The traditional action of Rabdosia rubescens (Hemsl.) H. Hara is heat-clearing and detoxifying, relieve sore throat, dissipate binds and disperse swelling. DLC, as an extract prepared from Rabdosiae Rubescentis Herba, could regulate the polarization of tumor associated macrophages (TAMs). For TAMs play an important role in the tumor microenvironment. It is worthy to further explore the mechanism of DLC on the polarized function of macrophages.

The aim of this study is to investigate the activity and molecular mechanisms of DLC on dissipating binds and dispersing swelling by modulating the gastric cancer microenvironment and macrophage polarization.

We conducted comprehensive qualitative and quantitative chromatographic analyses to characterize the main components of DLC. To evaluate its anti-tumor effects, immunofluorescence, MTT assay, plate cloning, transcriptomics analysis, western blotting, and siRNA knockdown experiments were performed to assess DLC's action on gastric cancer cell proliferation. Additionally, we utilized Trypan blue staining, a THP-1 and MGC-803 co-culture model, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and a mouse xenograft model with five distinct dosage groups to systematically investigate DLC's effects on macrophage polarization.

Key compounds in DLC were identified. The vivo tests demonstrated the tumor inhibition rate of the 5 g/kg DLC group reached 66.99 %, surpassing that of the 5-fluorouracil group (59.94 %). Mechanistically, DLC upregulated SIRT1 expression and suppressed NF-κB pathway, thereby preventing p65 from translocating into nuclear and modulating downstream p53/MDM2/USP7 signaling. Moreover, DLC enhanced M1 macrophage factors such as TNF-α, IL-6 while inhibiting M2 marker TGF-β, effectively repolarizing M2 TAMs toward an M1 phenotype. This effect was associated with suppressed protein expression of HIF-1α, p-p65, and p-PI3K.

This study provides insights into DLC's mechanisms in regulating tumor microenvironment remodeling and promoting macrophage polarization toward an anti-tumor phenotype. These results provide a solid basis for DLC's potential clinical treament in gastric cancer, highlighting its promise as a natural therapeutic agent.

A constitutively active serine/threonine kinase, casein kinase 2 (CK2) is involved in several physiological functions, such as DNA repair, apoptosis, and cell cycle control. New research emphasizes how critical CK2 is to the immune system's dysregulation in the tumor immune-microenvironment (TIME). The inhibition of immunological responses, including the downregulation of immune effector cells and the elevation of immunosuppressive proteins that aid in the development of tumor and immune evasion, has been linked to CK2 overexpression. CK2 maintains an immunosuppressive milieu that impedes anti-tumor immunity by encouraging the expressions and activities of immune checkpoint markers, regulating cytokines release, and boosting immune-suppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) to maintain immune evasion. It is a promising target for cancer treatment due to its complex role in immune regulation and oncogenic pathways. In this study, we address the therapeutic perspectives of targeting CK2 in oncotherapy and investigate the mechanisms by which it controls immunological responses in the TME. This review, comprehending the function of CK2 in immune suppression can facilitate the creation of innovative treatment approaches aimed at augmenting anti-tumor immunity and enhancing immunotherapy effectiveness.

Bacterial lysate proteins (BLPs) serve as potential immunostimulants, recognized by pattern recognition receptors (PRRs) on immune cells, eliciting a robust immune response. In this study, THP-1 macrophages were treated with varying doses of BLPs derived from Streptococcus pyogenes (SP), Streptococcus agalactiae (SA), and Serratia marcescens (SM). The results showed significant increases (p  < 0.05) in pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-12, granulocyte macrophage-colony stimulating factor (GM-CSF), eotaxin, and macrophage inflammatory protein (MIP)-1α, except for 5 µg of all BLPs for TNF-α and eotaxin, and 5 µg of SP for IL-12 production. No significant differences were found between the corresponding doses of SP and SA or SP and SM, except for GM-CSF in all doses, while SA and SM only showed a difference at the 5 µg dose for GM-CSF. Furthermore, there were no significant differences between the 10 and 20 µg doses of all BLPs, indicating that doses higher than 10 µg do not significantly enhance the pro-inflammatory response. Combination doses of SP + SM and SA + SM did not show significant differences, except for IL-1β, suggesting no synergistic effect. Cytotoxicity was observed to increase with higher BLP concentrations in a dose-dependent manner, with combinations of SP + SM and SA + SM exhibiting greater cytotoxicity than the individual BLPs. Proteomic analysis of BLPs identified immunostimulatory proteins, including heat shock proteins (HSPs; ClpB, DnaK, and GroEL), metabolic enzymes (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), enolase, and arginine deiminase (ADI)), and surface and secreted proteins (ESAT-6-like protein, CRISPR-associated endonuclease Cas9, OmpA, porin OmpC, and serralysin), which are involved in immune modulation, bacterial clearance, and immune evasion. This study underscores the potential of bacterial proteins as vaccine adjuvants or supplementary therapies; however, further research is essential to find a balance between immune activation and inflammation reduction to develop safer and more effective immunostimulants.

To describe the relationship between MTA1 expression and Oral leukoplakia (OLK) prognosis in cohort studies and its possible mechanism.

We assessed MTA1 expression levels in OLK and OSCC tissues and cell lines using immunohistochemistry and Western blot. Functional analyses were performed in vitro by CCK-8 and Western blot assays. We analyzed overall survival in our OSCC cohort and TCGA dataset and analyzed the microenvironmental landscape of different MTA1 expression patterns in OLK and OSCC by multiplex immunohistochemistry. The Cox proportional hazards regression model was used to determine multivariate hazard ratios for overall survival.

MTA1 is abnormally highly expressed in OLK and OSCC both in cells and tissue, promoting DOK cell proliferation and altering EMT through E-cadherin, Wnt3a, and β-catenin. Moreover, MTA1 gradually increased with increasing abnormal OLK proliferation and negatively correlated with OSCC prognosis. Notably, MTA1 shows a positive correlation with M2 macrophage infiltration levels. Additionally, we found that low expression of MTA1 and a low M2/M1 ratio panel predict good patient prognosis in OSCC.

We suggest that the aberrant expression of MTA1 may contribute to the malignant transformation of OLK and that MTA1 may represent a new prognostic marker for OLK and OSCC.

