Imaging-guided photodynamic control of autophagy-apoptosis switching in breast cancer using hypericin-functionalized upconverting nanoparticles.

The increasing global burden of cancer necessitates innovative therapeutic strategies. Cell therapy represents a major breakthrough in oncology, evolving rapidly from the successful application of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies to a multiplatform landscape characterized by the concurrent development of diverse strategies. Current research focuses on T cell receptor-engineered T (TCR-T) cells, tumor-infiltrating lymphocytes (TILs), gamma delta (γδ) T cells, CAR-natural killer (CAR-NK) cells, CAR-macrophages (CAR-Ms), and various strategies based on dendritic cells (DCs), B cells, and stem cells. The translational paradigm is expanding from the relatively mature field of hematologic malignancies to the more prevalent and mechanistically complex domain of solid tumors. In recent years, this field has exhibited a clear trend toward expansion from autologous therapies to allogeneic "off-the-shelf" platforms. Approaches such as CAR-NK and CAR-natural killer T (CAR-NKT) cell therapies exhibit significant clinical potential because of their low immunogenicity and reduced risk of graft-versus-host disease (GvHD). Concurrently, in vivo engineering technologies that directly deliver CAR genes in situ are emerging as promising approaches to lower costs and simplify manufacturing by bypassing complex ex vivo procedures. This review systematically outlines recent advances in these strategies, focusing on their mechanisms of action, target antigens, and clinical translation. Despite progress, formidable challenges remain, including tumor heterogeneity, the immunosuppressive tumor microenvironment (TME), and therapy-related toxicity. To address these challenges, future research will focus on novel target discovery, enhanced toxicity management, and scalable manufacturing processes. The integration of multidisciplinary technologies, such as multiomics analysis, artificial intelligence, and synthetic biology, will advance cell therapies toward safer, more effective, and widely accessible applications.

Bacterial infections, especially bloodstream infections (BSIs), compromise the overall survival of patients with hematological malignancies undergoing cellular therapies. The interplay between rectal colonization by different types of multidrug-resistant organisms (MDRO) and subsequent BSIs is not fully determined. We aimed to describe the natural history and risk factors for colonization by MDRO, as well as its impact on subsequent BSIs in patients treated with cellular therapies in an environment of antimicrobial resistance. Retrospective, single-center cohort study of consecutive adult hematological malignancies patients treated with allogeneic or autologous hematopoietic cell transplantation (HCT) or chimeric antigen receptor T-cell therapy between 2021 and 2024 in Attikon University Hospital (Greece), with ≥1 available rectal screening test for carbapenem-resistant gram-negative bacilli (CR-GNB) and vancomycin-resistant Enterococcus faecium (VRE). Univariate and multivariate Cox regression were implemented for identifying predictors of CR-GNB and VRE colonization. We also studied the concordance between rectal colonization and subsequent BSIs. One hundred eighty-two patients were included (male: 64%, mean age: 50.2 ± 13 yr, acute myeloid leukemia/myelodysplastic syndrome diagnosis: 55%, relapsing/refractory disease: 58%, allogeneic HCT: 85%). Median duration of hospitalization and neutropenia was 35 and 15 d, respectively. At baseline, 95% of patients were negative on rectal screening for both CR-GNB and VRE, and of those, 8.4% and 23% were colonized with CR-GNB and VRE during follow-up, respectively. Prior colonization with the same pathogen was independently associated with subsequent CR-GNB (HR: 13.0, 95% CI: 2.83 to 59.3) and VRE (HR: 4.83, 95% CI: 2.28 to 10.2) colonization. Seventy-nine patients had ≥1 BSIs (gram-positive: 60%, gram-negative: 38%), with three concordant CR-GNB BSIs among 16 colonized patients (18.7%) and two CR-GNB BSIs among 153 noncolonized patients (1.3%). Regarding VRE, we identified two concordant BSIs among 45 colonized patients (4.4%). Despite the high MDRO prevalence, we observed low rates of CR-GNB colonization in neutropenic patients treated with cellular therapies, with one patient out of five experiencing a concordant CR-GNB BSI. VRE colonization was more frequent, but it rarely resulted in a concordant BSI. These findings highlight the importance of infection control strategies and support de-escalation approaches in empirical antibacterial treatment of febrile neutropenia in this vulnerable population.

