Search Results (233)

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinomas and is defined by near-universal VHL inactivation, leading to constitutive HIF stabilisation, metabolic reprogramming, and an immunologically distinct tumour microenvironment (TME). Although ccRCC is characterised by abundant immune infiltration, this paradoxically correlates with poor prognosis, reflecting a TME that imposes interconnected physical, immunological, and metabolic barriers to effective immunotherapy. Chimeric antigen receptor (CAR)-based therapies have revolutionised the treatment of haematological malignancies, but their translation to ccRCC has encountered substantial hurdles. The first-in-human trial targeting carbonic anhydrase IX (CAIX) was limited by on-target off-tumour toxicity and CAR immunogenicity—lessons that fundamentally reshaped the field. CD70 has since emerged as the dominant clinical target, expressed in over 80% of ccRCCs with a highly restricted normal tissue distribution. The phase I COBALT-RCC trial of CTX130, an allogeneic CRISPR-Cas9-edited CD70-directed CAR-T cell product, provided formal proof of concept, achieving disease control in 81.3% of heavily pretreated patients and a durable complete response now exceeding three years—the first such sustained remission reported for any CAR-T cell product in a solid malignancy. Nevertheless, the low frequency of durable responses and universal loss of CAR-T cell persistence by day 28 underscore that major barriers remain. Beyond CD70, the field has diversified across multiple platforms, including CAR–natural killer (NK) cells, CAR–natural killer T (NKT) cells, and CAR–macrophages, each offering distinct biological advantages. This review synthesises current knowledge of the ccRCC TME, the preclinical landscape of CAR-based therapies, and emerging clinical evidence from more than 30 registered trials. We discuss target antigens; engineering strategies to overcome TME barriers, including cytokine armouring, chemokine receptor co-expression, switch receptors, and metabolic reprogramming; and rational combination approaches. We argue that the convergence of optimised target selection, cellular engineering, combination strategies, and biomarker-driven trial design may ultimately improve outcomes for patients with ccRCC. However, achieving a cure remains an aspirational goal, and significant barriers must first be overcome. Full article

Medulloblastoma is one of the most prevalent pediatric brain tumors. Currently, existing therapies for this devastating type of cancer can only prolong survival time with severe side-effects and relapse. These therapies are not curative for almost a third of treated patients, while most survivors are condemned to a poor quality of life. The addition of immune checkpoint inhibitors (ICIs) to immune therapy has given some hope to those suffering from this type of cancer. Although ICIs provide a valuable contribution to immunotherapy, the exploitation of immune checkpoint inhibition within existing therapeutic strategies to cure Medulloblastoma remains understudied. However, the identification of the main molecular subgroups of medulloblastoma is considered one of the success stories of oncology. This advancement in molecular profiling of MB paved the way to subgroup-directed clinical trials, which may lead to efficacious immune-targeted therapy. However, this relatively new development is still hampered by a substantial biological heterogeneity of the disease and the absence of a full understanding of the various mechanisms behind its resistance to existing therapeutic modalities. The inclusion of chimeric antigen receptor (CAR) T and CAR NK cell therapy within various therapeutic strategies and ongoing clinical trials has given fresh hope those suffering from this fatal disease. However, ongoing clinical trials suggest that this highly promising therapy can be impaired by a number of serious limitations, including cytokine release syndrome, Graft-versus-host disease, the scarcity of target antigens, and severe adverse events. Some of the ongoing clinical trials also suggest that CAR NK is less prone to some of these limitations. This review also highlights the contribution of mass spectrometry-based proteomics, and the increasing role of liquid biopsy rather than tissue biopsy. Full article

