Search Results (71)

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment–targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article

Adoptive cellular therapy with donor-derived T cells has always been an attractive strategy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to reduce the risk of relapse in acute myeloid and lymphoid leukemias. Donor lymphocyte infusion (DLI) is still the best-established option, especially in the preemptive phase when measurable residual disease (MRD) becomes positive and in the prophylactic setting—when MRD is not detectable. However, the clinical benefit of DLI is counterbalanced by the possible onset of graft-versus-host disease (GvHD), which continues to restrict its wide application. To address this challenge, several alternative cell-based strategies have been developed. One of these is represented by cytokine-induced killer (CIK) cells, generated from donor peripheral blood mononuclear cells through stimulation with anti-CD3 antibodies, interferon-γ, and interleukin-2. These cells are characterized by a hybrid phenotype, combining T-cell functions with natural killer-like properties, and exhibit antitumor activity in an MHC-unrestricted manner. CIK cells are generally well tolerated and associated with low toxicity but their efficacy is so far modest. Based on the experience of CAR-T in the treatment of B-cell lymphoid disease, CIK cells have been engineered with chimeric antigen receptors (CAR) developing the CARCIK cells. This novel cellular strategy represents a promising approach in the treatment of acute myeloid and lymphoid leukemia relapsed post-allo-HSCT. This review provides an overview of the current CAR-CIK experiences in the setting of acute leukemias and outlines future directions for their clinical translation. Full article

Osteosarcoma (OS) remains the most common primary malignant bone tumor in adolescents, with conventional treatments yielding only modest improvements in long-term survival. Immunotherapy has emerged as a promising strategy to overcome these limitations. B7-H3 (CD276) stands apart from other potential targets due to its high expression in tumors cells, as well as its strong association with tumor aggressiveness and poor prognosis. This review provides a comprehensive overview of B7-H3, covering its molecular structure, regulatory mechanisms, biological functions, and expression patterns in tumor tissues. We emphasize the dual roles of B7-H3—both immunoregulatory and non-immunoregulatory—in shaping the tumor microenvironment (TME) and facilitating immune evasion. Building on these insights, we summarize current immunotherapeutic strategies targeting B7-H3 in OS, including monoclonal antibodies (mAbs), chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates (ADCs), and bispecific antibodies (bsAbs). These four strategies have their own advantages and deficiencies. Excitingly, rapid advances in nanoparticle-based systems offer promising solutions to overcome the limitations, especially to develop more effective drug delivery systems and to reshape the TME by targeting immune cells. Despite promising progress, significant challenges remain. These include the absence of an identified B7-H3 receptor, the immunosuppressive and heterogeneous nature of the OS TME, and the need for improved targeting specificity and safety. Addressing these challenges through optimization of delivery systems, combination strategies, and the integration of nanotechnology may unlock the full potential of B7-H3-based immunotherapy in the treatment of OS. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has emerged as a transformative strategy in anticancer treatment, driven by advances in CAR construct design, manufacturing platforms, and expansion to diverse immune cell types. The landmark success of CD19-targeted CAR-T cell therapy in B cell malignancies has paved the way for broader clinical applications. As of 2025, the U.S. FDA has approved multiple autologous CAR-T products, underscoring their therapeutic promise. However, challenges persist, including cytokine release syndrome (CRS), neurotoxicity, product inconsistency, and the high cost and complexity of cell manufacturing. Variations in cell source, gene delivery methods, expansion protocols, and CAR design significantly influence the safety, efficacy, and scalability of these therapies. In this review, we comprehensively examine the current advances in manufacturing protocols for CAR-modified T cells, natural killer (NK) cells, and unconventional T cell subsets, including γδ T, invariant natural killer T (iNKT), and mucosal-associated invariant T (MAIT) cells. We also highlight emerging innovations such as in vivo CAR-T generation and off-the-shelf allogeneic approaches. By integrating updated strategies with a critical evaluation of current limitations, this review aims to support the development of standardized, robust, and accessible CAR-based immunotherapies. Full article

