Search Results (1,259)

Background: For almost two decades now, chimeric antigen receptor-natural killer cells (CAR-NK) have been investigated in pre-clinical breast cancer models, yet clinical evidence on efficacy remains scarce. This meta-analysis provides pooled evidence of pre-clinical CAR-NK effectiveness and safety in breast cancer and an overview of current clinical trials to support clinical translation. Methods: Following PRISMA guidelines and a registered protocol (PROSPERO, CRD420251131530), PubMed, Web of Science, and Scopus were searched up to 30 June 2025 for pre-clinical CAR-NK studies in breast cancer. Clinical studies were retrieved from clinicaltrials.gov and the International Clinical Trial Registry Platform (ICTRP) up to 1 March 2026. Pre-clinical studies without in vivo data or non-human CAR-NK cells were excluded. Primary outcomes were tumor burden (ratio of means, ROMs) and survival (median survival ratio, MSR). Data were analyzed in JASP™ and risk of bias (RoB) was assessed using SYRCLE’s tool. Results: Fourteen pre-clinical studies (38 CAR-NK treatment groups targeting EGFR, HER2, tissue factor, CD70, mesothelin, or folate receptor, with peripheral blood as the primary NK source, and a 5–10 million cell dose) and 11 early-phase clinical studies (targeting HER2, TROP2, PD-L1, MUC1, or NKG2D ligands under ongoing investigation) were included. In pooled pre-clinical analysis, CAR-NK significantly reduced tumor burden against untreated and unmodified/mock controls (ROM 0.311 [0.22–0.44] and 0.42 [0.33–0.53], p < 0.001, respectively). Survival was also prolonged significantly (MSR 1.47 [1.15–1.87], p = 0.010 vs. untreated; 1.30 [1.09–1.60], p = 0.007 vs. unmodified/mock NK cells). Subgroup analyses indicated improved efficacy with peripheral blood source and 5–10 M dosing. No treatment-related toxicities were reported. CAR-NK persistence was generally higher than unmodified/mock NK cells. Discussion and Conclusions: Significant heterogeneity was observed in ROM analysis which the multi-level meta-analysis configured as intra-study interventional variability. There was moderate RoB in pre-clinical studies. Published results from clinical trials remain limited, highlighting early stages of investigation. Overall, CAR-NK therapy demonstrated consistent pre-clinical efficacy and safety, supporting further translational and clinical evaluation in breast cancer. 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

Living therapies, including chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), and bacteria-based platforms, are emerging as promising approaches in cancer treatment because they can directly target tumors and modulate anti-tumor immunity. This narrative review summarizes current knowledge on these therapies, focusing on their mechanisms of action, therapeutic applications, major limitations, and recent advances in genetic engineering, synthetic biology, and delivery systems. CAR-T cell therapy has shown substantial clinical success in hematological malignancies through the genetic redirection of T cells against tumor-associated antigens, although its efficacy in solid tumors remains limited by antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). OVs selectively infect and lyse malignant cells while also stimulating local and systemic immune responses, and engineered OVs may further enhance therapeutic activity by reshaping the TME. Bacteria-based therapies exploit the natural tumor-targeting ability of selected strains, particularly in hypoxic regions, to deliver therapeutic agents and activate immune responses. Despite encouraging progress, safety concerns, immune-related barriers, and tumor complexity remain major challenges. Overall, integrating living therapies with modern biotechnological advances and existing treatment modalities may support more personalized and synergistic strategies for cancer management. Full article

Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and eliminate malignant cells. However, many cancers exhibit limited or variable responses to this class of treatment due to insufficient antigen presentation and impaired interferon (IFN) signaling, creating an immunologically “cold” tumor microenvironment (TME) characterized by poor immune cell infiltration and treatment resistance. Viral mimicry has emerged as a therapeutic strategy to overcome these limitations by reactivating innate antiviral pathways within tumor cells. Viral mimicry occurs through the reactivation of endogenous retroviruses (ERVs) and other retrotransposons (e.g., LINE-1), which subsequently stimulate downstream nucleic acid sensing pathways. The resulting type I/III IFN responses restore antigen presentation and attract cytotoxic immune cells, sensitizing resistant tumors to immunotherapy. However, systemic stimulation of these pathways can trigger context-dependent inflammation and adaptive resistance, highlighting the need for temporal and spatial control. In this review, we examine the mechanistic foundation and clinical trajectory of viral mimicry, with an emphasis on its potential integration with established treatments and engineered immune cell platforms. By identifying the molecular and clinical gaps, viral mimicry can be harnessed to enhance tumor-specific immune activation and overcome treatment resistance in cancer immunotherapy. Full article