Background: Cutaneous melanoma (CM) is a highly immunogenic malignant neoplasm. It features high mutational burden and intense lymphocytic infiltration, supporting the use of immunotherapies, especially inhibitors of the programmed cell death protein 1 (PD-1) checkpoint. Despite advances with anti-PD-1 therapies, such as nivolumab and pembrolizumab, many patients still experience resistance. This result highlights additional immunosuppressive mechanisms within the tumor microenvironment (TME) that limit T-lymphocyte-mediated responses. Objectives: The aim was to discuss the immunologic and metabolic bases of PD-1- and CD73-mediated pathways and evidence that CD73 inhibition can boost PD-1 inhibitor efficacy by acting on convergent immunosuppressive pathways. Methods: We conducted a narrative literature review focusing on tumor immunosuppression, purinergic signaling and checkpoint inhibitor-based immunotherapy. Results: The purinergic pathway, mediated by the ectonucleotidase CD73, is a critical regulator of tumor immunosuppression. CD73 converts extracellular adenosine monophosphate (AMP) into adenosine. This adenosine accumulates in the hypoxic and inflamed TME, exerting immunosuppressive effects. Adenosine acts as a “metabolic brake,” inhibiting proliferation, cytokine production, and cytotoxic activity of CD8⁺ T lymphocytes and natural killer (NK) cells. It also promotes the expansion of regulatory T cells (Tregs) and tumor progression. This axis may limit responses to PD-1 blockade, suggesting that complementary pathways are active. Conclusions: Integration of PD-1 and CD73 pathways suggests that CD73 inhibition may enhance PD-1 blockade by targeting convergent immunosuppressive mechanisms. This supports the exploration of combination strategies to broaden the benefits of immunotherapy in CM. Full article

Natural killer (NK) cells are increasingly recognized as a complementary platform to T-cell-based cancer immunotherapies. Their innate, MHC-unrestricted recognition, capacity to mediate antibody-dependent cellular cytotoxicity (ADCC) and comparatively favorable toxicity profile have given rise to a broad therapeutic pipeline that includes cytokine-supported regimens, adoptive NK products, bispecific and trispecific NK engagers, and chimeric antigen receptor (CAR)-engineered NK cells. Clinical data, particularly in hematologic malignancies, show that NK-cell-based strategies can be safe and biologically active, although limited persistence, suboptimal trafficking and immune escape remain key challenges. Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV)-driven epithelial cancer, illustrates how a tumor microenvironment (TME) can simultaneously impair NK function and create specific vulnerabilities that NK-focused therapies can exploit. This review summarizes NK biology and current therapeutic platforms, analyzes major limitations, highlights the specific context of NK-cell-based strategies in NPC and compares NK- and T-cell-based therapies with an emphasis on clinical translation. Full article

In recent years, the feasibility of immunotherapy targeting activated fibroblasts in pulmonary fibrosis has received further support. Recent studies have shown that transient FAP-targeted immunotherapy can alleviate pulmonary fibrosis by eliminating excessively activated fibroblasts, improving the aberrant extracellular matrix environment, and promoting alveolar cell lineage remodeling, suggesting that FAP-associated pathological stromal cells are amenable to therapeutic intervention. Based on this, research on FAP-centered engineered cell therapies is being gradually extended from settings such as myocardial fibrosis to pulmonary fibrosis. In this context, primary human NK cells represent a promising effector cell platform, as they are generally associated with a lower risk of severe treatment-related toxicities and relatively limited in vivo persistence, which may confer a more controllable therapeutic window. This feature is particularly important in fibrotic diseases, because long-term and continuous depletion of fibroblast populations may disrupt tissue homeostasis and injury repair. In addition, current studies of FAP-targeted CAR-NK therapy have mainly relied on NK cell lines such as NK-92, but these systems may not fully reflect the functional characteristics, receptor signaling, or clinical potential of primary human NK cells. Based on these considerations, it is necessary to develop a FAP-targeted cell therapy platform with greater clinical relevance for pulmonary fibrosis. In this study, we established a primary human FAP-CAR-NK-cell platform and conducted a proof-of-concept evaluation in pulmonary fibrosis-related models, including in vitro systems, a human pulmonary fibrosis-like organoid model, and an acute in vivo observation model. The main novelty of this study lies in the use of primary human NK cells for FAP-targeted intervention in pulmonary fibrosis-related models. We focused on whether these engineered cells could selectively target and eliminate FAP-positive activated fibroblasts, retain effector function in a fibrotic microenvironment, and show short-term feasibility after adoptive transfer. The study was not intended to assess long-term therapeutic efficacy or systemic safety, but rather to examine the feasibility of FAP-directed fibroblast targeting by primary human CAR-NK cells in pulmonary fibrosis and to provide a basis for further preclinical investigation. Full article