The tumor microenvironment (TME) is a complex, dynamic ecosystem where tumor cells interact with diverse immune and stromal cell types. This review provides an overview of the TME's evolving composition, emphasizing its transition from an early pro-inflammatory, immune-promoting state to a later immunosuppressive milieu characterized by metabolic reprogramming and hypoxia. It highlights the dual roles of key immunocytes-including T lymphocytes, natural killer cells, macrophages, dendritic cells, and myeloid-derived suppressor cells-which can either inhibit or support tumor progression based on their phenotypic polarization and local metabolic conditions. The article further elucidates mechanisms of immune cell plasticity, such as the M1/M2 macrophage switch and the balance between effector T cells and regulatory T cells, underscoring their impact on tumor growth and metastasis. Additionally, emerging therapeutic strategies, including checkpoint inhibitors and chimeric antigen receptor (CAR) T and NK cell therapies, as well as approaches targeting metabolic pathways, are discussed as promising avenues to reinvigorate antitumor immunity. By integrating recent molecular insights and clinical advancements, the review underscores the importance of deciphering the interplay between immunocytes and the TME to develop more effective cancer immunotherapies.

The susceptibility of cancer cells to DNA damages is influenced by their microenvironment. For example, unirradiated neighbors of irradiated cells can produce signals that reduce DNA damages. This phenomenon, known as Radiation-Induced Rescue Effect (RIRE), has profound implications on the efficacy of radiotherapy. Using bystander cells co-cultured with mock-irradiated cells as a control, we demonstrated, for the first time, two types of RIRE. Conditioned medium from naïve by stander cells, i.e., cells not exposed to irradiated cells, could mitigate UV-induced DNA damages in human breast carcinoma MCF7 cells, as judged by phospho-H2AX and 53BP1 immunostaining. This protective effect could be further enhanced by the prior treatment of bystander cells with factors from UV-irradiated cells. We named the former effect "basal RIRE" and the latter "active RIRE" which were cell type-dependent. As bystanders, MCF7 showed a significant active RIRE, whereas THP1-derived macrophages showed a strong basal RIRE but no active RIRE. Interestingly, RIRE of macrophages could further be modulated by polarisation. The basal RIRE of macrophages was abolished by M1 polarisation, while M2 and Tumour Associated Macrophages (TAM) demonstrated pronounced basal and active RIRE. When mixtures of MCF7 cells and polarised macrophages were used as bystanders, the overall RIRE was dictated by macrophage phenotypes: RIRE was suppressed by M1 macrophages but significantly enhanced by M2 and TAM. This study shows a previously unappreciated role of the innate immune system in RIRE. Depending on polarised phenotypes, macrophages in the tumour microenvironment can interfere with the effectiveness of radiotherapy by adjusting the RIRE magnitudes.

Once thought to be in a terminally differentiated state, macrophages are now understood to be highly pliable, attuned and receptive to environmental cues that control and align responses. In development of purpose, the centrality of metabolic pathways has emerged. Thus, macrophage inflammatory or reparative phenotypes are tightly linked to catabolic and anabolic metabolism, with further fine tuning of specific gene expression patterns in specific settings. Single-cell transcriptome analyses have revealed a breadth of macrophage signatures, with some new influencers driving phenotype. CD36/Scavenger Receptor B2 has established roles in immunity and lipid metabolism. Macrophage CD36 is a key functional player in metabolic expression profiles that determine phenotype. Emerging data show that alterations in the microenvironment can recast metabolic pathways and modulate macrophage function, with the potential to be leveraged for therapeutic means. This review covers recent data on phenotypic characterization of homeostatic, atherosclerotic, lipid-, tumor- and metastatic-associated macrophages, with the integral role of CD36 highlighted.

Tumor immunotherapy, modulating innate and adaptive immunity, has become an important therapeutic strategy. However, the tumor immune microenvironment's (TIME) complexity and heterogeneity challenge tumor immunotherapy. Hydrogel is a hydrophilic three-dimensional (3D) mesh structure with good biocompatibility and drug release control, which is widely used in drug delivery, agriculture, industry, etc. Hydrogels loaded with immune cells, cytokines, immune checkpoint inhibitors, and anti-tumor drugs can achieve targeted delivery and ultimately activate the immune response in the TIME. In this review, we will summarize the components of the TIME and their immune effects, the emerging immunomodulatory agents, the characteristics and functions of hydrogels, and how hydrogels regulate innate and adaptive immune cells in the TIME.

Portal vein tumor thrombus (PVTT) worsens the prognosis of hepatocellular carcinoma by increasing intrahepatic dissemination and inducing portal vein hypertension. However, the immune characteristics of PVTT remain unclear. Therefore, this study aims to explore the immune microenvironment in PVTT.

Time-of-flight mass cytometry revealed that macrophages and monocytes were the dominant immune cell type in PVTT, with a higher proportion than in primary tumor and blood (54.1% vs. 26.3% and 9.1%, p< 0.05). The differentially enriched clustering of inhibitory and regulatory immune cells in PVTT indicated an immune-suppressive environment. According to the single-cell RNA sequencing, TAM-C5AR1 was characterized by leukocyte chemotaxis and was the most common subpopulation in PVTT (36.7%). Multiplex fluorescent immunohistochemistry staining showed that the C5aR + TAM/Mφ were enriched in PVTT compared to both the primary tumor and liver and positively correlated with C5a (r=0.559, p< 0.001). Notably, THP-1 (monocyte cell line) was recruited by CSQT2 (PVTT cell line) and exhibited up-regulation of CD163, CD206, and PD-L1 upon stimulation. C5aR antagonist could reverse this. C5aR + TAMs could also inhibit Granzyme B in CD8 + T cells. High infiltration of C5aR + TAMs in PVTT correlated with poor differentiation ( p< 0.009) and was a risk factor for overall survival ( p= 0.003) and for reformation of PVTT after resection ( p= 0.007).

TAMs, especially C5aR + TAMs, were enriched in PVTT. C5aR + TAMs contribute to the development of PVTT and poor prognosis by reshaping the immunosuppressive environment.

