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The impact of the gut microbiome on tumor immunotherapy: from mechanism to application strategies.

Immunotherapy is one of the fastest developing areas in the field of oncology. Many immunological treatment strategies for refractory tumors have been approved and marketed. Nevertheless, much clinical and preclinical experimental evidence has shown that the efficacy of immunotherapy in tumor treatment varies markedly among individuals. The commensal microbiome mainly colonizes the intestinal lumen in humans, is affected by a variety of factors and exhibits individual variation. Moreover, the gut is considered the largest immune organ of the body due to its influence on the immune system. In t

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… expression of PD-L1 in multiple HNSCC cell lines and directly promotes immunosuppression | [ 145 ] Hepatocellular carcinoma (HepG-2) | γδT immunotherapy combined with antibiotics | 3-Indolepropionic acid (IPA) | | | IPA can stimulate γδT cells to release more cytotoxic cytokines, such as granzyme B and perforin …

Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma.

In the tumor milieu of head and neck squamous cell carcinoma (HNSCC), distinct B cell subpopulations are present, which exert either pro- or anti-tumor activities. Multiple factors, including hypoxia, cytokines, interactions with tumor cells, and other immune infiltrating lymphocytes (TILs), alter the equilibrium between the dual roles of B cells leading to cancerogenesis. Certain B cell subsets in the tumor microenvironment (TME) exhibit immunosuppressive function. These cells are known as regulatory B (Breg) cells. Breg cells suppress immune responses by secreting a series of immunosuppressi

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… CD19 + CD5 + CD1d + | Cervical cancer, cervical intraepithelial neoplasia | PBMCs | IL-10 | Inhibit the production of perforin and GrB by CD8 + T cells ( 57 ). HNSCC | Tumor-draining LNs | — | Good prognostic factor in TDLNs ( 50 ). …

CAR-T Cell Therapy in the Treatment of Pediatric Non-Hodgkin Lymphoma.

Non-Hodgkin lymphomas (NHL) are a group of cancers that originate in the lymphatic system, especially from progenitor or mature B-cells, T-cells, or natural killer (NK) cells. NHL is the most common hematological malignancy worldwide and also the fourth most frequent type of cancer among pediatric patients. This cancer can occur in children of any age, but it is quite rare under the age of 5 years. In recent decades, available medicines and therapies have significantly improved the prognosis of patients with this cancer. However, some cases of NHL are treatment resistant. For this reason, immu

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… The cytolytic degranulation of perforin and granzyme is considered the main mechanism by which CAR-T cells redirect the killing of target cells [ 43 ]. …

Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy.

Multiple sclerosis (MS) is a leading cause of chronic neurological disability in young to middle-aged adults, affecting ~2.5 million people worldwide. Currently, most therapeutics for MS are systemic immunosuppressive or immunomodulatory drugs, but these drugs are unable to halt or reverse the disease and have the potential to cause serious adverse events. Hence, there is an urgent need for the development of next-generation treatments that, alone or in combination, stop the undesired autoimmune response and contribute to the restoration of homeostasis. This review analyzes current MS treatmen

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… CD8 + T cells directly attack oligodendrocytes (via the secretion of granzymes and perforin), causing apoptosis and damaging neurons via the release of cytolytic granules, leading to axonal dissection. 28 Up to a quarter of CD8 + T cells in the active lesions of MS patients can produce IL-17 and are …

Cytokines in CAR T Cell-Associated Neurotoxicity.

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and

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… Topic | Key Points Mediators likely or possibly associated with ICANS | IFN γ, IL-15 , IL-6 , IL-10 , GM-CSF , IL-2, IL-2Rα, IL-1RA , CXCL10, Granzyme b Mediators likely NOT associated with ICANS | IL-4, IL-5, IL-7, IL-13, Ang-1 , perforin Mediators with indeterminate ICANS association | Ang-2 , Ang2 …

Microgel-Based 3D Bioprinting: A Convergent Strategy Integrating Material Design, Jamming Dynamics, and Biological Function.

Driven by rapid technological innovation and an increasing demand for personalized medicine, microgel-based bioprinting emerges as a versatile strategy for generating physiologically relevant tissue models and patient-specific constructs. By integrating microgel systems with 3D bioprinting, this approach enables the creation of complex, cell-laden architectures that closely recapitulate native tissue architecture and function. Pivotal to this potential are microgels that offer significant advantages over conventional hydrogel-based bioinks, including tunable rheological behavior, enhanced prin

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… For example, Wang et al. [ 75 ] encapsulated natural killer cells in sodium alginate (SA) porous microgels, protecting the cells while enabling sustained release of perforin and granzymes for potent antitumor activity. …

Dynamic Evolution of the Tumor Immune Microenvironment in Malignant Tumors and Emerging Therapeutic Paradigms.