Natural killer (NK) cells are promising effectors for cancer immunotherapy, as they can recognize and eliminate tumor cells without prior antigen sensitization. However, insufficient tumor recognition remains a critical limitation that reduces the anticancer efficacy of NK cells against solid tumors. To address this limitation, we developed a lipid-mediated cell membrane engineering strategy to enhance the targeting and cytotoxic efficacy of NK cells toward solid tumors, particularly ovarian cancer cells. In this strategy, poly-L-glutamic acid (PLE) was employed as an ovarian cancer-targeting module due to the specific affinity of PLE for cholesterol-rich membrane domains. To display PLE on NK cells, a lipid moiety is incorporated to anchor PLE onto the NK cell membrane via hydrophobic insertion, enabling rapid and non-genetic surface modification. As a result, the surface-engineered NK cells with PLE-Lipid (i.e., PLE-NK) displayed PLE on the NK cell surface, allowing direct recognition of ovarian cancer cells without compromising the intrinsic properties of NK cells. This enhanced recognition subsequently increased NK–cancer cluster formation by promoting interactions between membrane-presented PLE on NK cells and cholesterol on ovarian cancer cells. Consequently, PLE-NK cells exhibited enhanced cytotoxicity against ovarian cancer cells (i.e., OVCAR-3 cells) and effectively disrupted 3D tumoroids, while PLE-NK cells showed no off-target effects on normal fibroblasts. Collectively, these findings demonstrate that PLE-Lipid-mediated NK surface engineering provides a simple and effective strategy to improve the tumor targeting ability of NK cells and offers a promising platform for NK cell-based immunotherapy against ovarian cancer. Full article

Pancreatic ductal adenocarcinoma (PDAC) has high mortality rates, poor prognosis, and currently limited effective treatments. Natural killer (NK) cells from tumor-infiltrating lymphocytes (TIL) show promise for cancer treatment due to their ability to migrate to the tumor microenvironment (TME) and safe profile. However, expanding functional patient-derived NK cells remains challenging. Here, we cultured, expanded, and characterized TIL-NK cells isolated from central and peripheral tumor regions from PDAC. Ex vivo patient-derived PBMCs and TIL were cultured under IL-2, IL-15, and IL-12 stimulation. Phenotypical and functional NK cell characterization was assessed at the time of surgery and after 12 days of culture evaluating immunophenotype, expansion rate, and activation. A distinct distribution of NK cell infiltration was observed within the TME, with higher NK cell numbers in the periphery of the tumor compared to the central area. Most NK cells displayed a cytotoxic phenotype (CD56⁺ CD16⁺). Compared to PBMCs, TIL-NK cells expressed lower activation markers but superior tumor infiltration and expansion rates, particularly those isolated from the central regions. Notably, cytokine stimulation improved patient-derived NK cell activation and cytotoxic profile. This pilot study provides preliminary but critical insights regarding TIL-NK cells from PDAC patients, laying groundwork for developing NK cell-based immunotherapies for solid tumors. Full article