Chimeric antigen receptor (CAR) T cell therapy is now widely used for the treatment of various haematological malignancies, with emerging applications in solid tumours and autoimmune diseases. Alongside its demonstrated clinical activity, this therapeutic modality has a toxicity profile that differs from those associated with traditional cytotoxic therapies, other immunotherapies, and even other cell therapy approaches such as allogeneic haematopoietic stem cell transplantation. One increasingly recognized yet poorly understood complication is the development of post-CAR T cell therapy lymphoproliferative and lymphomatous disorders, which have a clinical and biological spectrum that remains incompletely characterized. These rare events include both CAR-transgene-positive and transgene-negative lymphomas with variable and sometimes overlapping clinical features. Causal attribution is difficult, given that these proliferations often emerge in the context of clonal haematopoiesis, inflammatory or infectious triggers, immune suppression and/or viral reactivation. In this Review, we synthesize the growing body of evidence on post-CAR T cell therapy lymphoproliferative disorders, drawing on the limited but increasing number of well-characterized cases. We outline the spectrum of lymphoproliferations described so far, highlight recurrent pathological and molecular features, and discuss factors that might promote clonal expansion or transformation, including pre-existing clonal haematopoiesis, dysregulated signalling pathways, inflammatory stimuli and, rarely, CAR-transgene vector integration. A clearer framework for these disorders might improve early recognition, guide diagnostic evaluation, support treatment decision-making, facilitate classification and consensus-building efforts, and inform future mechanistic studies and pharmacovigilance efforts.

Immunotherapy for senescent cell clearance: Hallmarks, strategies and translational challenges.

Impaired wound healing in patients with diabetes mellitus is a major clinical problem resulting from chronic hyperglycemia, which disrupts immune function and prolongs inflammation. Cell-based therapies such as mesenchymal stem cells (MSCs) and stromal vascular fraction (SVF) have shown promise in promoting tissue repair, yet comparative data between SVF and adipose-derived stem cells (ADSCs) remain limited. In this experimental study, a diabetic rat model was used to compare the effects of allogeneic SVF and allogeneic ADSCs on wound healing. Wound areas were measured on days 5, 10, and 14. Histological analyses, including assessments of reepithelialization, fibrosis, and epithelial tongue length, as well as cytokine level measurements, were performed to evaluate tissue regeneration and inflammation. Both SVF and ADSC groups demonstrated significantly smaller wound areas compared with controls at all time points ( P <0.05). On days 5, 10, and 14, the wound areas were 3.127±0.382, 0.833±0.360, and 0.552±0.185cm 2 in the control group; 1.968±0.533, 0.543±0.165, and 0.347±0.144cm 2 in the SVF group; and 2.242±0.565, 0.432±0.137, and 0.276±0.131cm 2 in the ADSC group, respectively. Histological evaluation revealed enhanced reepithelialization and greater epithelial tongue length in both treatment groups. No significant differences were observed between SVF and ADSC groups. IL-12 levels on day 5 decreased in the SVF group (76.01±13.65ng/L) and increased in the ADSC group (96.50±19.66ng/L) compared with the control group (84.81±15.03ng/L) ( P =0.047). Both allogeneic SVF and ADSC therapies significantly accelerated wound healing in diabetic rats. Given its simpler and faster isolation process, lower cost, and comparable efficacy to ADSCs, SVF may represent a practical and effective alternative for enhancing diabetic wound repair.

