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Cytokine-Engineered Chimeric Antigen Receptor-T Cell Therapy: How to Balance the Efficacy and Toxicity.

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the paradigm in hematological malignancies. However, its efficacy in treating solid tumors remains limited because the immunosuppressive tumor microenvironment (ITME) seriously blocks T cell activation, infiltration, and proliferation. Cytokines, driving potent assisted function by enhanced T cell expansion, persistence, and direct tumor cell killing, have long been acknowledged as promising candidates combined with CAR-T cells to improve treatment outcomes. Despite their preclinical success, significant toxicity occurs in

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… Myeloid‐derived suppressor cells (MDSCs), immature immune cells derived from bone marrow precursors, are recruited to tumor sites by chemokines including CCL1, CCL2, CCL5, and CXCL5 through CXCR2 interactions, where they suppress systemic immunity via arginase‐1‐mediated L‐arginine depletion. … Additionally, TAMs secrete IL‐4, IL‐10, and arginase‐1 to further recruit MDSCs into the ITME through JAK/STAT6‐dependent chemotaxis, thereby inhibiting cytotoxic T‐cell activity via PD‐1/PD‐L1 axis potentiation [ 63 ]. …

How histone modifications influence cellular radiosensitivity: Pharmaceutically targeting epigenetic regulators as a promising avenue to overcome radioresistance.

Cancer remains the leading cause of mortality worldwide. Radiotherapy (RT), a cornerstone of oncological treatment for over a century, has achieved great success in various cancers. However, radioresistance remains the primary factor leading to the failure of radiotherapy. Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure, either by loosening or tightening it. Here, we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal t

Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and inva

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… The mechanisms mediating the immunosuppressive role of TANs are not fully elucidated and include the local production of neutrophil extracellular traps (NETs) after IL-8 stimulation [ 241 – 243 ] and release of immunosuppressive signals such as TGF-β, Arginase-1 and ROS [ 244 – 247 ]. … MDSCs possess immunosuppressive properties, mainly through the production of Arginase 1 ( ARG1 ) and inducible nitric oxide synthase (iNOS) enzymes, and are highly expressed in cancers [ 282 ]. …

Common gamma chain cytokines-driven optimization of chimeric antigen receptor T cells: Mechanistic insights and future directions.

Malignant tumors represent a major threat to human life and health, posing persistent challenges in medical research. While chimeric antigen receptor T (CAR-T) cell therapy has demonstrated breakthrough efficacy in hematological malignancies such as leukemia and lymphoma, its application in solid tumors, including hepatocellular carcinoma, lung cancer, and pancreatic cancer, remains constrained by multiple bottlenecks. These limitations encompass the immunosuppressive tumor microenvironment, insufficient in vivo persistence of CAR-T cells, long-term treatment-induced exhaustion, and off-target

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… Additional studies reveal that IL-15 eliminates MDSCs and suppresses their secretion of immunosuppressive molecules, including IL-10, arginase 1, and TGF-β, further diminishing TME-mediated suppression[ 80 ]. …

Hemostasis at the edge between physiology and cancer.

Hemostasis lies at the edge between physiology and cancer, where the coagulation cascade-initiated by tissue factor, thrombin generation, and fibrin deposition-shifts from vascular repair to tumor promotion. The interplay between coagulation and cancer is now recognized as a two-way street, with tumor cells activating the clotting system and coagulation components feeding back to promote malignancy. Tumor cells not only foster proliferation and invasion by overexpressing tissue factor and activating Protease-Activated Receptors (PAR1/PAR2) signalling, but they also induce endothelial cells and

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… These cells limit T cell activity through nutrient depletion, such as arginase-mediated arginine consumption, and by expressing inhibitory checkpoint ligands, thereby reinforcing a locally immunosuppressive loop within the TME [ 41 ]. …

Воспаление и иммунная микроокружающая среда в миелопролазерных неоплазмах: патогенные механизмы и терапевтические возможности.

Филадельфия-отрицательная (Ph-отрицательная) миелопролиферативные новообразования (MPNs) включают полицифемию (PV), основную тромбоцитемию (ET) и первичный миэлофиброз (PMF), которые являются клональными гематопоэтическими расстройствами, вызванными соматическими генными мутациями в генах JAK2, CALR или MPL. Мутации активируют путь JAK-STAT и прерывают сигнализацию NF-IB, что приводит к хроническому подстрекательству, вызванному провоспалительными цитокинами и реактивными видами кислорода (ROS). Эта изменившаяся микроокружающая среда вызывает серьезные клинические особенности заболевания, таки

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… In MPNs, CD11b+CD14-CD33+ cells (MDSCs) were considerably more common in patients than in controls, and they were associated with increased production of arginase-1 (ARG1) mRNA and immunosuppressive activity towards autologous T cells [ 12 , 91 , 92 ]. …

Tumor microenvironment targeted nano-drug delivery systems for multidrug resistant tumor therapy.