The treatment of chronic lymphocytic leukemia (CLL) has significantly shifted from chemoimmunotherapy to targeted therapies like Bruton’s tyrosine kinase and BCL2 inhibitors. Despite these advancements, CLL remains an incurable disease characterized by immune dysregulation, therapeutic resistance, and cumulative toxicities. To overcome these challenges, novel immunotherapeutic strategies are emerging as fundamentally different approaches that target immune–tumor interactions. These innovations include novel monoclonal antibodies, bispecific antibodies that redirect T cell cytotoxicity, chimeric antigen receptor (CAR) T-cell therapies, and natural killer (NK) cell-based platforms. By actively engaging cellular cytotoxicity, these approaches show promise in high-risk and treatment-resistant scenarios where standard pathway inhibition is inadequate. Establishing optimal use, toxicity management, and combination strategies for these cell-engaging immunotherapies is now a critical priority in contemporary CLL research. Full article

Background: The chemokine CCL5 exhibits a complex role in cancer immunotherapy, yet its dual immunomodulatory functions in non-small cell lung cancer (NSCLC) remain poorly understood. Methods and Results: Based on a newly analyzed clinical cohort of 33 advanced NSCLC patients receiving anti-PD-1 therapy combined with platinum-based chemotherapy, we found that elevated baseline peripheral blood CCL5 levels significantly predicted shorter overall survival (27.6 months vs. not reached, HR = 2.779, p = 0.038) and a higher incidence of immune-related pneumonitis (p = 0.0072). These clinical observations were supported by the re-analysis of a previously published single-cell RNA sequencing (scRNA-seq) dataset (n = 8), which indicated that high CCL5 expression in peripheral blood T/NK cells was associated with a lower major pathological response (p = 0.029). To explore the underlying mechanisms, we conducted detailed analyses using a large, publicly available tumor scRNA-seq dataset (GSE243013, n = 234). These analyses revealed that high intratumoral CCL5 simultaneously promoted the recruitment of both immune effector cells (CD8⁺ T cells, NK cells) and immunosuppressive populations (Tregs, MDSCs). This paradoxical immune landscape correlated with elevated immune checkpoint expression and significantly higher TIDE scores (1.47 vs. 0.83, p < 0.001). CellChat and SCENIC network analyses identified intensified T cell–myeloid communication and key transcription factors (e.g., FOXP3, EOMES) mediating this dichotomy. Conclusions: This hypothesis-generating study raises the possibility that CCL5 orchestrates paradoxical immune responses and may serve as a biomarker in NSCLC. Further validation in larger prospective, independent cohorts is required. Full article

Background/Objectives: High-risk neuroblastoma (HR-NB) is a major cause of cancer-related death among children. The review aims to discuss various biochemical and genetic traits of neuroblastoma (NB) used for the potential of cell-based therapies. Methods: A comprehensive search was performed through MEDLINE, PubMed, Scopus, and ScienceDirect using various combinations of “neuroblastoma”, “tumor microenvironment (TME)”, “immune cells”, “non-immune cells”, “hematopoietic stem cell transplantation (HSCT)”, “autologous stem cell transplantation (ASCT)”, “natural killer cells (NK)”, “chimeric antigen receptor T cells (CAR-T)”, “CAR-NKT”, “tumor infiltrating lymphocytes (TIL)”, “bioinformatics”, and “neuro-antigens” in the published papers over the last decade. Reviews, systematic reviews, and clinical trials related to children’s NB were selected. The final set included 106 articles of interest. Results: Recent studies have shown that TME is crucial in determining the malignancy, immune evasion, and drug resistance of NB. Innate immune or non-immune cells play important roles in shaping the NB TME. Depleting or reprogramming TME factors can improve the effectiveness of immunotherapy. A number of clinical trials have studied and showed feasibility of using ASCT, NK cells, CAR-T, and CAR-NKT cells in the adoptive therapy for HR-NB. However, an unambiguous evaluation of the effectiveness of cell-based technologies in the HR-NB therapy is still complicated due to the lack of large randomized trials. Conclusions: The reported small and non-randomized studies that demonstrated controversial results cannot prove, undoubtedly, the promising potential of the cell-based technologies including ASCT, NKs, CAR-T, and CAR-NKT cells. Further randomized clinical trials, using the same treatment, will help determine the role in the multimodal treatment for HR-NB. Full article

