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Chimeric antigen receptor (CAR) NK and T cell therapy are promising immunotherapeutic approaches for the treatment of cancer. However, the efficacy of CAR NK/T cell therapy is often hindered by various factors, including the phenomenon of trogocytosis, which involves the bidirectional exchange of membrane fragments between cells. In this review, we explore the role of trogocytosis in CAR NK/T cell therapy and highlight potential strategies for its modulation to improve therapeutic efficacy. We provide an in-depth analysis of trogocytosis as it relates to the fate and function of NK and T cells, focusing on its effects on cell activation, cytotoxicity, and antigen presentation. We discuss how trogocytosis can mediate transient antigen loss on cancer cells, thereby negatively affecting the effector function of CAR NK/T cells. Additionally, we address the phenomenon of fratricide and trogocytosis-associated exhaustion, which can limit the persistence and effectiveness of CAR-expressing cells. Furthermore, we explore how trogocytosis can impact CAR NK/T cell functionality, including the acquisition of target molecules and the modulation of signaling pathways. To overcome the negative effects of trogocytosis on cellular immunotherapy, we propose innovative approaches to modulate trogocytosis and augment CAR NK/T cell therapy. These strategies encompass targeting trogocytosis-related molecules, engineering CAR NK/T cells to resist trogocytosis-induced exhaustion and leveraging trogocytosis to enhance the function of CAR-expressing cells. By overcoming the limitations imposed by trogocytosis, it may be possible to unleash the full potential of CAR NK/T therapy against cancer. The knowledge and strategies presented in this review will guide future research and development, leading to improved therapeutic outcomes in the field of immunotherapy. [ABSTRACT FROM AUTHOR]

Owing to non-responsiveness of a high number of patients to the common melanoma therapies, seeking novel approaches seem as an unmet requirement. Chimeric antigen receptor (CAR) T cells were initially employed against recurrent or refractory B cell malignancies. However, advanced stages or pretreated patients have insufficient T cells (lymphopenia) amount for collection and clinical application. Additionally, this process is time-consuming and logistically cumbersome. Another limitation of this approach is toxicity and cytokine release syndrome (CRS) progress and neurotoxicity syndrome (NS). Natural killer (NK) cells are a versatile component of the innate immunity and have several advantages over T cells in the application for therapies such as availability, unique biological features, safety profile, cost effectiveness and higher tissue residence. Additionally, CAR NK cells do not develop Graft-versus-host disease (GvHD) and are independent of host HLA genotype. Notably, the NK cells number and activity is affected in the tumor microenvironment (TME), paving the way for developing novel approaches by enhancing their maturation and functionality. The CAR NK cells short lifespan is a double edge sword declining toxicity and reducing their persistence. Bispecific and Trispecific Killer Cell Engagers (BiKE and Trike, respectively) are emerging and promising immunotherapies for efficient antibody dependent cell cytotoxicity (ADCC). CAR NK cells have some limitations in terms of expanding and transducing NK cells from donors to achieve clinical response. Clinical trials are in scarcity regarding the CAR NK cell-based cancer therapies. The CAR NK cells short life span following irradiation before infusion limits their efficiency inhibiting their in vivo expansion. The CAR NK cells efficacy enhancement in terms of lifespan TME preparation and stability is a goal for melanoma treatment. Combination therapies using CAR NK cells and chemotherapy can also overcome therapy limitations. [ABSTRACT FROM AUTHOR]

Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy with chimeric antigen receptor (CAR) immunotherapy has made tremendous progress with five CAR T therapies approved by the US Food and Drug Administration for hematological malignancies. However, CAR immunotherapy in solid tumors lags significantly behind. Some of the major hurdles for CAR immunotherapy in solid tumors include CAR T cell manufacturing, lack of tumor-specific antigens, inefficient CAR T cell trafficking and infiltration into tumor sites, immunosuppressive tumor microenvironment (TME), therapy-associated toxicity, and antigen escape. CAR Natural Killer (NK) cells have several advantages over CAR T cells as the NK cells can be manufactured from pre-existing cell lines or allogeneic NK cells with unmatched major histocompatibility complex (MHC); can kill cancer cells through both CAR-dependent and CAR-independent pathways; and have less toxicity, especially cytokine-release syndrome and neurotoxicity. At least one clinical trial showed the efficacy and tolerability of CAR NK cell therapy. Macrophages can efficiently infiltrate into tumors, are major immune regulators and abundantly present in TME. The immunosuppressive M2 macrophages are at least as efficient as the proinflammatory M1 macrophages in phagocytosis of target cells; and M2 macrophages can be induced to differentiate to the M1 phenotype. Consequently, there is significant interest in developing CAR macrophages for cancer immunotherapy to overcome some major hurdles associated with CAR T/NK therapy, especially in solid tumors. Nevertheless, both CAR NK and CAR macrophages have their own limitations. This comprehensive review article will discuss the current status and the major hurdles associated with CAR T and CAR NK therapy, followed by the structure and cutting-edge research of developing CAR macrophages as cancer-specific phagocytes, antigen presenters, immunostimulators, and TME modifiers. [ABSTRACT FROM AUTHOR]