Cancer is more than just a collection of tumor cells. The complex tumor system, including the tumor immune microenvironment (TIME), is continually changing. Tumor cells are in constant communication with all stromal elements (e.g., fibroblasts, endothelial cells, and extracellular matrix) and immune effector cells (e.g., T cells, B cells, natural killer cells, dendritic cells, macrophages, and myeloid-derived suppressor cells). Together, these intricate interactions among cell and molecular signaling pathways collectively drive tumor growth, tumor invasion, and metastasis and significantly aff

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… CD8 + T cells can recognize cancer‐specific antigens and destroy cancer cells through effector molecules such as perforin and granzyme, which are positively correlated with patient prognosis. …

Cardiovascular adverse effects of immunotherapy in cancer: insights and implications.

Immunotherapy has revolutionized cancer treatment, offering novel therapeutic strategies such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapy, and cancer vaccines. However, these modalities are associated with varying cardiovascular toxicities that may affect treatment continuation and patient outcomes. Cardiovascular complications from ICIs, such as myocarditis (incidence 0.04-1.14%, mortality 25-50%), arrhythmias, heart failure, and thromboembolic events, are primarily mediated by autoreactive T-cell activation and immune-related inflammation. CTLA-4 an

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… IFN-γ, perforin, and granzyme B are among the cytotoxic molecules and effector cytokines that are overproduced as a result of this activation, which eventually causes cardiac damage and the development of myocarditis ( 170 ). …

Emerging advances in drug delivery systems (DDSs) for optimizing cancer complications.

The management and treatment of tumor complications pose continuous challenges due to the inherent complexity. However, the advent of drug delivery systems (DDSs) brings promising opportunities to address the tumor complications using innovative technological approaches. This review focuses on common oncological complications, including cancer thrombosis, malignant serous effusion, tumor-associated infections, cancer pain, and treatment-related complications. Emphasis was placed on the application and potential of DDSs in mitigating and treating these tumor complications, and we delved into th

Immunologic tumor microenvironment modulators for turning cold tumors hot.

Tumors can be classified into distinct immunophenotypes based on the presence and arrangement of cytotoxic immune cells within the tumor microenvironment (TME). Hot tumors, characterized by heightened immune activity and responsiveness to immune checkpoint inhibitors (ICIs), stand in stark contrast to cold tumors, which lack immune infiltration and remain resistant to therapy. To overcome immune evasion mechanisms employed by tumor cells, novel immunologic modulators have emerged, particularly ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein

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… Of these, CTLs hold the mantle of prominence, functioning as the primary effector cells armed with a formidable arsenal of cytotoxic molecules, including granzymes and perforin, to engage and dismantle tumor targets [ 108 ]. …

Multiple myeloma: signaling pathways and targeted therapy.

Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug res

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… NK cells only secrete several cytokines such as interferon-gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF), perforin, and granzyme. Importantly, NK cells do not produce IL-1 and IL-6, which are key cytokines involved in the development of CRS [ 266 , 267 ]. …

Potential Immunotherapy Targets for Liver-Directed Therapies, and the Current Scope of Immunotherapeutics for Liver-Related Malignancies.

Liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is increasing in incidence and mortality across the globe. An improved understanding of the complex tumor microenvironment has opened many therapeutic doors and led to the development of novel pharmaceuticals targeting cellular signaling pathways or immune checkpoints. These interventions have significantly improved tumor control rates and patient outcomes, both in clinical trials and in real-world practice. Interventional radiologists play an important role in the multidisciplinary team given their expertise

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… NK cells are considered a part of the innate immune system and exercise their function through the secretion of perforins, granzymes, TNF-α, and interferon gamma (IFN-γ) leading to tumor cell lysis. …

Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation.

Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway - has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequ

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… Two distinct mechanisms of cytotoxicity have been identified, i.e. perforin and granzyme-dependent and Fas ligand-dependent ( 201 ). …

Cancer Cells Exploit Notch Signaling to Redefine a Supportive Cytokine Milieu.