Chimeric antigen receptor (CAR) T-cell therapy represents a major advance in modern immunotherapy. This narrative review summarizes evidence from the past five years, including case reports, case series, and clinical trials, on its application beyond hematologic malignancies, focusing on autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), as well as solid tumors including melanoma and primary cutaneous lymphomas. CD19-directed CAR T-cells have demonstrated clinical benefits in SLE and SSc, with sustained immune reset, reduced autoreactive antibody levels, and clinical improvement. In melanoma, CAR T-cells targeting GD2, cMET, and CD20 have shown in vivo expansion and tumor infiltration; however, clinical efficacy remains limited, with transient stabilization or disease progression in most patients. In primary cutaneous lymphomas, early-phase studies with anti-CD70 and anti-CCR4.30 CAR T-cells indicate partial tumor regression and disease stabilization, often requiring additional therapy. Key challenges include limited durability of immune reset due to persistent plasma cells in autoimmune disorders, tumor heterogeneity, antigen loss or overlap, infiltration barriers, resistance mechanisms, and T-cell depletion in solid tumors, collectively reducing response durability and safety. The main toxicities include grade 1–2 cytokine release syndrome and rare hematologic complications, while immune effector cell-associated neurotoxicity syndrome is uncommon. Clinical translation remains limited and requires larger studies to improve efficacy and define safety profiles. Full article

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is constrained by advanced age, comorbidities, unavailable donor, and transplant-related risks. Therefore, the development of disease-modifying therapeutic strategies has become a central focus in MF research. Chimeric antigen receptor T (CAR-T)-cell therapy has demonstrated robust efficacy across various hematologic malignancies. Its application in MF holds the potential not only to selectively eliminate malignant hematopoietic clones but also to modulate the immunosuppressive and profibrotic microenvironment through advanced cellular engineering, thereby enabling a dual therapeutic paradigm involving both clonal control and microenvironmental reprogramming. In this context, potential targets and pathways include CD123, myeloproliferative leukemia protein (MPL), fibroblast activation protein (FAP), the TGF-β signaling axis, the CXCR4–CXCL12 niche-regulatory axis, and molecules associated with myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Future strategies may optimize both efficacy and safety through combinatorial approaches, including integration with JAK inhibitors, development of armored CAR-T constructs, and bridging to hematopoietic stem cell transplantation. Collectively, CAR-T-cell therapy offers a promising avenue for shifting MF management from symptomatic control toward true disease modification. Full article

CD19-chimeric antigen receptor (CAR) has shown promising outcomes in B-cell malignancies. However, relapses due to poor CAR-T persistence and antigen escape have occurred. CD37 is a potential alternative immunotherapy for CD19⁻ tumors. Inferior CAR-T cytotoxicity was observed in CD37CAR-T compared to CD19CAR-T model that was possibly due to lower CD37CAR affinity. To alleviate CD37CAR functions, we optimized the most prevalent linkers, Whitlow (18aaL) and glycine–serine (GS4L). CD37.GS4L CAR-T showed higher transduction efficiency and T-cell expansion contributed by minimizing T-cell fratricide. In chronic antigen stimulation, CD37.GS4L CAR demonstrated robust T-cell proliferation while preserving stemness and a decrease in induced exhaustion phenotype, which resulted in greater tumoricidal activity among various CD37⁺ malignancies. In silico analysis showed that CD37.GS4L scFv altered structural dynamic behaviors by facilitating variable heavy-chain region closer to CD37 receptor with higher binding affinity and less aggregation of negatively charged protein, which contributed to lower tonic signaling during CAR activation and diminished exhaustion. Ultimately, effective anti-tumor control with notable memory T-cell persistence was exhibited in Burkitt lymphoma mice treated with CD37.GS4L CAR-T. Additionally, CD37.GS4L CAR-T illustrated the potential in vivo cytotoxicity in myeloma-inoculated mice. In summary, the flexibility and affinity of glycine–serine linker of CD37CAR can potentiate CAR-T functionality. Full article

