bims-carter 2025-12-21 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2025–12–21
twenty-six papers selected by
Luca Bolliger, lxBio

CAR T-cell therapy for neurological disorders: scientific rationale and mechanistic insights.
Synthetic biology approaches to enhance cancer immune responses.
Current landscape of CAR-therapy for osteosarcoma and rhabdomyosarcoma.
Bringing natural killer cells to the clinic: Opportunities beyond cancer.
Dual-targeted ping-pong CAR T cells: Leveraging peripheral expansion to improve solid tumor immunotherapy.
Automated GMP-compatible production of universal CAR Tregs for organ-targeted tolerance induction.
Cost-Effectiveness of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Blood Cancers: An Updated Systematic Review.
CAR T therapy - the role of the pharmacist.
cGAS/STING-mediated γδ T cell recruitment drives radioresistance: implications for improving radioimmunotherapy outcomes.
Key Clinical Frontiers of mRNA Loaded Lipid Nanoparticles in Cancer Vaccines.
Trispecific T cell engagers in hematological malignancies: Advancing beyond bispecific antibodies.
Cost-effectiveness of chimeric antigen receptor T-cell therapy for relapsed or refractory large B-cell lymphoma: a systematic review and meta-analysis.
A Newly Developed TGF-Β-Responsive CAR T Cell for Enhanced Proliferation and Cytokine Secretion.
A hierarchical and configurational analysis of Health Technology Assessment outcomes for cell and gene therapies.
Engineering CAR T NK and NKT cell therapies to target cancer stem cells and overcome stem like resistance.
Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors.
Immune Checkpoint Dysregulation in Autoimmune Disorders: A Narrative Review of Therapeutic Implications.
Charting the way forward for HTA in Asia-Pacific: HTAsiaLink's strategic plan.
Engineering the Future of Longevity R&D: The Case for AI-Driven, Integrated Biotechnology Ecosystems.
Unveiling the interplay between microbiota and PD1/PD-L1 axis in tumor immunity and immunotherapy.
Crosstalk Between Extracellular Vesicles and Regulatory T Cells Across Cancers: From Interaction to Therapeutic Potential.
Platelet-engineered CAR-T cells as adjuvant therapy after cancer surgery.
Phage therapy in cancer treatment: Mechanisms, emerging innovations, and translational progress.
Advancing rare disease therapeutics through digital twins: Opportunities in drug development and precision dosing.
Bacteriophages as vaccine platforms: Opportunities and challenges in translation.
Generative Artificial Intelligence in Medical Imaging: Foundations, Progress, and Clinical Translation.

Ther Adv Neurol Disord. 2025 ;18 17562864251396039

CAR T-cell therapy for neurological disorders: scientific rationale and mechanistic insights.

Dimitrios E Katsaros, Dimitrios Mougiakakos.

  The development and successful clinical application of engineered T cells expressing synthetic chimeric antigen receptors (CARs) represents a milestone in cancer therapy. This approach optimizes physiological in vivo T-cell activation against specific target antigens expressed on defined cell subsets with the goal of their deep and sustained depletion. Significant progress has been made in redesigning CAR T-cell constructs to improve patient safety, therapeutic efficacy, and accessibility. Efforts have also focused on streamlining manufacturing to improve availability and reduce costs, two critical challenges to widespread adoption. Beyond hematologic malignancies, CAR T-cell therapies are now increasingly being repurposed to tackle B-cell-mediated autoimmune diseases (AIDs). This is primarily achieved through broad B-cell depletion, but more targeted approaches-such as the selective elimination of autoantibody-producing B-cell subpopulations-are also being explored. Important considerations in their implementation are identifying the most pertinent patient groups, tailoring their treatment up to the point of CAR-infusion, and following up on their unique toxicity-profile. In the context of neurological AIDs-including refractory myasthenia gravis, Lambert-Eaton syndrome, multiple sclerosis, and stiff-person syndrome-early clinical experience suggests promising efficacy and tolerability, leading to a growing number of registered clinical trials. In this review, we provide an overview of the mechanism and evolution of CAR T-cell therapy, highlighting why its application in AIDs, particularly in neurology, represents a highly promising therapeutic strategy.

Keywords:  B cell depletion; CAR; autoimmune diseases; cell therapy; neuroimmunology; reset

DOI:  https://doi.org/10.1177/17562864251396039
Front Immunol. 2025 ;16 1698158

Synthetic biology approaches to enhance cancer immune responses.

Shuzhen Liu, Zhihao Zhong, Qihang Tu, Meiling Jin.