Bone tissue represents a dynamic tissue that undergoes continuous renewal and remodeling through the coupled actions of osteoblast-driven bone formation and osteoclast-mediated bone resorption. Proper coupling between these two processes is essential for maintaining bone homeostasis, whereas its disruption leads to skeletal pathology. Excessive osteoclast activity underlies disorders such as osteoporosis and Paget's disease, while osteoclast deficiency, either quantitative or functional, results in osteopetrosis. Osteopetrosis comprises a group of genetically heterogeneous and clinically variable rare metabolic bone diseases characterized by increased bone mass. Clinically, osteopetrosis is commonly classified into severe autosomal recessive osteopetrosis (ARO), also known as infantile malignant osteopetrosis, intermediate ARO, milder autosomal dominant osteopetrosis, and X-linked recessive osteopetrosis. Effective treatment options for both severe and milder forms of osteopetrosis remain an unresolved clinical challenge. This review sheds light on the potential of cell-based and gene-modified cell therapies as emerging strategies for the treatment of osteopetrosis. Current cell-based therapy approaches increasingly focus on induced pluripotent stem cells, while recent advances in gene therapy enable the correction of causative genetic defects through viral vector-mediated gene transfer, CRISPR/Cas9-based genome editing, or RNA interference-mediated gene silencing. In addition, the therapeutic potentials of immunological approaches based on recombinant human interferon gamma-1b is discussed. Despite significant progress, sustained research efforts are still required to translate cell and gene-modified cell therapy into effective and personalized clinical treatments for osteopetrosis.

Recent advances in multiple myeloma (MM) therapy, including quadruplet regimens, chimeric antigen receptor T cell therapies, and bispecific antibodies, have dramatically improved outcomes, necessitating disease assessment tools that are more sensitive than the conventional serological criteria. Consequently, minimal residual disease (MRD) negativity has emerged as a robust surrogate endpoint for survival. This review summarizes the current methodologies for MRD detection, primarily next-generation sequencing (NGS) and next-generation flow (NGF), and evaluates the prognostic significance of MRD negativity across the disease spectrum. We herein discuss key data from major clinical trials in both newly diagnosed and relapsed/refractory settings, highlighting the high rates of MRD negativity achieved with novel therapeutic classes. A central focus is the evolving paradigm of MRD-adapted therapy, which utilizes dynamic MRD assessment to guide treatment decisions by allowing escalation in high-risk patients or de-escalation to reduce toxicity in deep responders. In addition, we address the optimal timing for MRD testing and the challenges of integrating these assessments into routine clinical practice. In conclusion, this review emphasizes the growing utility of MRD as not only a prognostic biomarker but also a critical tool to drive personalized treatment strategies and further enhance long-term outcomes in MM patients.

Induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) hold great promise for drug discovery and cell therapy, but their immature phenotypes and limited proliferative capacity remain major challenges. We previously showed that direct oxygenation using an oxygen-permeable membrane enhances the differentiation of iPSC-derived liver progenitor cells (LPCs), although proliferation ceases during the terminal phase of maturation. Here, we demonstrate that combining direct oxygenation with co-culture of iPSC-derived liver sinusoidal endothelial cells (LSECs) overcomes this limitation. Under oxygenated conditions, co-cultured organoids exhibited robust increase in volume, whereas either oxygenation or co-culture alone was insufficient to support growth, indicating a synergistic effect. Importantly, oxygenated co-culture organoids maintained hepatic maturation comparable to oxygenated LPC monoculture organoids, based on albumin secretion and cytochrome P450 metabolic activities. Furthermore, oxygenation promoted spatial reorganization in co-cultured organoids, with LPCs occupying the center and LSECs forming a peripheral layer, suggesting improved architectural fidelity to the liver microenvironment. Together, this approach enables the scalable generation of highly mature liver organoids with enhanced structural and functional fidelity. • Liver progenitor cells (LPCs) and liver sinusoidal endothelial cells (LSECs) were generated from human iPS cells. • Direct oxygenation promoted hepatocytic maturation but not LPC proliferation. • LSEC co-culture alone failed to enhance LPC proliferation. • Combined oxygenation and LSEC co-culture enabled LPC expansion without loss of function. • This system provides a scalable platform for functional human hepatocyte production.