Difficult-to-treat systemic lupus erythematosus (D2T-SLE) remains a major unmet challenge in contemporary lupus care, yet it continues to be defined predominantly by clinical non-response rather than underlying biology. Current biomarkers largely quantify inflammatory burden, immune complex activity, or organ damage and do not reliably capture persistent activation of pathogenic pathways under therapy. Emerging multi-omics, single-cell, and longitudinal studies suggest that, in a subset of patients, apparent treatment failure may reflect incomplete attenuation of dominant immune circuits rather than uniformly elevated inflammation. We propose molecular refractoriness in systemic lupus erythematosus (SLE) as sustained, pathway-level immune activity despite apparently adequate, mechanism-directed therapy. We outline the major immune programs implicated in this process—including interferon-enriched, B-cell/plasmablast-associated, neutrophil extracellular trap (NET)-related, cytotoxic T-cell, and cytokine-associated states—and discuss their relevance for biomarker development and precision trial design. Importantly, we emphasize that interferon gene signatures (IGS) should be interpreted as context-dependent and non-specific markers of interferon responsiveness, reflecting combined activity of type I, II, and III interferons, and functioning primarily as predictive rather than mechanistic biomarkers. We further highlight critical limitations of a purely endotype-based model, including the need to distinguish true molecular refractoriness from damage-dominant and pseudo-refractory states, as well as the emerging role of immune-reset strategies such as cluster of differentiation 19 (CD19)-directed chimeric antigen receptor T-cell (CAR-T) therapy, which may overcome refractoriness independently of specific pathway dominance. These observations suggest that difficult-to-treat SLE encompasses biologically heterogeneous states that may not be fully captured by pathway-resolved stratification alone. Reframing D2T-SLE as a biologically heterogeneous state of incomplete immune attenuation may help bridge the gap between clinical treatment failure and mechanism-informed precision medicine in systemic lupus erythematosus. Full article

Renal cell carcinoma (RCC) is acknowledged as a heterogeneous malignancy underlined by complex genetic, metabolic, and immune dysregulation. In particular, molecular studies have revealed distinct oncogenic mechanisms that have been exploited and studied as therapeutic intervention targets. These include hypoxia-driven signaling, chromosomal translocations, and gene fusion events that affect tumor progression. This review provides a comprehensive overview of these targets and rethinks RCC management. Therapeutic concepts include the targeting of genomic fusion biology with emerging cell-based immunotherapies or targeted molecular inhibition, and orthomolecular therapeutic strategies are presented. Two clinical and pathological features are highlighted—namely, the TFE3 fusion proteins in translocation RCC and the growing role of hypoxia-inducible factor-2α (HIF-2α) inhibitors in clear-cell RCC. We also present recent data on novel immunotherapeutic approaches, including autologous hematopoietic stem and progenitor cell-based interferon-α gene therapy, as well as chimeric antigen receptor T-cell therapy. These therapies are discussed in light of their mechanistic rationale, translational potential, and existing clinical challenges due to unwanted side effects. At last, orthomolecular and natural product-based therapies are reviewed for their potential as adjunctive therapies that might be used for oxidative stress management, the targeting of tumor metabolism and immune effects, and to increase standard treatment tolerance. This review points to a multidimensional framework that might support further research and studies in precision-guided RCC management, as integrative approaches may enhance therapeutic efficacy, reduce toxicity, and support the development of personalized interventions for advanced or treatment-resistant RCC. Full article