АBSTRACT: With increasing incidence and geography, cancer is one of the leading causes of death, reduced quality of life and disability worldwide. Principal progress in the development of new anticancer therapies, in improving the efficiency of immunotherapeutic tools, and in the personification of conventional therapies needs to consider cancer-specific and patient-specific programming of innate immunity. Intratumoral TAMs and their precursors, resident macrophages and monocytes, are principal regulators of tumor progression and therapy resistance. Our review summarizes the accumulated evidence for the subpopulations of TAMs and their increasing number of biomarkers, indicating their predictive value for the clinical parameters of carcinogenesis and therapy resistance, with a focus on solid cancers of non-infectious etiology. We present the state-of-the-art knowledge about the tumor-supporting functions of TAMs at all stages of tumor progression and highlight biomarkers, recently identified by single-cell and spatial analytical methods, that discriminate between tumor-promoting and tumor-inhibiting TAMs, where both subtypes express a combination of prototype M1 and M2 genes. Our review focuses on novel mechanisms involved in the crosstalk among epigenetic, signaling, transcriptional and metabolic pathways in TAMs. Particular attention has been given to the recently identified link between cancer cell metabolism and the epigenetic programming of TAMs by histone lactylation, which can be responsible for the unlimited protumoral programming of TAMs. Finally, we explain how TAMs interfere with currently used anticancer therapeutics and summarize the most advanced data from clinical trials, which we divide into four categories: inhibition of TAM survival and differentiation, inhibition of monocyte/TAM recruitment into tumors, functional reprogramming of TAMs, and genetic enhancement of macrophages.

Breast cancer has the highest global incidence among all cancers, affecting more than 2 million individuals annually. Despite the availability of new drugs and novel treatment combinations, it is postulated that the incidence and mortality of breast cancer will rise by 40.8% and 51.9% respectively by 2040. Such dire statistics are associated with the clonal evolution of cancer cells that leads to therapeutic resistance and consequent relapse in breast cancer patients. On the other hand, the tumor microenvironment (TME) comprising of tumor cells, cancer-associated immune cells, re-programmed stromal cells, and the extracellular matrix (ECM) creates an immunosuppressive niche facilitating immune evasion. This review focuses on a critical cellular component of the tumor microenvironment, the tumor-associated macrophages (TAMs) in breast cancer immunotherapy. Macrophages are inherently plastic and can convert from an anti-tumor M1 phenotype to a pro-tumor M2 phenotype based on microenvironmental cues. Cancer cells facilitate these cues, allowing the tumor-associated macrophages to gain M2 phenotype and mediate immune evasion. Therefore, knowledge of the distinct role of tumor-associated macrophages in immune evasion can help design therapeutics such as engineered macrophages, M2 targeting drugs, and novel macrophage-mediated drug delivery strategies for long-term survival in breast cancer.

Follicular lymphoma (FL) is an immune-responsive tumor with spontaneous remission. T cells play a pivotal role in the anti-lymphoma immune response. However, the dynamics of T cells during treatment, their impact on FL clinical outcomes, and the risk factors contributing to T-cell cytopenia remain largely unexplored. T-cell and their subsets in the peripheral blood of FL patients at diagnosis, during 2-4 cycles and after 6 cycles of treatment, as well as healthy individuals were detected by flow-cytometry. The predictive effects of T cells for early progression and risks for T-cell cytopenia were analyzed. FL patients exhibited a significant decrease in CD3+, CD4+, and CD8 + T cells compared to healthy individuals, with aging intensifying the decline of CD3+, and CD4 + T cells. Notably, a reduction in CD4 + T cells, predominantly contributing to treatment-related T-cell reduction, was only observed in patients undergoing Bendamustine-based regimens. Moreover, a significantly decreased CD4 + and CD8 + T-cell at diagnosis rather than after induction therapy was observed in patients with treatment failure. Furthermore, lower CD4 + T-cell (< 260/uL) at baseline was independently correlated to early progression within 24 months. Finally, disease stage and albumin were the independent predictive factors for the decline of CD4 + T cells in FL patients. Overall, FL patients demonstrated compromised T-cell immunity, with a lower CD4 + T cell count at diagnosis correlating with treatment response and early progression. Therefore, monitoring CD4 + T cells at diagnosis might reflect immune status and aid in stratifying FL patients.

Reactive oxygen species (ROS) are a group of highly active molecules produced by normal cellular metabolism and play a crucial role in the human body. In recent years, researchers have increasingly discovered that ROS plays a vital role in the progression of chronic inflammation and tumor metastasis. The inflammatory tumor microenvironment established by chronic inflammation can induce ROS production through inflammatory cells. ROS can then directly damage DNA or indirectly activate cellular signaling pathways to promote tumor metastasis and development, including breast cancer, lung cancer, liver cancer, colorectal cancer, and so on. This review aims to elucidate the relationship between ROS, chronic inflammation, and tumor metastasis, explaining how chronic inflammation can induce tumor metastasis and how ROS can contribute to the evolution of chronic inflammation toward tumor metastasis. Interestingly, ROS can have a "double-edged sword" effect, promoting tumor metastasis in some cases and inhibiting it in others. This article also highlights the potential applications of ROS in inhibiting tumor metastasis and enhancing the precision of tumor-targeted therapy. Combining ROS with nanomaterials strategies may be a promising approach to enhance the efficacy of tumor treatment.

Nuclear factor kappa-B (NF-κB) is a nuclear transcription factor that plays a key factor in promoting inflammation, which can lead to the development of cancer in a long-lasting inflammatory environment. The activation of NF-κB is essential in the initial phases of tumor development and progression, occurring in both pre-malignant cells and cells in the microenvironment such as phagocytes, T cells, and B cells. In addition to stimulating angiogenesis, inhibiting apoptosis, and promoting the growth of tumor cells, NF-κB activation also causes the epithelial-mesenchymal transition, and tumor immune evasion. Therapeutic strategies that focus on immune checkpoint molecules have revolutionized cancer treatment by enabling the immune system to activate immunological responses against tumor cells. This review focused on understanding the NF-κB signaling pathway in the context of cancer.

Terpenoids are a large group of naturally occurring organic compounds with a wide range of components. A phytoconstituent in this group, andrographolide, which is derived from a plant called Andrographis paniculate, offers a number of advantages, including anti-inflammatory, anticancer, anti-angiogenesis and antioxidant effects. The present review elucidates the capacity of andrographolide to inhibit signaling pathways, namely the nuclear factor-κB (NF-κB), hypoxia-inducible factor 1 (HIF-1), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), Wnt/β-catenin and mitogen-activated protein kinase (MAPK) pathways, which are involved in cellular processes and responses such as the inflammatory response, apoptosis and angiogenesis. Inhibiting pathways enables andrographolide to exhibit its anticancer effects against breast, colorectal and lung cancer. The present review focuses on the anticancer effects of andrographolide, specifically in breast, colorectal and lung cancer through the NF-κB, HIF-1 and JAK/STAT signaling pathways. Therefore, the Google Scholar, PubMed and ScienceDirect databases were used to search for references to these prevalent types of cancer and the anticancer mechanisms of andrographolide associated with them. The following key words were used: Andrographolide, anticancer, JAK/STAT, HIF-1, NF-κB, PI3K/AKT/mTOR, Wnt/β-catenin and MAPK pathways, and the literature was limited to studies published between 2010 to 2023. The present review article provides details about the different involvements of signaling pathways in the anticancer mechanisms of andrographolide.

