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RNA demethylase ALKBH5 takes part in the modulation of N 6 -methyladenosine (m 6 A) modification and controls various cell processes. ALKBH5-mediated m 6 A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m 6 A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.

Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.

We previously showed that the chemokine CCL2 can recruit macrophages (Mφs) to the bone marrow (BM) in multiple myeloma (MM) and that myeloma-associated Mφs are important in drug resistance. Here, we explore the role of increased CCL2 expression in the BM microenvironment of MM and elucidate the underlying mechanism. Our results show that CCL2 expression is associated with the treatment status of MM patients. Mφs interact with MM cells and further upregulate their expression of CCL2. These increased level of CCL2 polarizes Mφs toward the M2-like phenotype and promotes Mφs to protect MM cells from drug-induced apoptosis. Mechanistically, CCL2 upregulated the expression of the immunosuppressive molecular MCP-1-induced protein (MCPIP1) in Mφs. MCPIP1 mediates Mφs’ polarization and protection via dual catalytic activities. Additionally, we found that CCL2 induces MCPIP1 expression via the JAK2-STAT3 signaling pathway. Taken together, our results indicate that increased CCL2 expression in MM patients’ BM polarizes Mφs toward the M2-like phenotype and promotes the protective effect of Mφs through MCPIP1, providing novel insight into the mechanism of Mφs-mediated drug resistance in MM.

Immunotherapy, exemplified by immune checkpoint blockade (ICB), has been extensively employed in antitumor treatments. Nevertheless, its efficacy in addressing low-immunogenic tumors has not yielded satisfactory results, primarily due to the depletion and inadequate infiltration of effector T cells within the tumor microenvironment (TME). Here, we construct an injectable water-in-oil emulsion hydrogel to load clinically used Celastrol (Gel@Cel), which addresses the limitations of Cel’s hydrophobicity. Cel can both inhibit tumor cell proliferation and promote tumor cell apoptosis, while simultaneously inducing immunogenic cell death, through activation of the AKT and MAPK pathways. In a model of clinically refractory hepatocellular carcinoma with malignant ascites, intraperitoneal administration of Gel@Cel significantly inhibits tumor progression and activates antitumor immune effects through lipase-controlled release of Cel, as compared to free Cel. Intriguingly, the Gel@Cel induces the activation of dendritic cells, resulting in the infiltration of cytotoxic T cells in the TME of ascites. Furthermore, the administration of Cel increases the expression of programmed cell death protein ligand-1 (PD-L1) in tumor cells. Moreover, combining the PD-1 antibody (αPD-1) with Gel@Cel further enhances the antitumor effect and amplifies the immune activation. In conclusion, Gel@Cel exhibits promising therapeutic potential in the treatment of low-immunogenic tumors, especially when combined with ICB therapy.

Multiple myeloma (MM) is a hematologic malignancy driven by clonal expansion of malignant plasma cells. Despite the long‐term disease control achieved with immunotherapies in some patients, treatment resistance remains a major cause of disease relapse. Accumulating evidence highlights the tumor immune microenvironment, especially macrophages, as a key contributor to immunotherapy failure in MM. Herein, we identified a subset of MM‐associated macrophages with high expression of fibroblast activation protein alpha (FAPα), defined as FAPα+ macrophages. Clinical data showed that FAPα+ macrophages were enriched in the bone marrow versus peripheral blood of MM patients, and their abundance positively correlated with tumor burden. In MM mouse models, depletion of FAPα+ macrophages significantly boosted the efficacy of anti‐PD‐1/PD‐L1 antibody therapy but not anti‐CTLA‐4 therapy; this combinatorial strategy also exerted enhanced anti‐tumor effects in EL4 lymphoma and CT26 colorectal carcinoma models. Mechanistically, FAPα stabilized PD‐L1 expression by maintaining its N‐glycosylation and inhibiting proteasomal degradation, and induced PD‐L1 synthesis via promoting vimentin (VIM) phosphorylation at the S72 residue. Additionally, FAPα+ macrophages accelerated T cell senescence by secreting soluble FAPα. Collectively, our findings demonstrate that FAPα+ macrophages mediate MM immune evasion via dual mechanisms, positioning them as promising therapeutic targets to potentiate anti‐tumor immunotherapies. Fibroblast activation protein alpha‐positive (FAPα+) macrophages, a distinct subset of multiple myeloma (MM)‐associated macrophages, drive immune evasion in MM through multi‐faceted mechanisms. FAPα physically interacts with vimentin (VIM) and triggers its phosphorylation at the S72 residue, which in turn induces PD‐L1 transcription. Additionally, FAPα sustains PD‐L1 protein stability by preserving its N‐glycosylation and suppressing proteasomal degradation of PD‐L1. Moreover, FAPα+ macrophages secrete soluble FAPα to accelerate T cell senescence, further facilitating MM immune escape. Collectively, these findings identify FAPα+ macrophages as a key mediator of MM immune evasion and a promising therapeutic target for developing novel anti‐MM immunotherapies.