This review synthesizes advanced preclinical and clinical studies published over the past 18 months evaluating mesenchymal stromal cells (MSCs) and MSC-derived products in kidney diseases. We focused on the translational relevance of MSC-based therapies against ischemia-reperfusion injury (IRI) and toxic acute kidney injury (AKI), as well as chronic kidney disease (CKD) progression in diabetic kidney disease (DKD) and lupus nephritis (LN). The renoprotective effects of MSC-based therapies are highly dependent on the timing of administration and the local pathological microenvironment. In IRI and AKI, therapeutic efficacy is confined to specific exposure windows and is driven by early modulation of mitochondrial dysfunction, inflammation and cell death. In DKD, MSCs from multiple sources consistently improve albuminuria, renal function and structural damage through anti-inflammatory, antifibrotic, autophagy-restoring and ferroptosis-inhibiting mechanisms. This nephroprotection appears to be largely independent of the glycaemic control. In LN, immune-contextual conditioning critically shapes the phenotypes of MSCs and MSC-derived extracellular vesicles (EVs), with optimized or engineered products outperforming the naïve approaches. In contrast, hypertension-related kidney disease illustrates how chronic ischemia and vascular remodelling limit MSC efficacy unless the underlying hemodynamic stress is corrected. Across diverse settings of acute and chronic kidney injury, MSC-based therapies act primarily as modulators of early pathogenic cascades rather than curative interventions for advanced damage. Their efficacy critically depends on timing, disease context and micro-environmental conditioning. Increasingly, cell-free strategies based on EVs offer scalable and potentially safer alternatives, supporting the translational development of context-adapted and combinatorial strategies.

NKG2D-based CAR-T cells for synovial sarcoma: A preclinical proof-of-concept study.

Postprostatectomy urinary incontinence (PPUI) is a prevalent complication following radical prostatectomy, with long‑term incontinence affecting up to one‑third of patients. Conventional treatments are limited by inconsistent efficacy, side effects or invasiveness, indicating demand for alternative therapies. This narrative review assessed clinical evidence of regenerative therapies, especially autologous stem cell approaches, for PPUI. We searched multiple databases for studies published between 2010 and 2024; eligible articles were clinical trials using stem cell therapies for PPUI, while non‑PPUI incontinence or non‑clinical outcome studies were excluded. Eight studies enrolling 311 patients were included: six used adipose‑derived stem cells (ADSCs) and two used muscle‑derived cells, administered via periurethral, transurethral or surgical implantation. Overall, 43.7% of patients achieved continence improvement, with efficacy ranging from 0% to 100% across studies; adverse events were mostly mild and self‑limiting. However, heterogeneity in study design, small sample sizes, inconsistent outcomes and short follow‑up restricted generalizability. Regenerative cell therapies, particularly ADSCs, are promising and well‑tolerated for PPUI. ADSCs are superior in easy harvest, scalability and multilineage differentiation. Although early data are encouraging, large‑scale, long‑term studies are required to confirm efficacy, optimize delivery and evaluate long‑term safety and durability.

This mini-review, inspired by the 20th Anniversary Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases conference, summarizes two decades of advances in human-specific lung disease modeling. We discuss endogenous stem cell-based platforms for both distal alveolar and proximal airway epithelia, including primary alveolar type II cells, bronchial and nasal epithelial cultures established as organoids, air-liquid interface cultures, and ex vivo preparations. Advances in iPSC-derived basal and alveolar epithelial cells, humanized graft models, and high-throughput therapeutic screening are highlighted. Collectively, these in vitro and in vivo models are transforming the study of lung development, injury, and repair, while accelerating drug discovery and regenerative medicine strategies. Finally, we emphasize the critical need for integrating immune components into organotypic cultures and for establishing rigorous validation and benchmarking standards to maximize translational relevance.

Implementation of artificial intelligence to automate physical disector in a fractionator design for quantification of stem cell-derived neurons.

Chimeric antigen receptor-based cellular therapy in autoimmune diseases: A systematic review and meta-analysis of clinical, serological and safety outcomes.

Cryopreservation of stem cell-derived aggregates for type 1 diabetes cell therapy: Considerations and challenges.