  Synthetic biology is being widely applied in tumor therapy, ranging from attenuating microbial toxicity to constructing synthetic gene circuits and developing CAR-T cells, all of which are reshaping the landscape of cancer immunotherapy. In this review, we summarize recent advances in microbial-based therapeutics that leverage bacteria's natural tropism for hypoxic tumor regions to deliver immunomodulatory payloads with high spatial precision. Parallel progress in CAR-T cell engineering has led to the development of armored and logic-gated constructs designed to overcome challenges such as antigen heterogeneity, the immunosuppressive tumor microenvironment, and T cell exhaustion. Synthetic biology further integrates these platforms via programmable genetic circuits capable of performing Boolean logic operations, ensuring therapeutic activation only in the presence of tumor-specific biomarkers. While this convergence offers the unprecedented precision, safety, and potency in reprogramming anti-tumor immunity, the clinical translation of these complex systems faces significant hurdles. Despite challenges in clinical translation-including safety concerns, immune clearance, and manufacturing complexity-the field is advancing toward multifunctional "smart" therapies, synergistic microbial-cell combinations, and personalized treatment strategies. Together, these innovations are defining a new generation of precision-engineered immunotherapies with the potential to transform the treatment of refractory malignancies.

Keywords:  CAR-T cells; cancer immunotherapy; engineered bacteria; synthetic biology; synthetic gene circuits

DOI:  https://doi.org/10.3389/fimmu.2025.1698158
Front Immunol. 2025 ;16 1696830

Current landscape of CAR-therapy for osteosarcoma and rhabdomyosarcoma.

Maria Stavrou, Tatiana Nicolaou, Maria Georgalli, Anastasia Constantinidou.

  Osteosarcoma (OS) and rhabdomyosarcoma (RMS) are the most prevalent pediatric sarcoma subtypes of the bones and soft tissues respectively. The lack in targeted treatment approaches alongside the generally dismal prognosis in the metastatic setting render the discovery of novel therapeutic modalities for these diseases a pressing need. Chimeric antigen receptor (CAR)-therapy has emerged as an innovative strategy for cancer management with marked success in the treatment of hematological malignancies. The specific approach employs genetic engineering to redirect the specificity of immune cells, primarily T cells, through the exogenous expression of fully synthetic receptors, eventually arming them with the capacity to recognize tumor associated antigens (TAA). CAR-based treatment for OS and RMS has been under investigation in pre-clinical studies over the past few years, while the first promising results from a clinical trial have recently been published. However, the so far limited efficacy of CAR-therapy in solid tumors due to various constraining factors, such as poor CAR-T cell trafficking to the tumor, minimal tumor infiltration and reduced in vivo persistence, still needs to be properly addressed. In this mini review we focus on the most recent CAR-therapy strategies explored in OS and RMS while we briefly review the evolution of CARs through the years and highlight existing challenges in the CAR field.

Keywords:  cancer; chimeric antigen receptor; osteosarcoma; rhabdomyosarcoma; targeted therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1696830
J Exp Med. 2026 Jan 05. pii: e20250612. [Epub ahead of print]223(1):

Bringing natural killer cells to the clinic: Opportunities beyond cancer.

Marjorie Cayatte, Valentin Picant, Marie Vétizou, Eric Vivier.

Natural killer (NK) cells are cytotoxic and cytokine-producing innate lymphocytes with established roles in antiviral and antitumor immunity. In recent years, the biology of NK cells has been exploited in innovative cancer immunotherapies, leading to clinical advances including allogeneic NK cell infusions, chimeric antigen receptor NK cells, and NK cell engager technologies. These studies pave the way to explore how advances in NK cell-based immunotherapies could be leveraged outside of oncology to selectively target pathogenic cells and restore tissue homeostasis in viral infections, neurodegenerative disorders, autoimmunity, and transplantation medicine.

DOI: https://doi.org/10.1084/jem.20250612
Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2518996122

Dual-targeted ping-pong CAR T cells: Leveraging peripheral expansion to improve solid tumor immunotherapy.

Amanda V Finck, Ziming Wang, Donna Gonzales, Nils Wellhausen, Sofía Castelli, Esha Banerjee, M Angela Aznar, Regina M Young, Carl H June.