Gliomas are the most common primary malignant tumours of the central nervous system (CNS), which are highly aggressive, with increasing morbidity and mortality rates year after year, posing a serious threat to the quality and expected survival time of patients. The treatment of gliomas is a major challenge in the field of neuro-oncology, especially high-grade gliomas such as glioblastomas (GBMs). Despite considerable progress in recent years in the study of the molecular and cellular mechanisms of GBMs, their prognosis remains bleak. Tumour-associated macrophages (TAMs) account for up to 50% of GBMs, and they are a highly heterogeneous cell population whose role cannot be ignored. Here, we focus on reviewing the contribution of classically activated M1-phenotype TAMs and alternatively activated M2-phenotype TAMs to GBMs, and exploring the research progress in reprogramming M1 TAMs into M2 TAMs.

In recent observational studies, a potential link between prostatitis and prostate cancer (PCa) has been hinted at, yet the causality remains ambiguous. In our endeavor to scrutinize the conceivable causal nexus between prostatitis and PCa, we embarked upon a Mendelian randomization (MR) study. MR circumvents arbitrary groupings by employing genetic variations that have a strong association with the exposure as instrumental variables to infer causal relationships between exposures and outcomes. The etiology of PCa remains elusive. Given that prostatitis and prostate cancer occupy the same anatomical region, MR can more effectively delineate their relationship by mitigating confounding variables. This method can indirectly elucidate disease correlations, thereby contributing to cancer prevention strategies. FinnGen Consortium data were used for the prostatitis genome-wide association study (GWAS), including 74,658 participants. UK biobank baseline data (ncase = 3436, ncontrol = 459574), European Bioinformatics Institute Database (ncase = 79148, ncontrol = 61106), and IEU openGWAS database (ncase = 79148, ncontrol = 61106) were used for PCa outcomes, mostly for European population samples. Data from the GWSAs for prostatitis were compared with data from the three GWASs for PCa, respectively, in an analysis of an MR. Utilizing the inverse variance weighting (IVW) methodology as our primary analytical framework, we delved into a meticulous exploration of the conceivable causal association between prostatitis and PCa. Furthermore, we deployed supplementary methodologies, including Maximum Likelihood, MR-Egger, weighted median, and MR-PRESSO, to thoroughly assess and scrutinize the causality aspect comprehensively. Cochran's Q statistic is employed as a metric to quantify the heterogeneity inherent in instrumental variables. The inverse variance weighted analysis revealed no discernible effect of prostatitis on PCa in the three PCa GWAS databases (odds ratio [OR]: 1.001, 95% Confidence Interval [CI]: 0.999-1.002, p = 0.28), (OR: 1.015, 95% CI: 0.981-1.050, p = 0.40), (OR: 1.015, 95% CI: 0.981-1.050, p = 0.40). Similarly, employing MR-Egger did not yield substantial evidence (OR: 0.999, 95% CI: 0.999-1.002, p = 0.89), (OR: 1.103, 95% CI: 1.006-1.209, p = 0.07), (OR: 1.103, 95% CI: 1.006-1.209, p = 0.07). The weighted median analysis also failed to provide convincing support for the impact of prostatitis on the incidence of PCa (OR: 1.001, 95% CI: 1.000-1.002, p = 0.064), (OR: 0.989, 95% CI: 0.946-1.034, p = 0.64), (OR: 0.989, 95% CI: 0.945-1.036, p = 0.65). The results of the MR showed no causality from prostatitis to PCa.

The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

Tumor associated macrophages (TAMs) are the predominant innate immune cells in the tumor microenvironment (TME). Cytokines induce the differentiation of macrophages into distinct types of TAMs, primarily characterized by two phenotypes: M1-polarized and M2-polarized. Cancer growth is suppressed by M1-polarized macrophages and promoted by M2-polarized macrophages. The regulation of macrophage M1 polarization has emerged as a promising strategy for cancer immunotherapy. Polysaccharides are important bioactive substances found in numerous plants, manifesting a wide range of noteworthy biological actions, such as immunomodulation, anti-tumor effects, antioxidant capabilities, and antiviral functions. In recent years, there has been a significant increase in interest regarding the immunomodulatory and anti-tumor properties of polysaccharides derived from plants. The regulatory impact of polysaccharides on the immune system is mainly associated with the natural immune response, especially with the regulation of macrophages. This review provides a thorough analysis of the regulatory effects and mechanisms of plant polysaccharides on TAMs. Additionally, an analysis of potential opportunities for clinical translation of plant polysaccharides as immune adjuvants is presented. These insights have greatly advanced the research of plant polysaccharides for immunotherapy in tumor-related applications.

Peritoneal metastases frequently occur in epithelial ovarian cancer (EOC), resulting in poor prognosis and survival rates. Tumor-associated-macrophages (TAMs) massively infiltrate into ascites spheroids and are multi-polarized as protumoral M2-like phenotype, orchestrating the immunosuppression and promoting tumor progression. However, the impact of omental conditioned medium/ascites (OCM/AS) on TAM polarization and its function in tumor progression remains elusive.

The distribution and polarization of TAMs in primary and omental metastatic EOC patients' tumors and ascites were examined by m-IHC, FACS analysis, and immunofluorescence. QPCR, immunofluorescence, FACS analysis, lipid staining assay, ROS assay, and Seahorse real-time cell metabolic assay characterized TAMs as being polarized in the ascites microenvironment. The oncogenic role of TAMs in tumor cells was demonstrated by co-cultured migration/invasion, proliferation, and spheroid formation assays. Mechanistic studies of the regulations of TAM polarization were performed by using RNA-Seq, GTPase pull-down, G-LISA activation assays, and other biochemical assays. A Yap1 macrophages (MФs) conditional knockout (cKO) mouse model demonstrated the roles of YAP1 in TAM polarization status and its pro-metastatic function. Finally, the anti-metastatic potential of targeting TAMs through restoring YAP1 by pharmacological agonist XMU MP1 was demonstrated in vitro and in vivo.

