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Despite new insights in molecular features of leukemic cells and the availability of novel treatment approaches and drugs, acute myeloid leukemia (AML) remains a major clinical challenge. In fact, many patients with AML relapse after standard therapy and eventually die from progressive disease. The basic concept of leukemic stem cells (LSC) has been coined with the goal to decipher clonal architectures in various leukemia‐models and to develop curative drug therapies by eliminating LSC. Indeed, during the past few years, various immunotherapies have been tested in AML, and several of these therapies follow the strategy to eliminate relevant leukemic subclones by introducing LSC‐targeting antibodies or LSC‐targeting immune cells. These therapies include, among others, new generations of LSC‐eliminating antibody‐constructs, checkpoint‐targeting antibodies, bi‐specific antibodies, and CAR‐T or CAR‐NK cell‐based strategies. However, responses are often limited and/or transient which may be due to LSC resistance. Indeed, AML LSC exhibit multiple forms of resistance against various drugs and immunotherapies. An additional problems are treatment‐induced myelotoxicity and other side effects. The current article provides a short overview of immunological targets expressed on LSC in AML. Moreover, cell‐based therapies and immunotherapies tested in AML are discussed. Finally, the article provides an overview about LSC resistance and strategies to overcome resistance. Expression of cell surface target antigens on leukemic stem cells (LSC) in acute myeloid leukemia (AML) (left image) and on normal hematopoietic stem cells (right panel). Most of the clinically relevant surface target antigens are not only expressed on AML LSC but also in normal stem cells. In several instances, expression levels are higher on AML LSC than on normal stem cells providing a (small) therapeutic window. Only a few potential surface targets, such as CLL1 (CD371), are selectively (aberrantly) expressed on AML LSC but not on normal stem cells.

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.

Background Natural killer (NK) cell immunotherapy has shown promising therapeutic potential for acute myeloid leukemia (AML), especially with advancements in chimeric antigen receptor-engineered NK cells (CAR-NK) and artificial intelligence (AI). Despite these developments, the field lacks comprehensive bibliometric analyses to identify research hotspots and trends, which could guide future precision treatments. Methods A bibliometric analysis of NK cell immunotherapy for AML was conducted using literature from 2000 to 2023 retrieved from the Web of Science Core Collection database. Data visualization tools like CiteSpace, VOSviewer, and RStudio were employed to analyze publication trends, country contributions, institutional collaborations, influential authors, and research themes. Results The analysis identified 1513 studies, with the United States and China leading global contributions. Notable institutions include the University of Minnesota and MD Anderson Cancer Center. Hot topics include allogeneic NK therapy, CAR-NK cell therapy, and memory-like NK cells. Emerging trends highlight the integration of intelligent NK cells and combinatory therapies, offering promising avenues for AML treatment. Despite progress, challenges such as NK cell expansion, activation, and resistance mechanisms remain critical areas for research. Conclusion This study provides a comprehensive overview of the research landscape, highlighting the transformative potential of NK cell immunotherapy in AML. It underscores the need for international collaboration and continued innovation to overcome existing challenges and advance precision therapies.

Chimeric antigen receptor (CAR)-NK cell therapy has the advantages of a low incidence of side effects and a low cost. However, the clinical outcomes are not satisfactory due to limited antitumor effects and a limited proliferative capacity. Recently, progress in CAR-NK cell therapy has been made in NK cell engineering, target design and combination with other agents to treat relapsed or refractory hematological malignancies, especially acute myeloid leukemia and multiple myeloma. This correspondence summarizes the preclinical and clinical updates for universal CAR-NK cell therapy reported at the ASH 2022 annual meeting.

BackgroundGlioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for \"off-the-shelf\" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM.MethodsCAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells.ResultsBoth B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts.ConclusionNot only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.

As early as 1863, Virchow observed that cancer often arises at sites of chronic inflammation. Modern epidemiological and clinical studies have confirmed the link between inflammation and cancer. Natural Killer (NK) cells actively participate in and regulate inflammatory processes; however, they are not strictly classified as classic ‘inflammatory cells’ in cellular taxonomy. NK cells rapidly identify and eliminate malignantly transformed cells in a non-major histocompatibility complex (MHC)-restricted manner, a characteristic that distinguishes them from other immune cells. Furthermore, their use in allogeneic settings carries a very low risk of graft-versus-host disease (GvHD), making them ideal candidates for developing ‘off-the-shelf’ cellular immunotherapies. Although early clinical attempts using unmodified NK cells showed limited efficacy, the past decade has witnessed rapid advancements in genetic engineering, cell expansion and differentiation, and synthetic biology, propelling NK cell therapy into a new era of development. This article aims to provide a systematic and multi-dimensional review of the latest research progress in NK cell therapy. We begin by revisiting the core biological basis of NK cell anti-tumor activity, focusing on design strategies, clinical breakthroughs, and bottlenecks of Chimeric Antigen Receptor NK (CAR-NK) cell therapy in hematological malignancies and solid tumors. We delve into antibody-based NK cell recruitment strategies (such as BiKEs/TriKEs) and techniques to enhance antibody-dependent cellular cytotoxicity (ADCC), and analyze cytokine-induced memory-like NK (CIML-NK) cells as a non-gene editing enhancement strategy. Simultaneously, we focus on the core challenges currently faced by NK cell therapies, particularly in solid tumors, including poor tumor infiltration, potent suppression by the tumor microenvironment (TME), and limited in vivo persistence. We summarize diversified synergistic strategies, such as combination with immune checkpoint inhibitors, radiotherapy, chemotherapy, targeted drugs, and direct modifications of the TME. Finally, this article discusses contentious points within the field and provides a forward-looking perspective on future directions, striving to offer a comprehensive and insightful reference for the translation of NK cell therapy from the laboratory to widespread clinical application.

Acute myeloid leukemia (AML), characterized by aggressive relapse and dismal survival, remains a formidable challenge despite conventional therapies. Chimeric antigen receptor (CAR)-engineered T and natural killer (NK) cells have emerged as groundbreaking immunotherapies, offering targeted eradication of leukemic stem cells (LSCs) and resistant blasts. CAR-T cells, leveraging antigens like CD123 and CD33, demonstrate early clinical success, with complete remission rates up to 66% in refractory/relapsed (R/R) AML. CAR-NK cells complement this approach through inherent tumor surveillance, reduced toxicity, and \"off-the-shelf\" feasibility. However, barriers such as antigen escape, heterogeneous immunosuppressive microenvironments (including intratumoral microbiota variations), and on-target/off-tumor toxicity persist, limiting durable responses. Innovations in dual-targeting CARs, cytokine-armored constructs, and CRISPR-edited universal cells aim to overcome these hurdles. Emerging strategies integrating checkpoint inhibitors, metabolic modulators, and AI-driven antigen selection promise to enhance efficacy and safety. This review synthesizes the evolving landscape of CAR-T/NK therapies, critically analyzing preclinical breakthroughs, clinical trial outcomes, and persisting challenges. By addressing manufacturing scalability, cost barriers, and long-term safety, cellular immunotherapy holds transformative potential to redefine AML management. As the field advances, interdisciplinary collaboration and biomarker-guided personalization will be pivotal in translating laboratory innovations into life-saving therapies for AML patients.