Background/Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor with dismal prognosis and limited treatment options. Immunotherapy, including personalized approaches using tumor-infiltrating lymphocytes (TILs) and allogeneic natural (NK) or engineered killer cells (chimeric antigen receptor NK, NK-CAR), and oncolytic viruses (OV), has shown some potential in GBM. Combining different therapeutic strategies may enhance treatment efficacy. Here, we present a xenograft GBM mouse model with multiparametric detection for various immunotherapy research applications. Methods: In a xenograft GBM NOD-Prkdcs scid Il2rgem1/Smoc (NSG) mouse model based on orthotopic transplantation of patient-derived GBM cultures retaining tumor heterogeneity, intravenous and intratumor immunotherapeutic interventions by TIL and OV therapy were performed. Xenograft engraftment was evaluated using intravital MRI; delivery of OV and TILs to the tumor and changes in the tumor and peritumoral space were assessed using intravital confocal microscopy; and metabolic and structural changes in the tumor and peritumoral environment were assessed via fluorescence lifetime imaging microscopy (FLIM) and optical coherence tomography (OCT). The intravital imaging data were compared with the results of preliminary and final histological and immunocytochemical data. Results: Both OV and TILs demonstrated tumor-specific targeting and delivery across the blood–brain barrier. Further, we showed that in this model the xenograft response to both therapeutic treatments can be assessed using FLIM and OCT. Conclusions: Overall, this work presents an optimized mouse model suitable for assessing the effect of combined TIL immunotherapy and OV on GBM in translational studies. Full article

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment. Full article

Chimeric Antigen Receptor (CAR)-T cell therapy has transformed the treatment landscape of cancer, yet major challenges remain in enhancing efficacy, reducing adverse effects, and expanding accessibility. Autologous CAR-T cells, derived from individual patients, have achieved remarkable clinical success in hematologic malignancies; however, their highly personalized nature limits scalability, increases costs, and delays timely treatment. Allogeneic CAR-T cells generated from healthy donors provide an “off-the-shelf” alternative but face two critical immune barriers: graft-versus-host disease (GvHD), caused by donor T-cell receptor (TCR) recognition of host tissues, and host-versus-graft rejection, mediated by recipient immune responses against donor HLA molecules. Recent advances in genome engineering, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9, allow precise modification of donor T cells to overcome these limitations. For example, TRAC gene knockout eliminates TCR expression, preventing GvHD, while disruption of HLA molecules reduces immunogenicity without impairing cytotoxicity. Beyond hematologic cancers, CRISPR-edited allogeneic CAR-T cells targeting the NKG2D receptor have shown promise in preclinical studies and early-phase trials. NKG2D CAR-T cells recognize stress ligands (MICA/B, ULBP1–6) expressed on over 80% of diverse solid tumors, including pancreatic and ovarian cancers, thereby broadening therapeutic applicability. Nevertheless, the genomic editing process carries risks of off-target effects, including potential disruption of tumor suppressor genes and oncogenes, underscoring the need for stringent safety and quality control. This review examines the distinguishing features of allogeneic versus autologous CAR-T therapy, with a particular focus on NKG2D-based allogeneic CAR-T approaches for solid tumors. We summarize current strategies to mitigate immune barriers, discuss practical manufacturing challenges, and analyze available clinical data on NKG2D CAR-T trials. Collectively, these insights underscore both the promise and the hurdles of developing safe, universal, and scalable allogeneic CAR-T therapies for solid malignancies. Full article

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising platform for off-the-shelf immunotherapy due to their safety advantages over CAR-T cells, including lower risk of graft-versus-host disease, cytokine release syndrome, and neurotoxicity. However, their persistence and efficacy are limited by immunological challenges such as host T-cell-mediated rejection, NK cell fratricide, and macrophage-mediated clearance. This review summarizes gene editing strategies to overcome these barriers, including β2-microglobulin (B2M) knockout and HLA-E overexpression to evade T and NK cell attacks, CD47 overexpression to inhibit phagocytosis, and TIGIT deletion to enhance cytotoxicity. In addition, we discuss functional enhancements such as IL-15 pathway activation, KIR modulation, and transcriptional reprogramming (e.g., FOXO1 knockout) to improve persistence and antitumor activity. We also highlight the role of induced pluripotent stem cell (iPSC)-derived NK platforms, enabling standardized, scalable, and multiplex gene-edited products. Finally, we explore artificial intelligence (AI) applications in immunogenomic profiling and predictive editing to tailor NK cell therapies to patient-specific HLA/KIR/SIRPα contexts. By integrating immune evasion, functional reinforcement, and computational design, we propose a unified roadmap for next-generation CAR-NK development, supporting durable and broadly applicable cell-based therapies. Full article