Abundant polyunsaturated fatty acids (PUFAs) in OCM/AS suppressed RhoA-GTPase activities, which, in turn, downregulated nuclear YAP1 in MФs, leading to increased protumoral TAM polarization accompanied by elevated OXPHOS metabolism. Abolishment of YAP1 in MФs further confirmed that a higher M2/M1 ratio of TAM polarization could alleviate CD8+ T cell infiltration and cytotoxicity in vivo. Consistently, the loss of YAP1 has been observed in EOC metastatic tissues, suggesting its clinical relevance. On the contrary, restoration of YAP1 expression by pharmaceutical inhibition of MST1/2 induced conversion of M2-to-M1-like polarized MФs, elevating the infiltration of CD8+ T cells and attenuating tumor growth.

This study revealed that PUFAs-enriched OCM/AS of EOC promotes M2-like TAM polarization through RhoA-YAP1 inhibition, where YAP1 downregulation is required for accelerating protumoral M2-like TAM polarization, thereby causing immunosuppression and enhancing tumor progression. Conversion of M2-to-M1-like polarized MФs through Yap1 activation inhibits tumor progression and contributes to developing potential TAMs-targeted immunotherapies in combating EOC peritoneal metastases.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor with a high metastatic potential. Perineural invasion (PNI) occurs in the early stages of PDAC with a high incidence rate and is directly associated with a poor prognosis. It involves close interaction among PDAC cells, nerves and the tumor microenvironment. In this review, we detailed discuss PNI-related pain, six specific steps of PNI, and treatment of PDAC with PNI and emphasize the importance of novel technologies for further investigation.

The tumor microenvironment (TME) plays a crucial role in the progression, invasion, and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the CC TME, but studies on their correlation with CC progression are still controversial. This study aimed to investigate the relationship between TAM infiltration, the STAT3/NF-κB signaling pathway, and Overall Survival (OS) in CC patients.

In a retrospective study, 691 CC patients who had received a definitive histopathologic diagnosis of CC scored by the FIGO staging system and not undergone preoperative treatment were selected from a database. The effect of TAM infiltration on tumor progression biomarkers using Tissue Microarray (TMA) and immunohistochemistry was evaluated. Furthermore, the impact of the expression of these biomarkers and clinical-pathological parameters on recurrence-free (RF) and OS using Kaplan-Meier and multivariable Cox regression methods was also analyzed.

High stromal CD163 + 204 + TAMs density and via STAT3 and NF-κB pathways was relevant to the expression of E-cadherin, Vimentin, MMP9, VEGFα, Bcl-2, Ki-67, CD25, MIF, FOXP3, and IL-17 (all p < 0.0001). In addition, elevated TNM staging IV had a strong association correlation with STAT3 and NF-κB pathways (p < 0.0001), CD25 (p < 0.001), VEGFα (p < 0.001), MIF (p < 0.0001), and Ki-67 (p < 0.0001). On the other hand, overall and recurrence survival was shown to be strongly influenced by the expression of SNAIL (HR = 1.52), E-cadherin (HR = 1.78), and Ki-67 (HR = 1.44).

M2-TAM and via STAT3/NF-κB pathways had a strong effect on CC tumor progression which reverberated in the severity of clinicopathological findings, becoming an important factor of poor prognosis.

Antigenic cell fragments, pathogen-associated molecular patterns, and other immunostimulants in bacterial lysates or extracts may induce local and systemic immune responses in specific and nonspecific paradigms. Based on current knowledge, this review aimed to determine whether bacterial lysate has comparable functions in infectious diseases and cancer treatment. In infectious diseases, including respiratory and urinary tract infections, immune system activation by bacterial lysate can identify and combat pathogens. Commercially available bacterial lysates, including OM-85, Ismigen, Lantigen B, and LW 50020, were effective in children and adults in treating respiratory tract infections, chronic obstructive pulmonary disease, rhinitis, and rhinosinusitis with varying degrees of success. Moreover, OM-89, Uromune, Urovac, Urivac, and ExPEC4V showed therapeutic benefits in controlling urinary tract infections in adults, especially women. Bacterial lysate-based therapeutics are safe, well-tolerated, and have few side effects, making them a good alternative for infectious disease management. Furthermore, a nonspecific immunomodulation by bacterial lysates may stimulate innate immunity, benefiting cancer treatment. "Coley's vaccine" has been used to treat sarcomas, carcinomas, lymphomas, melanomas, and myelomas with varying outcomes. Later, several similar bacterial lysate-based therapeutics have been developed to treat cancers, including bladder cancer, non-small cell lung cancer, and myeloma; among them, BCG for in situ bladder cancer is well-known. Proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, may activate bacterial antigen-specific adaptive responses that could restore tumor antigen recognition and response by tumor-specific type 1 helper cells and cytotoxic T cells; therefore, bacterial lysates are worth investigating as a vaccination adjuvants or add-on therapies for several cancers.

Chronic subdural hematoma (CSDH) is a prevalent form of intracranial haemorrhage encountered in neurosurgical practice, and its incidence has notably risen in recent years. Currently, there is a lack of studies that have comprehensively classified the cells present in hematomas removed during surgery, and their correlation with CSDH recurrence remains elusive. This study aims to analyse the subcellular populations and occupancy levels within peripheral blood.

This study analyses the subcellular populations and occupancy levels within peripheral blood and postoperatively removed hematomas by single-cell sequencing and attempts to analyse the effect of different cell occupancies within peripheral blood and intraoperatively removed hematomas on CSDH.

The single-cell sequencing results showed that the cells were classified into 25 clusters by differential gene and UMAP dimensionality reduction clustering analyses and further classified into 17 significant cell populations by cell markers: pDCs, CD8 T cells, CD4 T cells, MigDCs, cDC2s, cDC1s, plasma cells, neutrophils, naive B cells, NK cells, memory B cells, M2 macrophages, CD8 Teffs, CD8 MAIT cells, CD4 Tregs, CD19 B cells, and monocytes. Further research showed that the presence of more cDC2 and M2 macrophages recruited at the focal site in patients with CSDH and the upregulation of the level of T-cell occupancy may be a red flag for further brain damage. ROS, a marker of oxidative stress, was significantly upregulated in cDC2 cells and may mediate the functioning of transcription proteins of inflammatory factors, such as NFκB, which induced T cells' activation. Moreover, cDC2 may regulate M2 macrophage immune infiltration and anti-inflammatory activity by secreting IL1β and binding to M2 macrophage IL1R protein.