Notch signaling is a well-known key player in the communication between adjacent cells during organ development, when it controls several processes involved in cell differentiation. Notch-mediated communication may occur through the interaction of Notch receptors with ligands on adjacent cells or by a paracrine/endocrine fashion, through soluble molecules that can mediate the communication between cells at distant sites. Dysregulation of Notch pathway causes a number of disorders, including cancer. Notch hyperactivation may be caused by mutations of Notch-related genes, dysregulated upstream p

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… Indeed, the activation of Notch2 signaling on CD8+ T cells, mediated by Dll4 or Jagged1 expressed by DCs, is required for the activation and proliferation of human CD8+ T cells and for the release of effector cytokines including IFN-γ, along with TNFα, perforin, and granzyme B ( 36 , 37 , 200 , 207 ) …

Tumor Biology Hides Novel Therapeutic Approaches to Diffuse Large B-Cell Lymphoma: A Narrative Review.

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-dru

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… Host response (HR) | cluster signatures: TCR, CD2, CD3 δ, ε, γ; CD6, Cd28, GATA3, cMAF, CXCR6, NKp30, LAT, FYN, SLAP, LAG3, CD100, perforin, TIRC7, LAIR-1, complement 1qB, 1S, 4A; complement 3α receptor, C1 inhibitor, CD14, CD163, FGR, BIT/SIRPα, granulin, LAMP1, cathepsins B, D; GILT, IFN-induced transmembrane …

Hematopoietic Tumors

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Aging modulation of the immune system and immunotherapy efficacy in cancer.

Immunosenescence is characterized by immune decline and chronic inflammation. With advancing age, the incidence of tumors increases significantly. Understanding how immunosenescence influences the initiation and progression of tumors, as well as its implications for tumor immunotherapy, has become a matter of urgent importance. This review begins with an analysis of the phenotypic changes and underlying mechanisms associated with immune system and immune cell aging, and further explores the interplay between immunosenescence and tumorigenesis. Evidence indicates that cytokines, cell interactio

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… Desdín-Micó et al. identified T cells deficient in mitochondrial transcription factor A as accelerators of immune system aging ( 29 ), while Ovadya et al. found that perforin gene knockout resulted in a more rapid accumulation of senescent cells across multiple murine organs, thereby accelerating aging …

Bispecific antibodies as powerful immunotherapeutic agents for urological cancers: Recent innovations based on preclinical and clinical evidence.

Conventional immunotherapy has emerged as a key option for cancer treatment. However, its efficacy has been limited in urological cancers, especially prostate cancer, because of the immunosuppressive tumor microenvironment (TME), difficulty in drug delivery, aberrant immune response, and damage to normal cells. Bispecific antibodies (BsAbs) are engineered proteins with two different antigen-binding domains, designed using different technologies and in various formats. BsAb-based tumor immunotherapy has yielded optimistic results in preclinical and clinical investigations of many tumor types, i

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… Further, activated T cells can induce tumor cell necrosis or apoptosis by producing perforin and granzyme or stimulating death ligands, such as the Fas-FasL pathway 75 . Blinatumomab induces cancerous cell removal in Philadelphia chromosome-negative B cell ALL by redirecting human T cells 77 . …

COVID-19 in patients with anemia and haematological malignancies: risk factors, clinical guidelines, and emerging therapeutic approaches.

Extensive research in countries with high sociodemographic indices (SDIs) to date has shown that coronavirus disease 2019 (COVID-19) may be directly associated with more severe outcomes among patients living with haematological disorders and malignancies (HDMs). Because individuals with moderate to severe immunodeficiency are likely to undergo persistent infections, shed virus particles for prolonged periods, and lack an inflammatory or abortive phase, this represents an overall risk of morbidity and mortality from COVID-19. In cases suffering from HDMs, further investigation is needed to achi

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… SARS-CoV-2 can attack the β-1 chain of Hb and detach it from iron to form perforin. Therefore, often less Hb is available to carry oxygen and carbon dioxide (CO 2 ). …

CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity.

Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T cell therapy in solid tumors remains challenging. This review summarized the development of CAR-T technologies, emphasized the challenges and solutions in CAR-T cell therapy for solid tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies and the novel use of CAR-Treg, CAR-NK and CAR-M cells. Besides, CAR-based cell therapy have extended its reach beyond oncology

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… Upon activation, CAR-Tregs can curb rejection responses by releasing granule enzymes and perforin to eliminate cytotoxic T cells ( 180 ). …