Chimeric antigen receptor (CAR)-engineered immune cells, particularly CAR T lymphocytes and CAR natural killer (NK) cells, have revolutionized cancer immunotherapy. However, their therapeutic efficacy and safety can be influenced by the tumor microenvironment, particularly the presence of mesenchymal stem cells (MSCs). MSCs are immunomodulatory cells which can alter the function of tumor-infiltrated immune cells in both supportive and suppressive ways. Results obtained in recently conducted experimental studies demonstrate that MSCs modulate proliferation, cytotoxicity, cytokine production and anti-tumor activity in CAR-expressing immune cells in both a juxtacrine and a paracrine manner. While MSCs can enhance CAR cell viability and persistence through trophic support, they may also impair cytotoxic function and promote an immunosuppressive phenotype under certain conditions. Understanding the dualistic nature of MSCs in CAR-based immunotherapy for malignant diseases is critical for optimizing clinical outcomes. Additionally, MSCs may serve as vehicles for targeted delivery of immunomodulatory agents, and should be considered as active components in the design of next-generation CAR-based immunotherapies. Accordingly, in this review article we emphasize molecular and cellular mechanisms involved in MSC-dependent modulation of CAR-expressing immune cells, paving the way for more efficient CAR-based immunotherapy for malignant diseases. Full article

Solid tumors pose significant therapeutic challenges due to their resistance to conventional treatments and the complexity of the tumor microenvironment. Cell-based immunotherapies offer a promising approach, enabling precise, personalized treatment through immune system modulation. This review explores several emerging cellular therapies for solid tumors, including tumor-infiltrating lymphocytes, T cell receptor-engineered T cells, CAR T cells, CAR natural killer cells, and macrophages. Tumor-infiltrating lymphocytes and their modified versions, T cell receptor-engineered T cells and CAR T cells, provide personalized immune responses, although their effectiveness can be limited by factors like variation in tumor antigens and the suppressive nature of the tumor environment. Natural killer cells engineered with chimeric receptors offer safer, non-major histocompatibility complex-restricted targeting, while modified macrophages exploit their natural ability to enter tumors and reshape the immune landscape. CAR-modified macrophages and macrophages conjugated with drugs are also considered as therapy for solid tumors. The review also examines the implications of autologous versus allogeneic cell sources. Autologous therapies ensure immunologic compatibility but are limited by scalability and manufacturing constraints. Allogeneic approaches offer “off-the-shelf” potential but require gene editing to avoid immune rejection. Integrating synthetic biology, gene editing, and combinatorial strategies will be essential to enhance efficacy and expand the clinical utility of cellular immunotherapies for solid tumors. Full article

The clinical use of T lymphocytes engineered with chimeric antigen receptors (CARs) has revolutionized the treatment of patients with refractory or relapsed hematological malignancies. CAR natural killer (CAR-NK) cells are NK cells engineered with CARs to specifically target cell antigens expressed on the membrane of tumor cells. CAR-NK cells could offer some advantages with respect to CAR-T cells, related to their specific and innate anti-tumor activity, availability as an “off the shelf” cellular therapy, reduced costs, and improved safety. Promising efficacy of CAR-Nk cell therapy was observed in clinical trials based on the treatment of some hematological malignancies. However, to date, the clinical experience of CAR-NK cell therapy has been preliminary, with the evaluation of only a limited number of patients. Furthermore, CAR-NK cell therapy has been limited by the short persistence of these cells and by the suboptimal cytotoxic activity of some CAR-NK preparations. Therefore, studies based on the enrollment of a number of patients is required to carefully assess and confirm the safety and the efficacy of CAR-NK cell therapy in hematological malignancies and to compare their efficacy with respect to allogeneic CAR-T cells. Full article