The detailed classification of cells in the peripheral blood and hematoma site of CSDH patients helps us to understand the mechanism of CSDH generation and the reduction in the probability of recurrence by regulating the ratio of cell subpopulations.

Communication between cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) plays a crucial role in accelerating nasopharyngeal cancer (NPC) metastasis and radioresistance. However, the mechanisms through which NPC cells regulate the properties and activation of TAMs during NPC progression are not yet fully understood.

A high-metastatic NPC subclone (HMC) and a low-metastatic NPC subclone (LMC) were screened from the CNE-2 cell line and exosomes were collected from HMCs and LMCs, respectively. The effects of HMC- and LMC-derived exosomes (HMC-Exos and LMC-Exos) on the regulation of TAM activation were evaluated by assessing the levels of inflammation-related or immunosuppression-related genes. The role of miRNA-193b-3p (miR-193b) in mediating communication between NPCs and TAMs was assessed using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot analysis, Transwell assays, and clonogenic survival assays.

HMCs and HMC-Exos exhibited a greater capacity to facilitate macrophage protumorigenic activation than LMCs and LMC-Exos. miR-193b levels derived from HMC-Exos were higher than those from LMC-Exos, and miR-193b levels were higher in metastatic NPC tissue-derived TAMs than in non-metastatic NPC tissue-derived TAMs. The upregulated miR-193b was packaged into exosomes and transferred to macrophages. Functionally, miR-193b up-regulation accelerated TAM activation by directly targeting mitogen-activated protein/ERK kinase kinase 3 (MEKK3). As a result, miR-193b-overexpressed macrophages facilitated NPC cell invasion and radioresistance.

These data revealed a critical role for exosomal miR-193b in mediating intercellular communication between NPC cells and macrophages, providing a potential target for NPC treatment.

Chimeric antigen receptors (CARs) are genetically engineered receptors that recognize antigens and activate signaling cascades in a cell. Signal recognition and transmission are mediated by the CAR domains derived from different proteins. T cells carrying CARs against tumor-associated antigens have been used in the development of the CAR T cell therapy, a new approach to fighting malignant neoplasms. Despite its high efficacy in the treatment of oncohematological diseases, CAR T cell therapy has a number of disadvantages that could be avoided by using other types of leukocytes as effector cells. CARs can be expressed in a wide range of cells of adaptive and innate immunity with the emergence or improvement of cytotoxic properties. This review discusses the features of CAR function in different types of immune cells, with a particular focus on the results of preclinical and clinical efficacy studies and the safety of potential CAR cell products.

When it comes to the diagnosis of solid tumors, biopsy is always the gold standard. However, traumatic and inflammatory stimuli are so closely related to tumor initiation and development that the acute inflammatory response induced by biopsy can give rise to changes in the tumor microenvironment, including recruitment of immunosuppressive cells (M2 macrophages, Treg cells, Tumor-associated neutrophils) and secretion of inflammation-associated cytokines, to create immunosuppressive conditions that enable the increase of circulating tumor cells in the peripheral circulation and promote the metastatic spread of tumors after surgery. In this review, we discuss dynamic changes and inhibitory characteristics of biopsy on tumor microenvironment. By investigating its mechanism of action and summarizing the current therapeutic strategies for biopsy-induced tumor immunosuppressive microenvironment, the future of using biopsy-induced inflammation to improve the therapeutic effects and prognosis of patients is prospected.

To investigate the mechanisms by which periodontal ligament cells (PDLCs) convert biomechanical stimulation into inflammatory microenvironment inducing root resorption (RR).

RNA sequencing was employed to explore mechanisms in force-inflammatory signal transduction. Then resorption volume, odontoclastic activity, PDLC pyroptotic ratio and NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis pathway activation were analysed under force and pyroptosis inhibition. Further osteoclast formation, macrophage number and transwell polarization demonstrated the effects of PDLC pyroptosis on osteoclastogenesis and M1 polarization.

RNA sequencing revealed that NLRP3-mediated PDLC pyroptosis induced by Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)/NLRP3 pathway may be involved in mechano-inflammatory signal transduction. PDLC pyroptosis under force and the expression of NLRP3-mediated pyroptosis pathway in force-enhanced PDLCs were significantly increased, both in vivo and in vitro. MCC950 administration was sufficient to reduce PDLC pyroptosis and alleviate RR, odontoclast formation and M1 polarization in vivo. Further in vitro exploration showed that MCC950 treatment reduced PDLC force-promoted pyroptosis and blocked NLRP3-mediated pyroptosis pathway. Moreover, by treating THP-1 with force-pretreated PDLCs or supernatants, NLRP3-mediated PDLC pyroptotic released products induced osteoclast formation and M1 polarization.

NLRP3-mediated PDLC pyroptosis promotes RR. PDLCs transmit excessive force into inflammation signals through TLR4/NFκB/NLRP3 pathway, inducing PDLC pyroptosis, which directly promotes odontoclast formation and subsequent RR or promotes M1 polarization to indirectly trigger odontoclastogenesis and RR.

Tumor drug resistance emerges from the interaction of two critical factors: tumor cellular heterogeneity and the immunosuppressive nature of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) constitute essential components of the TME. M2-like TAMs are essential in facilitating tumor metastasis as well as augmenting the drug resistance of tumors. This review encapsulates the mechanisms that M2-like TAMs use to promote tumor drug resistance. We also describe the emerging therapeutic strategies that are currently targeting M2-like TAMs in combination with other antitumor drugs, with some still undergoing clinical trial evaluation. Furthermore, we summarize and analyze various existing approaches for developing novel drugs that target M2-like TAMs to overcome tumor resistance, highlighting how targeting M2-like TAMs can effectively stop tumor growth, metastasis, and overcome tumor drug resistance.

To study the reeducation effect of copper thiol complexes on macrophage morphology and cytokine expression.

The effect of copper thiol complexes was assessed on murine macrophages by the cell morphology observed through optical microscopy, while the expression of cytokines by protein abundance after stimulation. A viability experiment was performed on PMBC to confirm that copper complexes do not affect other cells.