Background: Chimeric antigen receptor (CAR) T cells achieve cure in the therapy of hematological malignancies. In solid tumors, however, CAR-T cells face an immunosuppressive tumor microenvironment (TME) which crucially impedes their cytotoxic capacities. Citrate accumulating in the TME is a crucial metabolite in mediating immune suppression and is consumed by cancer cells promoting growth of various tumors, including melanoma; blocking the citrate transporter pmCiC with gluconate abrogates citrate-mediated tumor growth. Methods: To bolster treatment of melanoma, we explored gluconate as adjuvant for CAR-T cell therapy. Results: First, gluconate did not impair CAR-T cell functional capacities with regard to cytotoxicity, cytokine secretion, and persistence in a “stress test” based on repetitive antigen stimulation with cognate cancer cells. The addition of gluconate antagonized the citrate-mediated enhanced proliferation of melanoma cells. As a consequence, the elimination of citrate-boosted melanoma cells by CSPG4-specific CAR-T cells was augmented in the presence of gluconate. Conclusions: Taken together, these data suggest that counteracting citrate-mediated enhanced tumor growth with gluconate may improve the cytotoxic activity of CAR-T cells against melanoma. Full article

Hematologic malignancies arise and progress within a systemic ecosystem in which the gut microbiota is an increasingly recognized, partially modifiable component. Across acute leukemias, chronic lymphocytic leukemia, plasma cell disorders, lymphomas, and clonal myeloid neoplasms, human studies consistently report reduced microbial diversity, depletion of barrier-supportive, short-chain fatty acid-producing commensals, and enrichment of Gram-negative, pro-inflammatory, or hospital-adapted taxa. These alterations are associated with pre-leukemic clonal expansion, adverse genetic and immunological features, progression from precursor conditions, and inferior outcomes after chemotherapy, immunochemotherapy, chimeric antigen receptor T-cell therapy, and allogeneic hematopoietic stem cell transplantation. Mechanistic work in animal models and ex vivo systems demonstrates that microbiota-derived signals and metabolites—including Th17/IL-17-skewing consortia and the lipopolysaccharide intermediate ADP heptose sensed by the cytosolic receptor ALPK1—can actively modulate hematopoietic stem and progenitor cell fitness, inflammatory circuits, and malignant cell survival, supporting a causal role in disease biology. At the same time, major knowledge gaps remain because most human cohorts are small, single-center, and cross-sectional, frequently rely on 16S rRNA profiling, and are vulnerable to dietary, geographic, and treatment-related confounding. Within this context, three translational domains appear particularly promising: pharmaco-microbiomics, microbiome-informed risk stratification, and rational microbiota-targeted interventions, particularly diet-based strategies and antimicrobial stewardship. Here, we provide an integrated, disease-spanning synthesis of these data, emphasizing clonal hematopoiesis and myeloid neoplasms as emerging examples of microbiota–marrow crosstalk and outlining practical priorities for embedding microbiome science into future hematologic trials. Routine microbiome profiling or empiric microbiota-directed therapies cannot yet be recommended in everyday hematology practice, but integrating microbiome science into prospective therapeutic and transplant trials offers a realistic path to improved disease modeling, biomarker development, and rational adjunctive strategies to enhance outcomes for patients with hematologic malignancies. Full article

Background/Objectives: Chimeric antigen receptor (CAR) T cell therapy has profoundly transformed the cancer treatment landscape, achieving unprecedented clinical success in patients with hematological malignancies. However, challenges such as cytokine release syndrome, neurotoxicity, antigen escape, and limited efficacy in solid tumors remain, underscoring the need for robust preclinical modeling to evaluate novel CAR T cell products. Methods: This review provides a comprehensive overview of in vitro and in vivo preclinical modeling for CAR T cell functionality and toxicity assessment. We examine traditional experimental approaches and their limitations, discuss emerging technologies, and highlight how these strategies can be integrated to advance future CAR T cell therapies. Results: In vitro assays provide insights into efficacy but fail to model trafficking, dynamic immune cell interactions, and complex tumor microenvironments. In vivo mouse models allow for more complex physiological evaluation but are limited by species differences. Next generation platforms, such as patient-derived tumor organoids and organ- or multi-organ-on-a-chip microfluidics are emerging as potential tools to model CAR T cell therapy in physiologically relevant contexts and computational approaches are being increasingly used to develop novel CAR designs and predict patient responses. Conclusions: By integrating traditional experimental approaches with innovative technologies, the CAR T cell field is poised to generate more clinically relevant and predictive data thereby accelerating the development of safer, more effective, and personalized CAR T cell therapies. Full article