Background/Objectives: Natural killer (NK) cells play a crucial role in tumor surveillance by exerting cytotoxic activity and modulating immune responses. However, tumors employ diverse evasion strategies that limit NK cell effectiveness. This review aims to explore the molecular mechanisms of NK cell activation and inhibition in cancer, the influence of the tumor microenvironment, and the latest advancements in NK cell-based immunotherapies, including adoptive NK cell transfer and Chimeric Antigen Receptor-Natural Killer (CAR-NK) cell therapies. Methods: A comprehensive literature review was conducted, prioritizing peer-reviewed studies from the last decade on NK cell biology, tumor immune evasion, and immunotherapeutic applications. The analysis includes data from preclinical models and clinical trials evaluating NK cell expansion strategies, cytokine-based stimulation, and CAR-NK cell therapy developments. Results: NK cells eliminate tumors through cytotoxic granule release, death receptor pathways, and cytokine secretion. However, tumor cells evade NK-mediated immunity by downregulating activating ligands, secreting immunosuppressive molecules, and altering the tumor microenvironment. Novel NK cell-based therapies, such as CAR-NK cells and combination approaches with immune checkpoint inhibitors, enhance NK cell persistence and therapeutic efficacy against both hematologic and solid malignancies. Clinical trials suggest improved safety profiles compared to CAR-T therapies, with reduced cytokine release syndrome and graft-versus-host disease. Conclusions: While NK cell-based immunotherapies hold great promise, challenges remain, including limited persistence and tumor-induced immunosuppression. Addressing these hurdles will be critical for optimizing NK cell therapies and advancing next-generation, off-the-shelf immunotherapeutics for broader clinical applications. Full article

The innate immune system plays an important role in protecting the organism via recognizing the danger signals and pathogens through pattern recognition receptors. By sensing the danger signal and conveying the signaling towards the elimination of the threat, several families of these receptors, expressed on different myeloid and innate lymphoid cells, serve as the first defense line in the innate immunity. Toll-like receptors, C-type lectin receptors, and many other receptors therefore illustrate the importance of the protective role of the immune system. This was additionally confirmed by CAR T-cell-based cancer immunotherapy, where the patient’s own immune system is being used for successful tumor elimination. CAR T-cells have proven themselves to be a potent therapeutic option, yet in some cases their efficiency could be enhanced. Innate immune sensors that include strong activation and signaling domains, for instance, part of the Toll-like receptors, MyD88 (Myeloid Differentiation Primary Response gene), NKG2D (Natural killer group 2-member D), and many other domains, could be used as a CAR building module to increase the functionality and potency of the CAR T-cells. Full article

Thoracic malignancies (lung cancers and malignant pleural mesothelioma) are prevalent worldwide and are associated with high morbidity and mortality. Effective treatments are needed for patients with advanced disease. Cell therapies are a promising approach to the treatment of advanced cancers that make use of immune effector cells that have the ability to mediate antitumor immune responses. In this review, we discuss the prospect of chimeric antigen receptor-T (CAR-T) cells, natural killer (NK) cells, T cell receptor-engineered (TCR-T) cells, and tumor-infiltrating lymphocytes (TILs) as treatments for thoracic malignancies. CAR-T cells and TILs have proven successful in several hematologic cancers and advanced melanoma, respectively, but outside of melanoma, results have thus far been unsuccessful in most other solid tumors. NK cells and TCR-T cells are additional cell therapy platforms with their own unique advantages and challenges. Obstacles that must be overcome to develop effective cell therapy for these malignancies include selecting an appropriate target antigen, combating immunosuppressive cells and signaling molecules present in the tumor microenvironment, persistence, and delivering a sufficient quantity of antitumor immune cells to the tumor. Induced pluripotent stem cells (iPSCs) offer great promise as a source for both NK and T cell-based therapies due to their unlimited expansion potential. Here, we review clinical trial data, as well as recent basic scientific advances that offer insight into how we may overcome these obstacles, and provide an overview of ongoing trials testing novel strategies to overcome these obstacles. Full article