Cancer immunotherapy has recently become an essential approach for treating cancer, showing considerable promise as a substitute for surgery, radiation therapy, and conventional chemotherapy. It primarily aims to boost the host’s natural defense system to combat cancer malignancies by utilizing components of immune checkpoint blockades (ICBs), mainly programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), along with elements of adoptive cellular therapies (ACTs) like Chimeric Antigen Receptor (CAR) therapy, T Cell Receptor (TCR) therapy and Tumor-Infiltrating Lymphocyte (TIL) therapy. However, cancer cells tend to undermine the effectiveness of cancer immunotherapeutic strategies by employing one or more immune evasion mechanisms. This review briefly highlights how key mechanisms of cancer immune evasion confer resistance to immunotherapy and how the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR)/Cas9 systems, as gene-editing tools, are poised to enhance cancer immunotherapy for treating challenging cancers. We emphasize that (CRISPR/Cas9) systems can be used to explore and positively alter the genes of the immune system, boosting the effectiveness of cancer immunotherapy by editing immune checkpoints, TILs, and CAR-T cells, and disrupting genes, facilitating tumors’ evasion of the immune system. Furthermore, we highlight the growing interest in emerging base editor technology to engineer natural killer (NK) cells to overcome NK-cell-based immunotherapy challenges, particularly human leukocyte antigens (HLA)-mediated limitations, and to engineer CAR-T cells for improved immunotherapy outcomes. Full article

Wilms tumor (WT) is the most common malignant renal tumor in childhood and represents one of the major success stories of pediatric oncology, with very good survival achieved through risk-adapted multimodal therapy. Nevertheless, a subset of patients—particularly those with diffuse anaplasia, blastemal-type tumors persisting after chemotherapy, or relapsed disease—continues to experience poor outcomes and significant long-term treatment-related morbidity. These challenges highlight the need for novel therapeutic strategies beyond conventional cytotoxic approaches. Growing evidence indicates that WT is characterized by a complex and distinctive tumor microenvironment (TME) shaped by its developmental origin and triphasic histology. Immune cell infiltration, inflammatory mediators, and immune checkpoint pathways interact differently with blastemal, epithelial, and stromal tumor components, generating heterogeneous immune surveillance and escape mechanisms. In particular, tumor-associated macrophages (TAMs), functionally impaired natural killer (NK) cells, and immunosuppressive stromal elements play a central role in shaping an immune milieu that may limit the efficacy of immune-based therapies. Although immunotherapy has changed the management of several adult malignancies and some pediatric cancers, its translation to WT has so far been limited, with modest results in unselected patient populations. Recent immunogenomic and proteogenomic studies, however, suggest the existence of biologically distinct WT subsets with different immune features and potential susceptibility to targeted immunotherapeutic approaches. This narrative review integrates pathological, immunological, and clinical perspectives to summarize current knowledge on the WT immune microenvironment, mechanisms of tumor immune evasion, and emerging immunotherapeutic strategies. By providing a unified framework, it aims at supporting a multidisciplinary approach for the rational development of future immune-based and combination therapies tailored to specific WT subgroups. Full article