The M1 shape was reported after treatment with copper thiol complexes at 1-200 µM, while M2 behavior was documented between 50 and 800 µM. Surprisingly, a thin elongate morphology was observed between 400-800 µM like the M2 shape. The expression of M1 cytokines was noted ranging from 1 to 100 µM, with the highest yield at 1 µM (2243 pg/µL) for the copper-penicillamine complex. M2 production behavior was observed at 1-800 µM, with the highest abundance close to 1150 pg/µL (200-400 µM) was quantified from the copper-cysteine complex. Finally, LCCu complexes did not induce a cytotoxic response on PBMC while exhibiting a high IL-4 and IL-10 production, similar to their gold analogs.

The capacity of copper thiol complexes to reeducate M1 to M2 morphoexpression can be promising for cell protection by using copper thiol penicillamine or immuno-regeneration of tissues when using copper thiol cysteine.

Anti-cancer therapeutics have achieved significant advances due to the emergence of immunotherapies that rely on the identification of tumors by the patients' immune system and subsequent tumor eradication. However, tumor cells often escape immunity, leading to poor responsiveness and easy tolerance to immunotherapy. Thus, the potentiated anti-tumor immunity in patients resistant to immunotherapies remains a challenge. Reactive oxygen species-based dynamic nanotherapeutics are not new in the anti-tumor field, but their potential as immunomodulators has only been demonstrated in recent years. Dynamic nanotherapeutics can distinctly enhance anti-tumor immune response, which derives the concept of the dynamic immuno-nanomedicines (DINMs). This review describes the pivotal role of DINMs in cancer immunotherapy and provides an overview of the clinical realities of DINMs. The preclinical development of emerging DINMs is also outlined. Moreover, strategies to synergize the antitumor immunity by DINMs in combination with other immunologic agents are summarized. Last but not least, the challenges and opportunities related to DINMs-mediated immune responses are also discussed.

Circulating tumor cells (CTCs) are cancer cells that detach from the primary tumor, enter the bloodstream or body fluids, and spread to other body parts, leading to metastasis. Their presence and characteristics have been linked to cancer progression and poor prognosis in different types of cancer. Analyzing CTCs can offer valuable information about tumors' genetic and molecular diversity, which is crucial for personalized therapy. Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), play a significant role in generating and disseminating CTCs. Certain proteins, such as EpCAM, vimentin, CD44, and TGM2, are vital in regulating EMT and MET and could be potential targets for therapies to prevent metastasis and serve as detection markers. Several devices, methods, and protocols have been developed for detecting CTCs with various applications. CTCs interact with different components of the tumor microenvironment. The interactions between CTCs and tumor-associated macrophages promote local inflammation and allow the cancer cells to evade the immune system, facilitating their attachment and invasion of distant metastatic sites. Consequently, targeting and eliminating CTCs hold promise in preventing metastasis and improving patient outcomes. Various approaches are being explored to reduce the volume of CTCs. By investigating and discussing targeted therapies, new insights can be gained into their potential effectiveness in inhibiting the spread of CTCs and thereby reducing metastasis. The development of such treatments offers great potential for enhancing patient outcomes and halting disease progression.

As an immune checkpoint molecule, CD200 serves a foundational role in regulating immune homeostasis and promoting self-tolerance. While CD200 expression occurs in various immune cell subsets and normal tissues, its aberrant expression patterns in hematologic malignancies and solid tumors have been linked to immune evasion and cancer progression under pathological conditions, particularly through interactions with its cognate receptor, CD200R. Through this CD200/CD200R signaling pathway, CD200 exerts its immunosuppressive effects by inhibiting natural killer (NK) cell activation, cytotoxic T cell functions, and M1-polarized macrophage activity, while also facilitating expansion of myeloid-derived suppressor cells (MDSCs) and Tregs. Moreover, CD200/CD200R expression has been linked to epithelial-to-mesenchymal transition and distant metastasis, further illustrating its role in cancer progression. Conversely, CD200 has also been shown to exert anti-tumor effects in certain cancer types, such as breast carcinoma and melanoma, indicating that CD200 may exert bidirectional effects on cancer progression depending on the specific tumor microenvironment (TME). Regardless, modulating the CD200/CD200R axis has garnered clinical interest as a potential immunotherapeutic strategy for cancer therapy, as demonstrated by early-phase clinical trials. However, further research is necessary to fully understand the complex interactions of CD200 in the tumor microenvironment and to optimize its therapeutic potential in cancer immunotherapy.

As the largest proportion of myeloid immune cells in tumors, macrophages play an important role in tumor growth and regression according to their different phenotypes, thus reprogramming macrophages has become a new research direction for cancer immunotherapy. Yeast-derived whole β-glucan particles (WGPs) can induce M0 macrophages to differentiate into M1 macrophages and convert M2 macrophages and tumor-associated macrophages (TAMs) into M1 macrophages. In vitro, studies have confirmed that WGP-treated macrophages increase the activating receptors in natural killer cells (NK cells) and enhance the cytotoxicity of NK cells. The extracellular regulated protein kinases (ERK) signaling pathway is involved in WGP-mediated regulation of the macrophage phenotype. Further in vivo studies show that oral WGP can significantly delay tumor growth, which is related to the increased proportion of macrophages and NK cells, the macrophage phenotype reversal, and the enhancement of NK cell immune function. NK-cell depletion reduces the therapeutic efficacy of WGP in tumor-bearing mice. These findings revealed that in addition to T cells, NK cells also participate in the antitumor process of WGP. It was confirmed that WGP regulates the macrophage phenotype to regulate NK-cell function.

The tumor microenvironment (TME) is composed of various stromal components, including immune cells such as tumor-associated macrophages (TAMs), which play a crucial role in cancer initiation and progression. TAMs can exhibit either a tumor-suppressive M1 or a tumor-promoting M2 phenotype. First, we aimed to develop a 3D human heterotypic model consisting of head and neck squamous cell carcinoma (HNSCC) cells and different subtypes of macrophages to replicate the interactions between immune cells and cancer cells. We further investigated the behavior of Foslip®, a liposomal formulation of temoporfin, using a macrophage-enriched 3D model.

Monocytes were differentiated into M1 and M2 macrophages, which represent two distinct subtypes. Following histological and molecular characterization, these macrophages were used to establish a 3D spheroid model of HNSCC enriched with either polarized macrophages or conditioned media. Flow cytometry and fluorescence microscopy were used to assess the accumulation and distribution of Foslip®. The cytotoxic effect of Foslip®-mediated photodynamic therapy (PDT) was evaluated using flow cytometry.