In recent years, nano-drug delivery systems (Nano-DDS) that target the tumor microenvironment (TME) to overcome multidrug resistance (MDR) have become a research hotspot in the field of cancer therapy. By precisely targeting the TME and regulating its unique pathological features, such as hypoxia, weakly acidic pH, and abnormally expressed proteins, etc., these Nano-DDS enable effective delivery of therapeutic agents and reversal of MDR. This scientific research community is increasing its investment in the development of diversified systems and exploring their anti-drug resistance potential.

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… During this transition, MICs may secrete a series of immunosuppressive factors, such as IL-10, ROS, iNOS, arginase 1, and TGF-β, which inhibit the activity of T and NK cells, thereby weakening the anti-tumor ability of the immune system 37 . …

Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascu

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… M2 macrophages contribute to the control of the inflammatory process through several actions; in particular, M2a macrophages are associated with arginase production, which is believed to determine collagen deposition and fibrosis development. …

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. TNBC diagnoses account for approximately one-fifth of all breast cancer cases globally. The lack of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER-2, CD340) results in a lack of available molecular-based therapeutics. This increases the difficulty of treatment and leaves more traditional as well as toxic therapies as the only available standards of care in many cases. Recurrence is an additional serious problem, contributing substantially to its higher mortality rate as compared to

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… Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma J. Exp. Med. 2005 202 931 939 10.1084/jem.20050715 16186186 PMC2213169 129. Nagaraj S. Gupta K. Pisarev V. Kinarsky L. Sherman S. Kang L. Herber D.L. Schneck J. Gabrilovich D.I. …

Neurotransmitters in cancer: how receptor signaling and posttranslational modifications modulate tumor progression and offer new therapeutic targets.

Recent studies highlight the multifaceted roles of neurotransmitters in tumor immunomodulation, offering novel avenues for increasing therapeutic efficacy. These signaling molecules are classified into cholinergic agents, monoamines, amino acids, and peptides and regulate tumorigenesis, metastasis, and immune evasion via autocrine/paracrine pathways and receptor-mediated interactions. Notably, neurotransmitters influence tumor cell proliferation, apoptosis, and immune cell activity by modulating intracellular signaling cascades through posttranslational modifications (serotonylation and dopami

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… Additionally, catecholamines contribute to the maintenance of myeloid-derived suppressor cell survival while simultaneously increasing the expression of PD-L1 and arginase 1. These processes collectively contribute to the establishment of an immunosuppressive microenvironment. …

Bridging the gap: ferroptosis of immune cells in the tumor microenvironment.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a pivotal immunomodulatory mechanism within the tumor microenvironment (TME). Beyond its well-established role in tumor cell elimination, emerging evidence reveals that immune cell subsets exhibit distinct susceptibility to ferroptosis, with profound consequences for antitumor immunity. This review systematically delineates the dual and cell-type-specific roles of ferroptosis across innate and adaptive immune populations: while ferroptosis-mediated depletion of immunosuppress

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… First, through metabolic regulation, their lipid peroxidation products (4-HNE and Malondialdehyde, MDA) directly activate arginase-1 (ARG1) and inducible nitric oxide synthase (iNOS), effectively suppressing T cell function ( 53 ). …

Advances in nanotechnology-enabled adjuvants for peptide-based cancer vaccines.

Peptide-based vaccines only contain peptide epitopes and exclude unnecessary biological materials, which greatly reduces the risk of causing an undesired immune response and further improves the safety profile, garnering considerable interest in vaccine development. However, the immunogenicity induced by these peptides alone is not potent enough to elicit an effective immune response. Recently, combining the adjuvants with peptide antigens has shown promising effects to realize a satisfying immune response. In this review, we discuss the development of immunoadjuvants to enhance the safety and

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… Incomplete Freund’s adjuvant reduces arginase and enhances Th1 dominance, TLR signaling and CD40 ligand expression in the vaccine site microenvironment. J. ImmunoTher. Cancer 2020, 8, e000544. …

Extracellular vesicles in multiple myeloma-bone marrow niche crosstalk: from cellular dialogue to clinical perspectives.

Multiple myeloma (MM) is a haematological neoplasia defined by the clonal expansion of malignant plasma cells within the intricate and dynamic ecosystem of the bone marrow (BM). Although genetic aberrations intrinsic to tumour cells play a critical role in MM initiation, the advancement and aggressiveness of the disease are heavily influenced by ongoing signalling exchanges and persistent interactions with the surrounding microenvironment. Extracellular vesicles (EVs) are increasingly recognized as essential messengers in this reciprocal communication, acting as membrane-encapsulated vehicles

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… Specifically, Bahman et al. demonstrated that MM-derived exosomes polarize M0 macrophages toward an M2-like phenotype with pro-tumoral and anti-inflammatory activity, expressing high levels of typical M2 markers, including CD206, IL-10 and Arginase 1 [ 67 ]. …

Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors.

Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells,

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… Impact on adaptive immunity MDSCs inhibit T cell proliferation by suppressing the immune response of T cells in several ways: (i) by generating arginase-1 (ARG-1)-dependent depletion and chelating L-cysteine depletion of L-arginine to inhibit T cell proliferation; (ii) by interfering with the signaling …

Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

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… Myeloid-specific Bmal1 knockout (M-BKO) macrophages polarize toward a protumor M2-like phenotype, with high expression of immunosuppressive genes such as arginase 1 ( Arg1 ) and solute carrier family 7 member 8 ( Slc7a8 ), and enhanced glycolysis through the mROS-HIF-1α axis [136] , [137] . …

Tumour Immunotherapy and Applications of Immunological Products: A Review of Literature.

Malignant tumors, characterized by uncontrolled cell proliferation, are a leading global health challenge, responsible for over 9.7 million deaths in 2022, with new cases expected to rise to 35 million annually by 2050. Immunotherapy is preferred to other cancer therapies, offering precise targeting of malignant cells while simultaneously strengthening the immune system's complex responses. Advances in this novel field of science have been closely linked to a deeper knowledge of tumor biology, particularly the intricate interplay between tumor cells, the immune system, and the tumor microenvir

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… In the TME, MDSCs release arginase, nitric oxide and reactive oxygen species (ROS) to inhibit T cell activation/proliferation by depleting essential nutrients like arginine and cysteine from the environment as factors that impair T cell metabolism/function [ 90 ]. …

Cancer Resistance to Immunotherapy: Comprehensive Insights with Future Perspectives.

Cancer immunotherapy is a type of treatment that harnesses the power of the immune systems of patients to target cancer cells with better precision compared to traditional chemotherapy. Several lines of treatment have been approved by the US Food and Drug Administration (FDA) and have led to remarkable success in the treatment of solid tumors, such as melanoma and small-cell lung cancer. These immunotherapies include checkpoint inhibitors, cytokines, and vaccines, while the chimeric antigen receptor (CAR) T-cell treatment has shown better responses in hematological malignancies. Despite these

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… Additionally, N2 neutrophils, myeloid suppressor cells, and M2 macrophages may also interfere with the immune response through the secretion of reactive oxygen species, arginase-1, and inducible nitric-oxide-synthase enzymes that enhance the proliferation and function of regulatory T cells while inhibiting …

A Journey through the Inter-Cellular Interactions in the Bone Marrow in Multiple Myeloma: Implications for the Next Generation of Treatments.

Tumors are composed of a plethora of extracellular matrix, tumor and non-tumor cells that form a tumor microenvironment (TME) that nurtures the tumor cells and creates a favorable environment where tumor cells grow and proliferate. In multiple myeloma (MM), the TME is the bone marrow (BM). Non-tumor cells can belong either to the non-hematological compartment that secretes soluble mediators to create a favorable environment for MM cells to grow, or to the immune cell compartment that perform an anti-MM activity in healthy conditions. Indeed, marrow-infiltrating lymphocytes (MILs) are associate

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… To achieve these suppressive functions, MDSCs produce arginases (ARG1), reactive oxygen species (ROS), cyclooxygenase-2 (COX2), inducible NOS (iNOS), IL6, IL10, IL18, and reduce metabolic factors required for T-cell activation. …

Innovative Approaches in the Battle Against Cancer Recurrence: Novel Strategies to Combat Dormant Disseminated Tumor Cells.

Cancer recurrence remains a great fear for many cancer survivors following their initial, apparently successful, therapy. Despite significant improvement in the overall survival of many types of cancer, metastasis accounts for ~90% of all cancer mortality. There is a growing understanding that future therapeutic practices must accommodate this unmet medical need in preventing metastatic recurrence. Accumulating evidence supports dormant disseminated tumor cells (DTCs) as a source of cancer recurrence and recognizes the need for novel strategies to target these tumor cells. This review presents

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… MDSCs suppress activation of T and NK cells through the production of reactive oxygen species (ROS) and arginase 1 (Arg-1), along with recruitment of other immune suppressive cells such as regulatory T cells [reviewed in ( 144 )]. …

Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most s

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… AML blasts also evade immune attack through immune editing, a mechanism by which AML cells function like myeloid-derived suppressor cells by secreting arginase-1, indoleamine 2–3 dioxygenase, and inducible nitric oxide synthetase, which suppress T-cell function by inducing anergy, cell cycle arrest, …