Chronic inflammatory diseases and autoimmune diseases are overlapping but distinct immune-mediated disorders that represent a growing worldwide health concern, characterised by persistent inflammation, tissue damage, and progressive organ dysfunction. In the United States alone, more than $180 billion is spent annually on managing these conditions, yet fewer than 10% of patients achieve long-term remission. These figures highlight the limitations of conventional therapies, which often control symptoms rather than adequately modify the underlying disease process. This review provides a focused and comparative overview of emerging therapeutic strategies across representative immune-mediated disorders, with particular emphasis on mesenchymal stem cells, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, chimeric antigen receptor T-cell therapies, therapeutic vaccines, microbiome-modulating interventions, and nanotechnology-based drug delivery systems. In parallel, artificial intelligence (AI) is increasingly contributing to biomarker discovery, drug repurposing, and treatment stratification, thereby supporting the development of predictive and personalised medicine. Overall, these advances support a shift toward mechanism-based, multimodal, and more durable treatment strategies, although further clinical validation remains necessary. Full article

Glypican-3 (GPC3)-targeted chimeric antigen receptor T (CAR-T) cell therapy is a promising approach for hepatocellular carcinoma (HCC), but marked interpatient variability and antigen heterogeneity limit its broader application. Here, we established a patient-derived organoid (PDO)-based platform to functionally evaluate autologous GPC3-targeted CAR-T cell activity in HCC. HCC PDOs preserved key histologic features and heterogeneous GPC3 expression patterns of the original tumors. In co-culture assays, CAR-T cell cytotoxicity was associated with GPC3 expression levels and was accompanied by IFN-γ and IL-2 release, supporting the feasibility of using PDOs for functional assessment of CAR-T cell sensitivity. We further found that matrix conditions strongly influenced organoid architecture, viral transduction, CAR-T cell infiltration, and killing efficiency, with lower Matrigel concentrations providing a more permissive setting for functional assessment. Importantly, in GPC3-low PDOs, pretreatment with the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) reduced DNA methyltransferase 3 alpha (DNMT3A) expression, increased surface GPC3 expression, and significantly enhanced CAR-T-mediated cytotoxicity. Together, these findings provide proof-of-concept evidence supporting the use of HCC PDOs as a patient-derived platform for modeling selected determinants of GPC3-targeted CAR-T cell activity and for exploring combination strategies to improve therapeutic efficacy. Full article

Background: Trichosporon japonicum is a rare but highly lethal pathogen causing fungemia in immunocompromised patients. With the expanding use of chimeric antigen receptor T (CAR-T) cell therapy, the spectrum of opportunistic fungal infections is changing, yet data on T. japonicum infections in this setting remain scarce. Case Presentation: A 69-year-old man with diffuse large B-cell lymphoma developed catheter-associated fungemia after CAR-T cell reinfusion. He initially presented with neck pain and white oral mucosal patches, followed by fever four days later. T. japonicum was isolated from both peripheral blood and central venous catheter tip cultures, identified by microscopic examination, mass spectrometry, and molecular sequencing. Antifungal prophylaxis was initiated before fever onset based on close monitoring of white blood cell count, procalcitonin, interleukin-6, and C-reactive protein; treatment was subsequently adjusted according to species identification and antifungal susceptibility results. Infection was controlled within two weeks after catheter removal and immune recovery. The patient remained well at six-month follow-up. Conclusion: This case adds to the limited literature on T. japonicum fungemia in patients receiving CAR-T therapy. Our experience, together with a review of the literature, underscores that successful management requires prompt catheter removal, immune restoration, and combination therapy with voriconazole and amphotericin B, as echinocandin monotherapy should be avoided. Awareness of this pathogen in immunocompromised patients is critical. Full article