Acute promyelocytic leukemia differentiation syndrome (APL DS) is a common and severe complication seen in patients with APL treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). The presenting symptoms of APL DS are diverse, and rare symptoms are easy to be misdiagnosed. Therefore, it is very crucial to identify DS from uncommon signs to avoid delay in treatment. Here, we report a patient of APL who developed severe abdominal pain during ATRA and ATO therapy, with increasing leukocyte count. Organic diseases were firstly excluded, and empiric treatment for DS was adopted. The abdominal pain was gradually relieved and the patient eventually achieved complete remission. This case history suggests that APL DS may manifest as severe abdominal pain, and the early identification of DS and immediate treatment could improve the prognosis of patients.

Acute myeloid leukemia (AML) is a common and lethal hematopoietic malignancy that is highly dependent on the bone marrow (BM) microenvironment. Infiltrating immune and stromal cells are important components of the BM microenvironment and significantly influence the progression of AML. This study aimed to elucidate the value of immune/stromal cell-associated genes for AML prognosis by integrated bioinformatics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and used the ESTIMATE algorithm to calculate immune scores and stromal scores; we then identified differentially expressed genes (DEGs) based on these scores. Overall survival analysis was applied to reveal common DEGs of prognostic value. Subsequently, we conducted a functional enrichment analysis, generated a protein–protein interaction (PPI) network and performed an interrelation analysis of immune system processes, showing that these genes are mainly associated with the immune/inflammatory response. Finally, eight genes (CD163, CYP27A1, KCNA5, PPM1J, FOLR1, IL1R2, MYOF, VSIG2) were verified to be significantly associated with AML prognosis in the Gene Expression Omnibus (GEO) database. In summary, we identified key microenvironment-related genes that affect the outcomes of AML patients and might serve as therapeutic targets.

Macrophages (MΦs) are an abundant component in the multiple myeloma (MM) environment and contribute to MM drug resistance. We previously showed that interleukin-32 (IL-32) is highly expressed in MM patients and induces the immunosuppressive function of MΦs. The present study was designed to explore the role of IL-32 in MΦ-mediated MM drug resistance and the underlying mechanism. Our analysis revealed that IL-32 expression was upregulated in relapsed MM patients and associated with CD206+ M2 MΦ infiltration. Subsequently, we found that the most active isoform, IL-32γ, promoted MΦs to protect MM cells from drug-induced apoptosis both in vitro and in vivo. Furthermore, by evaluating many parameters, including surface markers, cytokines, metabolic enzymes and characteristic molecules, IL-32γ was verified to induce the polarization of M2 MΦs, a function that was partly dependent on increasing the expression of colony-stimulating factor 1 (CSF1). Taken together, the results of our study indicate that IL-32γ promotes MΦ-mediated MM drug resistance and modifies MΦs toward the M2 phenotype, providing a crucial theoretical basis for targeted MΦ immunotherapy.

Dihydroartemisinin (DHA), an active metabolite and derivative of artemisinin, is the most effective antimalarial drug and has strong antitumor activity in various tumor types. It has recently been reported that DHA can induce autophagy and has significant effects on multiple myeloma (MM), but the mechanisms and the relationship between the autophagy and apoptosis induced by DHA remain to be elucidated. Herein, we demonstrated that DHA significantly induces cell death in a dose- and time-dependent manner via the extrinsic and intrinsic apoptosis pathways. Moreover, DHA-induced autophagy, which plays a prodeath role in MM, can regulate canonical apoptosis and vice versa. Furthermore, the P38/MAPK signaling pathway is responsible for decreased autophagy and increased apoptosis. DHA induces autophagy and apoptosis also through the inhibition of the Wnt/β-catenin signaling pathway. In addition, DHA shows a strong effect in a xenograft mouse model. Collectively, these findings reveal that DHA, as an artemisinin-based drug, could be an effective and safe therapeutic agent for MM.

Interleukin-32 (IL-32), a novel proinflammatory cytokine, is highly expressed in various cancer tissues and in established cancer cell lines. IL-32 has been revealed to serve a crucial role in human cancer development, including tumour initiation, proliferation and maintenance. The expression of IL-32 is regulated by numerous factors, including genetic variations, hypoxia and acidosis in the tumour microenvironment. Understanding the underlying mechanisms of IL-32 expression and its function are critical for the discovery of novel therapeutic strategies that target IL-32. This is a review of the current literature on the regulation and function of IL-32 in cancer progression, focusing on the molecular pathways linking IL-32 and tumour development.