  Clinical responses to CD19-directed CAR T cell therapy in B cell malignancies are strongly associated with robust CAR T cell expansion in the peripheral blood. In contrast, CAR T cells targeting solid tumors do not encounter cognate antigen in the periphery, resulting in limited expansion and subtherapeutic peak concentrations. To overcome this, we engineered dual-targeted and dual-costimulated CAR T cells (CD19/28ζ-M5BBζ) that recognize CD19+ B cells, thereby promoting peripheral expansion and increasing the pool of solid tumor-directed CAR T cells available for tumor infiltration without the need for lymphodepletion. In immunocompetent C57BL/6 mouse models of pancreatic ductal adenocarcinoma and melanoma, these dual-targeted CAR T cells demonstrated enhanced peripheral expansion, improved anti-tumor efficacy, and increased survival without added dysfunction or toxicity compared to single antigen-targeted CAR T cells. We translated our findings to human CAR T cells by developing a pancreatic/xenograft model with CD19+ B cells in the periphery and again demonstrated that treatment with dual CAR T cells showed significantly enhanced tumor clearance and survival compared to single antigen-targeted CAR T cells. In conclusion, we demonstrate that dual-targeted CAR T cells boost peripheral expansion, and anti-tumor efficacy, providing a strategy for enhancing outcomes for patients treated with clinical CAR T products targeting solid tumors.

Keywords:  CAR T cells; cellular therapy; immuno-oncology; lymphodepletion; solid tumors

DOI:  https://doi.org/10.1073/pnas.2518996122
J Transl Med. 2025 Dec 17. 23(1): 1399

Automated GMP-compatible production of universal CAR Tregs for organ-targeted tolerance induction.

Kavitha Lakshmi, Alexandra von Jutrzenka-Trzebiatowski, Liliana Loureiro, Karla Elizabeth González Soto, Katja Peter, José Manuel Marín Morales, Samikshya Santosh Nirmala, Nicole Berndt, Claudia Arndt, Yueyuan Hu, Jing-Wun Li, Claudia Peitzsch, Anna Taubenberger, Rebekka Wehner, Marc Schmitz, Kristina Hölig, Hinrich Abken, Ezio Bonifacio, Martin Bornhäuser, Michael Bachmann, Anja Feldmann, Anke Fuchs.

   BACKGROUND: Adoptive transfer of regulatory T cells (Tregs) has demonstrated safety, feasibility and early signs of efficacy in promoting immunological tolerance in inflammatory conditions such as graft-versus-host disease (GvHD). Chimeric antigen receptor (CAR)-engineered Tregs offer localized activation and suppression compared to polyclonal Tregs, but their clinical translation is limited by high manufacturing costs, lengthy developing times and fixed single-antigen specificity. To address these limitations, we employed the universal adapter Reverse CAR (RevCAR) system, which harbors a peptide epitope lacking intrinsic antigen specificity but provides flexibility in targeting through the use of an antigen-specific RevCAR Target Module (RevTM). As a proof-of-concept, we used a RevTM targeting carcinoembryonic antigen (CEA), which is highly expressed in the gastrointestinal (GI) tract, as a potential strategy to achieve localized immunosuppression in GI acute GvHD.
METHODS: To support clinical translation, we established an automated, GMP-compatible, clinical-scale manufacturing process. Tregs were magnetically enriched from leukapheresis using the CliniMACS® Plus, followed by high-purity sorting on the MACSQuant® Tyto®. The sorted cells were virally transduced and the RevCAR Tregs were expanded on the CliniMACS Prodigy® to obtain clinically relevant cell numbers. The harvested products were evaluated for phenotype, stability, antigen specificity and suppressive function.
RESULTS: Across five manufacturing runs, Tregs (CD4+CD25highCD127lowFOXP3+) with a median initial purity of 94% were expanded to achieve a median therapeutic yield of 602 × 106 cells. The final product maintained a high purity (median: 91.9%) and exhibited high RevCAR expression (median: 60% RevCAR+). Mass cytometry analysis revealed that expanded RevCAR Tregs predominantly exhibited a central memory phenotype with high expression of functional and homing markers. Under experimental pro-inflammatory conditions, the cells maintained stable FOXP3 and Helios expression with minimal pro-inflammatory cytokine production. Importantly, RevCAR Tregs showed antigen-specific activation upon target engagement via the CEA-specific RevTM and robust, dose-dependent suppression.
CONCLUSION: The study establishes a scalable, GMP-compatible process for manufacturing pure, stable and functional universal RevCAR Tregs for clinical applications. Furthermore, the RevCAR system offers a promising approach toward an allogenic, off-the-shelf Treg therapy capable of treating diverse immune-mediated diseases with spatial precision.

Keywords:  Automated expansion; Closed-system manufacturing; Good manufacturing practice; Precision immunotherapy; Regulatory T cells; Treg cell therapy; Universal adapter CAR

DOI:  https://doi.org/10.1186/s12967-025-07431-0
Pharmacoecon Open. 2025 Dec 15.

Cost-Effectiveness of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Blood Cancers: An Updated Systematic Review.