We developed heterotypic spheroids characterized by a mixed phenotype of evenly distributed macrophages. In this 3D co-culture model, both M1 and M2 macrophages showed significantly higher accumulation of Foslip® compared to the cancer cells. Although this differential accumulation did not drastically affect the overall PDT efficiency, spheroids generated with conditioned media exhibited a significant enhancement in photo-induced cell death, suggesting that the microenvironment could modulate the response to Foslip®-PDT.

3D models of HNSCC cells and macrophages provide valuable insights into the complex response of HNSCC cells to PDT using Foslip® in vitro. This model can be used to screen immunomodulatory nanomedicines targeting TAMs in solid head and neck tumors, either alone or in combination with standard therapies.

Here, we describe the production and characterization of a novel p65fl/fl/LysMCre mouse model, which lacks canonical nuclear factor-kappaB member RelA/p65 (indicated as p65 hereafter) in bone marrow-derived macrophages. Cultured bone marrow-derived macrophages that lack p65 protein reveal NF-κB signaling deficiencies, a reduction in phagocytic ability, and reduced ability to produce nitrites. Despite abnormal bone marrow-derived macrophage function, p65fl/fl/LysMCre mice do not exhibit differences in naïve systemic immune profiles or colony forming units and time to death following Salmonella infection as compared to controls. Additionally, p65fl/fl/LysMCre mice, especially females, display splenomegaly, but no other obvious physical or behavioral differences as compared to control animals. As bone marrow-derived macrophages from this transgenic model are almost completely devoid of canonical nuclear factor-kappaB pathway member p65, this model has the potential for being very useful in investigating bone marrow-derived macrophage NF-kappaB signaling in diverse biological and biomedical studies.

The incidence and mortality rate of gastric cancer (GC) have remained high worldwide. Although some progress has been made in immunotargeted therapy, the treatment effect remains limited. With more attention has been paid to the immune potential of tumor-associated macrophages (TAMs), but the specific mechanisms of tumor immunity are still unclear. Thus, we screened marker genes in TAMs differentiation (MDMs) through single-cell RNA sequencing, and combined with GC transcriptome data from TCGA and GEO databases, the clinical and TME characteristics, prognostic differences, immune infiltration, and drug sensitivity among different subtypes of patients with GC in different data sets were analyzed. A prognostic model of GC was constructed to evaluate the prognosis and immunotherapy response of patients with GC. In this study, we extensively studied the mutations in MDMs such as CGN, S100A6, and C1QA, and found differences in the infiltration of immune cells and immune checkpoints including M2 TAMs, T cells, CD274, and CTLA4 in different GC subtypes. In the model, we constructed a predictive scoring system with high accuracy and screened out key MDMs-related genes associated with prognosis and M2 TAMs, among which VKORC1 may be involved in GC progression and iron death in tumor cells. Therefore, this study explores the therapeutic strategy of TAMs reprogramming in-depth, providing new ideas for the clinical diagnosis, treatment, and prognosis assessment of GC.

Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design.

We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments.

The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors.

The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.

Cell proliferation and function require nutrients, energy, and biosynthesis activity to duplicate repertoires for each daughter. It is therefore not surprising that tumor microenvironment (TME) metabolic reprogramming primarily orchestrates the interaction between tumor and immune cells. Tumor metabolic reprogramming affords bioenergetic, signaling intermediates, and biosynthesis requirements for both malignant and immune cells. Different immune cell subsets are recruited into the TME, and these manifestations have distinct effects on tumor progression and therapeutic outcomes, especially the mutual contribution of glycolysis and cholesterol metabolism. In particularly, glycolysis-cholesterol metabolic axis interconnection plays a critical role in the TME modulation, and their changes in tumor metabolism appear to be a double-edged sword in regulating various immune cell responses and immunotherapy efficacy. Hence, we discussed the signature manifestation of the glycolysis-cholesterol metabolic axis and its pivotal role in tumor immune regulation. We also highlight how hypothetical combinations of immunotherapy and glycolysis/cholesterol-related metabolic interventions unleash the potential of anti-tumor immunotherapies, as well as developing more effective personalized treatment strategies.

In recent years, chimeric antigen receptor-T (CAR-T) cell therapy has emerged as a novel immunotherapy method. It has shown significant therapeutic efficacy in the treatment of haematological B cell malignancies. In particular, the CAR-T therapy targeting CD19 has yielded unprecedented efficacy for acute B-lymphocytic leukaemia (B-ALL) and non-Hodgkin's lymphoma (NHL). In haematologic malignancies, tumour stem cells are more prone to stay in the regulatory bone marrow (BM) microenvironment (called niches), which provides a protective environment against immune attack. However, how the BM microenvironment affects the anti-tumour efficacy of CAR-T cells and its underlying mechanism is worthy of attention. In this review, we discuss the role of the BM microenvironment on the efficacy of CAR-T in haematological malignancies and propose corresponding strategies to enhance the anti-tumour activity of CAR-T therapy.

Gastric cancer is a highly heterogeneous disease, which makes it challenging to develop effective targeted therapies. Although the potassium voltage-gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have found evidence of involvement in the occurrence and development of various cancers, there are still some limitations in our understanding of KCND2's roles in gastric cancer.

We analyzed the correlation between KCND2 expression and clinical features as well as immune infiltration using the Cancer Genome Atlas (TCGA) database. Functional assays of KCND2 were conducted using Cell counting Kit-8 (CCK8), clone formation assay and cell cycle analysis. Additionally, immunofluorescence, flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR) techniques were used to investigate tumor proliferation and immune cell infiltration at different levels of KCND2 expression in vivo.

KCND2 was markedly elevated in gastric cancer and its expression appeared to link to different grades, T stages, and N stages. In addition, KCND2 was an independent predictor of prognosis, and its elevated levels in TCGA database revealed a more unfavorable prognosis for patients with gastric cancer. KCND2 strengthened the viability at the cellular level by boosting the proliferation of gastric cancer cells and reducing their death rate. Additionally, it also highlights that KCND2 the abilities of proliferating of gastric cancer cells by stimulating NF-κB both in cell and animal levels. In addition, the findings provided proof that in animal levels, KCND2 might regulate the immune system by associating with promoting M2 macrophages, which are known to play critical roles in cancer progression. Mechanistically, KCND2 was found to lead to the infiltration of M2 macrophages through activation of NF-κB, ultimately promoting the advancement of gastric cancer.

Overall, these findings suggest that KCND2 is likely to be available as an underlying therapeutic target for gastric cancer.