Chimeric antigen receptor (CAR) T cell therapy can result in impressive remissions in hematological malignancies, but relapse is common because a minority of infused cells acquire a long-lived, memory-like state. All US Food and Drug Administration-approved CAR T cell products incorporate either 4-1BB or CD28 costimulatory domains, each conferring distinct phenotypic outcomes, but how these signals control early fate decisions is incompletely understood. Here we show that costimulatory domains control memory fate acquisition through asymmetric cell division. CD28 CAR T cells have higher CAR surface expression and enhanced surface proteome asymmetry after the first division, yet paradoxically they show muted transcriptional, epigenetic and metabolic divergence between daughter cells, correlating with reduced long-term persistence. Conversely, 4-1BB CAR T cells have less surface polarization but more pronounced transcriptional, metabolic and epigenetic divergence, yielding proximal effector-prone and distal persistence-prone daughters. Integrating surface proteomics, transcriptomics, metabolomics and chromatin accessibility, we show how costimulatory domains tune asymmetric cell division to shape CAR T cell fate, providing a mechanistic foundation for optimizing cellular immunotherapy.

ABCA4-associated retinopathies (Stargardt disease) are the most common inherited macular dystrophy and a leading cause of early onset central vision loss. Biallelic pathogenic variants in the ABCA4 gene cause impaired clearance of retinoid byproducts, leading to toxic bisretinoid accumulation, retinal pigment epithelium dysfunction, and progressive photoreceptor degeneration. Clinical presentation and disease progression are highly heterogeneous, largely influenced by genotype, age at onset, and environmental modifiers. Current management remains supportive and includes low-vision rehabilitation and counseling. Recent advances in molecular genetics, retinal imaging, and translational science have substantially expanded the therapeutic pipeline for ABCA4 retinopathy. Disease-modifying strategies under active investigation include visual-cycle modulation, deuterated vitamin A analogs, retinol-binding protein antagonists, gene augmentation and editing approaches, antisense oligonucleotides, and cell-based regenerative therapies. Several pharmacologic agents have demonstrated promising structural outcomes in clinical trials, while gene-based and regenerative approaches continue to evolve amid challenges related to gene size, delivery efficiency, and long-term safety. Optogenetic therapy has emerged as a gene-agnostic option for functional vision restoration in advanced disease stages. This review provides an integrated overview of ABCA4 retinopathy, summarizing disease mechanisms, current management strategies, emerging therapies, and the evolving clinical trial landscape. Emphasis is placed on stage-adapted treatment paradigms, appropriate monitoring endpoints, and the potential role of combination therapies. Ongoing innovation and precision-based approaches offer cautious optimism for durable disease modification and functional preservation in this currently untreatable condition.

Stem cells at the tumor frontier: Mechanistic insights, therapeutic challenges, and emerging horizons.

Smoldering multiple myeloma (SMM) represents a heterogeneous precursor stage between monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma (MM). Advances in diagnostic criteria, particularly the adoption of the SLiM-CRAB framework, have improved the distinction between SMM and MM and reduced the risk of misclassification. Contemporary risk stratification models, such as the Mayo 20/2/20 criteria and International Myeloma Working Group refinements, integrate both static and dynamic biomarkers to provide more accurate predictions of progression. Genomic and immunological studies have further revealed key drivers of disease evolution, patterns of clonal evolution, and immune dysregulation, which may guide therapeutic decisions. Clinical trials have demonstrated that early intervention with lenalidomide or daratumumab can delay progression. In contrast, intensive multi-agent regimens, such as those used in the GEM-CESAR and ASCENT trials, have achieved high rates of minimal residual disease negativity and suggest curative potential. Nevertheless, the long-term survival benefits of these strategies remain uncertain, and the risks of toxicity in asymptomatic patients require careful consideration. Ongoing studies, including CAR-PRISM and ImmunoPRISM, are evaluating cellular and antibody-based therapies for high-risk SMM. Collectively, these advances highlight the need for refined, individualized approaches that balance the benefits and risks in the management of SMM.