Nishma Patel, Suzanne Farid, Manuel Gomes.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is an area of rapid development, showing the promise of curing blood cancers. While substantial health gains may justify high costs, it is currently unclear the extent to which the overall cost effectiveness of these therapies is driven by i) context-specific factors, such willingness-to-pay thresholds and study perspective, or ii) important subgroups such as line of treatment and therapy product.
OBJECTIVE: This paper aims to critically review published evidence on the cost effectiveness of CAR T-cell therapies and assess the key factors that drive their cost effectiveness.
METHODS: We conducted a systematic review using PubMed, Scopus and Ovid (Embase) databases to identify full economic evaluations of CAR T-cell therapies published up to January 2024. One reviewer screened and extracted data from the studies and the second reviewer assessed a sample of the full-text studies against the inclusion/exclusion criteria. Studies were critically appraised using the CHEERS checklist. Cost data are presented in 2022 US dollars.
RESULTS: The review identified 45 full cost-effectiveness studies of CAR T-cell therapies. These studies considered a total of 92 treatment comparisons, which included tisagenlecleucel (n = 37), axicabtagene ciloleucel (n = 28), brexucabtagene autoleucel (n = 7), lisocabtagene maraleucel (n = 8), idecabtagene vicleucel (n = 6), ciltacabtagene autoleucel (n = 4) and relmacabtagene autoleucel (n = 2). Incremental cost ranged from - US$74,980 to US$714,178 and incremental quality-adjusted life year (QALY) gains ranged from - 0.02 to 10.77. The resulting cost-per-QALY-gained ratios ranged from - US$37,490,000 to US$7,972,845, and the range of willingness-to-pay (WTP) thresholds between US$36,184 to US$317,825. The price of CAR T-cell therapy represented 75% (mean US$391,060) of the total cost of CAR T-cell therapy but was not the sole factor influencing cost effectiveness. Hospitalisation made up 6% of the total cost (mean US$34,152), while adverse events accounted for 9% (mean US$47,350). Regression analysis indicated cost effectiveness did not change according to important clinical or contextual factors.
CONCLUSIONS: The findings demonstrate that the cost effectiveness of CAR T-cell therapies is determined by a combination of factors: the relative difference between the cost of the CAR T-cell therapy and comparator, the magnitude of the QALY gains and the WTP thresholds. Their cost- effectiveness does not differ according to therapy product, line of treatment, or country.

DOI: https://doi.org/10.1007/s41669-025-00614-x
Ceska Slov Farm. 2025 ;74(2): 103-107

CAR T therapy - the role of the pharmacist.

Marcela Heislerová.

  CAR-T therapy uses and advances the ability of the human immune system to attack tumor cells. It can currently only be administered in specialized treatment centers in the Czech Republic, which must be able to ensure the collection of T lymphocytes, their sending for preparation, the subsequent administration of CAR-T preparations, as well as the recognition, monitoring and management of possible adverse effects of the treatment (1). The aim of this article is to highlight the role of hospital pharmacists, who are key to the correct handling of these highly specialized preparations. Due to the difficulty of handling and the high price of these preparations, it is necessary to have all steps standardized and documented. Hospital pharmacists are guarantors of the correct handling of all medicinal products in hospitals and play an important role in the management of CAR-T therapies. They actively participates not only in providing CAR-T preparations for medical facilities, but also in solving irregularities and defects connected with their application. Patient care is complex and is based on the multidisciplinary cooperation of health professionals, in which hospital pharmacists also have their place.

Keywords:  CAR-T therapy; Medication Management; hospital pharmacist

DOI:  https://doi.org/10.36290/csf.2025.014
J Clin Invest. 2025 Dec 15. pii: e200465. [Epub ahead of print]135(24):

cGAS/STING-mediated γδ T cell recruitment drives radioresistance: implications for improving radioimmunotherapy outcomes.

Brooke C Braman, David R Raleigh.

Radiotherapy is a key treatment modality in many malignancies, but radiation-induced immunosuppression can undermine its outcomes and diminish the efficacy of combinatorial strategies, like radioimmunotherapy. In this issue of the JCI, Deng et al. implicate cGAS/STING signaling in the recruitment of γδ T cells that drive downstream radioresistance. Radiation-induced microparticles containing double-stranded tumor DNA led to activation of the cGAS/STING pathway in macrophages, promoting γδ T cell recruitment through CCL20 signaling. In mouse models, γδ T cell-dependent recruitment of myeloid-derived suppressor cells and T cell suppression curbed radiotherapy efficacy and drove antitumor immunity. Ablation of γδ T cells improved the efficacy of radiotherapy alone and radiotherapy combined with immune checkpoint inhibitors in mouse models, supporting further investigation of γδ T cell targeting to improve clinical outcomes with radioimmunotherapy. The findings also add complexity to the function of the cGAS/STING pathway in setting the balance between antitumor immunity and immunosuppression.