Invariant natural killer T (iNKT) cells are a unique lymphocyte subset that bridge innate and adaptive immunity through recognition of glycolipid antigens presented by CD1d. Upon activation by ligands such as α-galactosylceramide (α-GalCer), iNKT cells rapidly secrete cytokines, including IFN-γ and TNF-α, thereby activating dendritic cells, natural killer (NK) cells, and cytotoxic T lymphocytes (CTLs) to promote antitumor immunity. Despite their therapeutic promise, clinical translation has been limited by rapid α-GalCer clearance, induction of iNKT cell anergy following repeated stimulation, and the immunosuppressive tumor microenvironment (TME). Recent advances in lipid-engineered nanoparticle systems offer solutions to these challenges by improving ligand stability, enhancing antigen-presenting cell targeting, and enabling controlled release that sustains Th1-biased activation while reducing anergy. Liposomal and polymer-based nano-formulations enhance bioavailability and promote more durable IFN-γ-mediated responses. In parallel, chimeric antigen receptor (CAR)-engineered iNKT cells provide antigen-specific tumor targeting while preserving intrinsic CD1d-restricted immunomodulatory functions, demonstrating encouraging safety and efficacy in early-phase studies. Combination strategies further strengthen iNKT-based immunotherapy. Integration with chemotherapy, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4, and cytokine support enhances effector activation, counteracts TME-induced suppression, and improves therapeutic outcomes. However, challenges remain, including optimization of dosing, control of off-target immune activation, scalable manufacturing, and long-term safety evaluation. Collectively, the convergence of nanotechnology, CAR engineering, and rational combination approaches establishes iNKT cell-based therapy as a promising next-generation immunotherapeutic strategy. Continued refinement of delivery systems, genetic engineering platforms, and translational protocols may enable durable immune reprogramming and improved clinical outcomes in resistant and immunosuppressive cancers. Full article

Cancer immunotherapy has revolutionized the treatment of cancer by harnessing the immune system to recognize and destroy malignant cells. However, a substantial proportion of patients exhibit primary or acquired resistance to these therapies, underscoring the urgent need to identify novel molecular targets to enhance therapeutic efficacy. Autophagy, an evolutionarily conserved cellular process of degradation and recycling, has emerged as a critical modulator of tumor immunity and the function of immune cells. In cancer cells, autophagy modulates antigen presentation, immunogenic cell death, metabolic reprogramming, and resistance to immune-mediated cell death. Concurrently, autophagy rigorously governs the viability, differentiation, and functional capacity of immune cells, including T cells, dendritic cells, macrophages, and natural killer (NK) cells. Dysfunctional autophagic flux in the tumor microenvironment can enhance immune evasion and limit the efficacy of immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. In this review, we provide an in-depth analysis of emerging molecular targets involved in the regulation of autophagy relevant to cancer immunotherapy. This includes key signaling pathways such as PI3K/AKT/mTOR, AMPK, Beclin-1 complexes, ULK1, and lysosomal regulators. Additionally, we explore the rational integration of the pharmacological modulation of autophagy, including small molecules, natural compounds, and nanoparticle-based drug delivery systems, with immunotherapeutic approaches. We highlight the importance of rational drug selection and combination therapies to overcome resistance to immunotherapy and minimize toxicity. Understanding the context-dependent role of autophagy will be essential for the development of next-generation, precision-targeted cancer immunotherapies. Therefore, a comprehensive understanding of the context-specific functions of autophagy in tumor and immune cells is crucial for devising precision-targeted combination methods that overcome immunotherapy resistance and produce more sustainable cancer treatment outcomes. Full article

Cancer immunotherapy has experienced substantial progress in recent years, particularly with the advancement of chimeric antigen receptor (CAR) technology, which enables immune cells to selectively target tumor-associated antigens. CARs, now in their fifth generation, are engineered by combining monoclonal antibody fragments with signaling and co-stimulatory domains and have been successfully applied to T cell, natural killer (NK) cell, and macrophage-based therapies. Notable clinical successes, such as tisagenlecleucel and lisocabtagene maraleucel underscore the therapeutic potential of CAR-T, CAR-NK and CAR-macrophages (CAR-Ms), which are currently being evaluated in numerous clinical trials. One promising extension of this approach involves the use of extracellular vesicles (EVs) derived from these immune cells. These nano-sized vesicles offer a cell-free platform to deliver diverse anticancer mediators, addressing the complex and dynamic nature of tumor environments. In this review, we examine the therapeutic potential and immunogenic properties of CAR-derived EVs, along with their role in modulating immune responses. Furthermore, we explore their application as targeted delivery vehicles for chemotherapeutic agents, with the goal of enhancing anti-tumor efficacy while minimizing systemic toxicity. Full article