greatly reducing the occurrence of toxic side effects. In this paper, we mainly review the advantages of NDDS and the mechanisms that enhance conventional immunotherapy in solid tumors, and summarize the recent advances in NDDS-based therapeutic strategies, which will provide valuable ideas for the development of novel tumor immunotherapy regimen.

Tumor-associated macrophages (TAMs) play a critical role in tumor progression and metastasis. Modulation of TAM polarization is one of the most effective strategies to change the immunosuppressive tumor microenvironment (TME). In this study, organic polymer nanoparticles (CPHT) were prepared using hyaluronic acid (HA)-conjugated disulfide-bonded polyethylene imide (PEIS) as a carrier through a self-assembly strategy. These nanoparticles were modified by transferrin (Tf) and loaded with chlorin e6 (Ce6). The results showed that CPHT had good dispersion with a particle size of about 30 nm. CPHT gradually disintegrated under the exposure with a high concentration of glutathione (GSH) in tumor cells, proving the possibility for the controlled release of Ce6 and photodynamic therapy. An in vitro test showed that the uptake of CPHT in tumor cells was mediated by both HA and Tf, indicating the active tumor-targeting capacity of CPHT. CPHT significantly downregulated the ratio of CD206/CD86 and triggered the upregulation of immune factors such as TNF-α and iNOS, suggesting the repolarization of TAMs. We also found that CPHT effectively induced ferroptosis in tumor cells through lipid peroxide accumulation, GSH depletion, and downregulation of lipid peroxidase (GPX4) expression. Animal experiments confirmed that CPHT not only effectively inhibited the growth of tumors in situ but also significantly decelerated the growth of the distal tumor. Elevated levels of CD86 and IFN-γ and decreased expression of CD206 were observed at the tumor sites post CPHT treatment. These results confirmed the value of CPHT as a multifunctional nanoplatform that can tune the TME and provide new hope for tumor treatment.