DOI: https://doi.org/10.1172/JCI200465
Int J Nanomedicine. 2025 ;20 14935-14953

Key Clinical Frontiers of mRNA Loaded Lipid Nanoparticles in Cancer Vaccines.

Lili Cao, Jie Min, Meipin Yu, Zhongfeng Zhang, Dan Yuan, Dingchao Chen.

  Cancer vaccines are promising, but clinical translation is constrained by inefficient antigen delivery and suboptimal immune activation. Lipid nanoparticles (LNPs)-validated for potency and safety in COVID-19 mRNA vaccines-offer a versatile, scalable, and immunogenic platform. Key barriers persist: precise targeting of tumors or lymphoid tissues, efficient intracellular mRNA release, and the immunosuppressive tumor microenvironment. This review synthesizes design principles for mRNA-loaded LNPs, emphasizing lipid chemistry, organ-selective biodistribution, and nano-engineering strategies that strengthen antigen presentation and T-cell priming. We also examine combination approaches with checkpoint blockade, chemotherapy-induced immunogenic cell death, and molecular adjuvants. Clinically, signals of efficacy are emerging-most notably the KEYNOTE-942 study, in which mRNA-4157 combined with pembrolizumab showed a sustained improvement in recurrence-free survival at 5 years compared with pembrolizumab alone-highlighting both the potential and the remaining questions for this modality. Finally, we outline manufacturing and regulatory considerations and map future directions-including thermostable formulations, self-amplifying RNA, and AI-guided lipid discovery-to address translational bottlenecks and expand global access to LNP-based cancer vaccines.

Keywords:  immunotherapy; lipid nanoparticles; mRNA cancer vaccines; nanomedicine; organ-selective delivery

DOI:  https://doi.org/10.2147/IJN.S565558
Semin Hematol. 2025 Nov 20. pii: S0037-1963(25)00051-4. [Epub ahead of print]

Trispecific T cell engagers in hematological malignancies: Advancing beyond bispecific antibodies.

Kyung-Nam Koh, Dae Hee Kim, Hyori Kim.

  The success of bispecific T cell engagers (BiTEs) in hematological malignancies has catalyzed the development of trispecific antibodies that simultaneously target 3 molecular entities. These next-generation immunotherapeutics address the key limitations of bispecific constructs including antigen escape, limited T cell activation, and on-target off-tumor toxicity. Trispecific constructs employ 2 primary strategies: dual tumor antigen targeting combined with CD3 engagement to prevent antigen escape, and integration of co-stimulatory signals (CD28, 4-1BB) to enhance T cell function. Early clinical data demonstrated promising efficacy signals, particularly in multiple myeloma where BCMA×CD38×CD3 constructs achieved 90% overall response rates in early-phase trials. Safety profiles mirror bispecific antibodies with cytokine release syndrome and neurotoxicity as primary concerns. Trispecific T cell engagers represent a significant advancement in precision immunotherapy for hematological malignancies. Although early clinical results are encouraging, challenges remain in optimal target selection, manufacturing complexity, and resistance mechanisms. Ongoing clinical trials will define their role in the evolving treatment landscape.

Keywords:  Hematological malignancies; Immunotherapy; T cell engagers; Trispecific antibodies

DOI:  https://doi.org/10.1053/j.seminhematol.2025.11.002
J Med Econ. 2025 Dec;28(1): 2216-2235

Cost-effectiveness of chimeric antigen receptor T-cell therapy for relapsed or refractory large B-cell lymphoma: a systematic review and meta-analysis.

Taylor J Loftus, Jeong-Yeon Cho, Manuel Meraz, Teerapon Dhippayom, Allison M Bock, Charlotte B Wagner, Kednapa Thavorn, Nathorn Chaiyakunapruk.

   AIMS: Cost-effectiveness evidence of chimeric antigen receptor T-cell therapy (CAR-T) for the treatment of relapsed or refractory large B-cell lymphoma (r/r LBCL) remains controversial given the potential CAR-T has to cure patients coupled with the high cost of therapy. This study aims to synthesize the cost-effectiveness data of CAR-T for the treatment of r/r LBCL in adults using a systematic review and meta-analysis.
METHODS: Cost-effectiveness analyses of CAR-T for the treatment of r/r LBCL from inception through November 2024 were identified through database searches (MEDLINE, EMBASE, and CENTRAL). Costs were converted to 2023 US dollars using purchasing power parity. Incremental net benefit (INB) was calculated using country-specific willingness-to-pay thresholds and pooled using a random-effects model. Results were stratified by country income level and line of therapy. The risk of bias was assessed using the ECOBIAS checklist. Protocol registered at PROSPERO #CRD42024602683.
RESULTS: Thirty-four studies were included in this systematic review. Twenty-six studies compared CAR-T to platinum-based chemotherapy with autologous stem cell therapy (ASCT) for r/r LBCL and eight studies compared between CAR-T therapies. As 2nd-line therapy for LBCL, CAR-T was found to have an INB of $28,846 (95% Confidence Interval [CI]: -$43,265 to $100,957; I2 = 0%) (n = 9) compared to platinum-based chemotherapy with ASCT in high-income countries (HICs). As 3rd-line therapy against the same comparator, CAR-T had an INB of $48,838 (95% CI: -$156,625 to $254,302; I2 = 79%) (n = 9) for HICs.
CONCLUSIONS: Over a lifetime horizon, CAR-T was not significantly cost-effective for the treatment of r/r LBCL, though positive INBs suggest a trend toward cost-effectiveness as 2nd or 3rd-line therapy in HICs. Further cost-effective analyses should be conducted to compare between CAR-T products for the treatment of patients with r/r LBCL, as well as between CAR-T products and emerging novel therapies for r/r LBCL treatment, as this study did not address these comparisons.

Keywords:  Cost-effectiveness analysis; I10; I19; chimeric antigen receptor T-cell therapy; economic evaluation; hematopoietic stem cell therapy; large B-cell lymphoma

DOI:  https://doi.org/10.1080/13696998.2025.2600217
Adv Pharm Bull. 2025 Sep;15(3): 646-656

A Newly Developed TGF-Β-Responsive CAR T Cell for Enhanced Proliferation and Cytokine Secretion.

Shafieeh Mansoori, Mohammad Ali Shokrgozar, Monireh Gholizadeh, Shahriyar Abdoli, Soheila Ajdary, Zahra Sharifzadeh.

   Purpose: Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising cancer treatment. Nevertheless, the tumor microenvironment (TME) of solid tumors provides substantial challenges to CAR T cell efficacy. Tumor growth factor-beta (TGF-β), a potent immunosuppressive cytokine in the TME, impedes T cell activation, proliferation, and cytotoxicity, diminishing the anti-tumor potency of CAR T cells. This study investigates whether TGF-βRII CAR T cells can overcome these barriers and remain functional in TGF-β-rich environments.
Methods: We developed a novel TGF-βRII CAR T cell (TGF-βRII-CD28CD3z) and a dominant-negative TGF-β receptor (dnTβRII) T cell utilizing Jurkat cells. Transduction efficiency and surface expression were confirmed using flow cytometry. T cell activation and proliferation were assessed by CD69 and Ki-67 expression, respectively. IL-2 and IFN-γ secretion were quantified using ELISA kits.
Results: Flow cytometry confirmed the successful cell surface expression of the designed receptors: 62% and 24% for TGF-βRII CAR and dnTβRII, respectively. TGF-βRII CAR T cells were markedly activated in a dose-dependent manner, with optimal responses at 10 ng/mL TGF-β. The Ki-67 expression of CAR T cells, used as a proliferation marker, increased 1.21-fold (from 79.5% to 96%) upon exposure to 10 ng/mL TGF-β. At 5 ng/mL TGF-β, the cells' proliferation was maintained at a 1.04-fold increase. Cytokine analysis revealed a 1.9-fold increase in IL-2 (130±4 pg/mL) and a 2.7-fold increase in IFN-γ (146±21.9 pg/mL) secretion at 10 ng/mL TGF-β. Additionally, at 5 ng/mL TGF-β, IL-2 secretion increased 1.6-fold (110±10.7 pg/mL), and IFN-γ secretion increased 1.7-fold (94.3±10.2 pg/mL). In contrast, dnTβRII T cells also produced IL-2 (95 pg/mL±22, 2.7-fold increase) but failed to sustain proliferation or IFN-γ production at 10 ng/mL TGF-β.
Conclusion: Our findings demonstrate that the TGF-βRII CAR T cells not only resist TGF-β-mediated suppression but also promote activation, proliferation, and cytokine release in the presence of TGF-β. This underscores their therapeutic potential as an innovative approach to overcome TGF-β-driven immunosuppression and improve the CAR T cell therapy efficacy in solid tumors.

Keywords:  Adoptive cellular immunotherapy; Chimeric antigen receptor therapy; Immunosuppression; Solid tumor; Transforming growth factor beta; Tumor microenvironment

DOI:  https://doi.org/10.34172/apb.025.45483
Front Pharmacol. 2025 ;16 1695961

A hierarchical and configurational analysis of Health Technology Assessment outcomes for cell and gene therapies.

Ziyad S Almalki, Renad M Alshammari, Nadia A Dahduli, Mouaddh Abdulmalik Nagi, Syeda Juweria, Moayad M Alhamdani, Yazan M Alzahrani, Saja H Almazrou, Nehad Jaser Ahmed, Abdullah K Alahmari, Areej A Alshlowi.

   Background: Cell and gene therapies (CGTs) challenge traditional Health Technology Assessment (HTA), creating a fragmented global access landscape. This study identifies the determinants of CGT reimbursement outcomes by quantifying the influence of key variables and identifying the configurations leading to a positive recommendation.
Methods: A dual-methodology approach was employed. We constructed a comprehensive dataset of all HTA decisions for CGTs across seven major jurisdictions between January 2017 and July 2025. Hierarchical Linear Modeling (HLM) was used to identify independent predictors of HTA outcomes, and Fuzzy-Set Qualitative Comparative Analysis (fsQCA) was used to identify sufficient pathways to success. Novel composite indicators were developed to measure system-level adaptability and the influence of patient advocacy groups (PAGs).
Results: The HLM analysis, accounting for data clustering (Intraclass Correlation Coefficients (ICCs): 42% country-level, 24% agency-level variance), confirmed that strong clinical efficacy (Coef. = 0.40), high unmet need, and disease rarity were significant positive predictors. High therapy cost was a powerful negative predictor (Coef. = -0.29 per $1M USD). Crucially, high System Adaptability (Coef. = 0.35) and strong PAG Influence (Coef. = 0.28) emerged as major positive determinants. The fsQCA revealed three distinct pathways to a positive recommendation with high consistency: a "Transformative Value" path (consistency: 0.93), a "Strategic Mitigation" path (consistency: 0.90), and an "Economic Dominance" path (consistency: 0.94). The overall QCA solution explained a majority of positive outcomes (solution coverage: 0.68).
Conclusion: HTA success for CGTs is not determined by isolated attributes but by the strategic alignment of therapy-level evidence, agency-level processes, and country-level context. The influence of organized patient advocacy and the structural flexibility of HTA systems are critical, previously under-quantified components of this alignment.

Keywords:  Health Technology Assessment; cell and gene therapies; decision-making; reimbursement; value

DOI:  https://doi.org/10.3389/fphar.2025.1695961
Discov Oncol. 2025 Dec 14.

Engineering CAR T NK and NKT cell therapies to target cancer stem cells and overcome stem like resistance.

Omer Qutaiba B Allela, Abdulkareem Shareef, S Renuka Jyothi, Priya Priyadarshini Nayak, J Bethanney Janney, Gurjant Singh, Ashish Singh Chauhan, Firdavs Oripov, Hayder Naji Sameer, Ahmed Yaseen, Rasim M Salih, Mohaned Adil.



Keywords:  CAR-NK; CAR-T; Cancer stem cells; Cellular immunotherapy; Therapeutic resistance

DOI:  https://doi.org/10.1007/s12672-025-04276-3
Sci Transl Med. 2025 Dec 17. 17(829): eadq4060

Coordinate tumor-antigen uptake and dendritic cell activation by chimeric antigen receptors.

Yahya Mohammadzadeh, Vojislav Gligorovski, Olga Egorova, Gabriele Casagrande Raffi, Jort J van der Schans, Ali Ghasemi, Katharina Jonas, Bruno Torchia, Alan Guichard, Rachel Marcone, Amaia Martinez-Usatorre, Anna Köck, Raphael Genolet, Nadine Fournier, Tatiana V Petrova, Daniel E Speiser, Sahand Jamal Rahi, Nahal Mansouri, Michele De Palma.

Effective antitumor immunity requires dendritic cells (DCs) to internalize, process, and present tumor antigens to T cells. Adoptive transfer of DCs that were loaded ex vivo with tumor antigens has been shown to stimulate antitumor immunity in patients with cancer, but clinical responses have been mixed. To address the limitations of traditional DC-based therapies, we constructed and functionally screened a panel of chimeric antigen receptors (CARs) optimized for expression and activity in DCs. Through this screening, we identified key functional components that guided the development of an inducible platform centered on an instructive chimeric antigen receptor (iCAR). This iCAR enabled DCs to (i) recognize a surface molecule present on cancer cells or their extracellular vesicles (EVs), such as disialoganglioside GD2 (expressed in melanoma and other tumors of neuroectodermal origin) or HER2 (expressed in some epithelial cancers), thereby promoting the acquisition of tumor-derived material containing putative tumor antigens; (ii) undergo immunostimulatory activation to prime antigen-specific T cells via both cross-dressing and cross-presentation; and (iii) transactivate the expression of the therapeutic cytokine interleukin-12 (IL-12) in response to antigen uptake. The iCAR converted melanoma-derived EVs from immune-suppressive to stimulatory cues for DCs in cell culture assays. Moreover, systemic administration of iCAR-DCs enhanced antigen-specific T cells, expanded low-frequency T cell clonotypes, and delayed tumor growth in immunotherapy-resistant melanoma models without the need for ex vivo antigen loading or cell maturation. iCAR-DCs may therefore provide a platform for antigen-agnostic cancer immunotherapy that integrates antigen uptake with programmable DC activation.

DOI: https://doi.org/10.1126/scitranslmed.adq4060
Cureus. 2025 Nov;17(11): e97002

Immune Checkpoint Dysregulation in Autoimmune Disorders: A Narrative Review of Therapeutic Implications.

Diwan Mahmood Khan, Rohit Kumar, Mahavadi Sriharsha, Srihita Mahavadi, Arnaw Kishore.

  Immune checkpoints act like dimmer switches that keep immune responses in balance. In autoimmune disease, problems usually fall into four overlapping types: weak inhibitory signals, too much co-stimulation, metabolic or epigenetic rewiring of checkpoint pathways, and a mismatch between tissue and blood findings. This narrative review focused on human and translational studies from PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (Embase), Web of Science, and Scopus (to 2025), prioritizing tissue-based data, trials of checkpoint agonists or co-stimulation blockade, cell-based tolerance (low-dose interleukin-2 (IL-2), chimeric antigen receptor regulatory T cells (CAR-Tregs), and extracellular vesicle (EV) approaches. Tissue profiling tracks disease activity better than blood alone. Immunometabolic stress, especially lactate-driven protein lactylation and ferroptosis, can blunt programmed cell death protein-1/cytotoxic T-lymphocyte associated protein-4 (PD-1/CTLA-4) braking and destabilize regulatory T cells (Tregs). A practical biomarker panel pairs lesion immunohistochemistry/spatial maps of PD-1/programmed death-ligand-1 (PD-L1) and second-wave checkpoints with soluble PD-1, PD-L1, CTLA-4, and EV cargo under strict pre-analytical control. Therapy should be staged: first, lower the inflammatory and metabolic load, then restore inhibitory tone with checkpoint agonists or co-stimulation blockade, and add Treg support and EV-guided delivery when regulation is fragile. Safety needs vaccine timing, age-/sex-aware dosing, and composite panels that distinguish flare from over-suppression. The next step is endotype-first, spatially informed, biomarker-anchored trials to achieve durable, safer immune rebalancing.

Keywords:  autoimmune disorders; co-stimulation blockade; ctla-4; extracellular vesicles; immune checkpoints; pd-1/pd-l1; regulatory t cells

DOI:  https://doi.org/10.7759/cureus.97002
Int J Technol Assess Health Care. 2025 Dec 19. 41(1): e87

Charting the way forward for HTA in Asia-Pacific: HTAsiaLink's strategic plan.

Ryan Jonathan Sitanggang, Lapad Pongcharoenyong, Natcha Kongkam, Wendy Babidge, Auliya Suwantika, Izzuna Mudla Mohamed Ghazali, Ling-Chen Chien, Miyoung Choi, Saudamini Vishwanath Dabak, Sitanshu Kar, Takashi Fukuda, Wanrudee Isaranuwatchai, Yot Teerawattananon, Benjamin Shao Kiat Ong.

  Health Technology Assessment (HTA) informs resource allocation and policy decisions, particularly to achieve Universal Health Coverage (UHC). Recognizing the increasing demand for evidence-informed decision-making, the HTAsiaLink network was established in 2011 as a regional platform to strengthen individual and institutional capacity in HTA research and facilitate the integration of HTA evidence into policy decisions across the Asia-Pacific.Over the years, HTAsiaLink has expanded to over fifty members from twenty economies. In 2024, a structured strategic planning process was undertaken to ensure its continued growth and strengthen its impact on HTA development and implementation. This process involved a targeted review of strategic plans from international networks, alongside comprehensive member engagement, to develop a data-driven and adaptable plan responsive to the evolving healthcare landscape and member needs. As a result, five strategic priorities, corresponding action items, and success indicators were identified.This commentary outlines the needs and processes involved in developing the network's first-ever strategic plan, emphasizing the critical role of member engagement in shaping its future direction. We believe that this experience offers transferable insights for other HTA networks, particularly those operating in low- and middle-income country contexts, on the collaborative development of strategic plans that are responsive to shared objectives, accommodate varying institutional capacities, and align with regional priorities.

Keywords:  Asia-Pacific; HTAsiaLink; Health Technology Assessment; capacity building; evidence-informed decision-making; network; strategic plan

DOI:  https://doi.org/10.1017/S0266462325100573
Aging Dis. 2025 Dec 11.

Engineering the Future of Longevity R&D: The Case for AI-Driven, Integrated Biotechnology Ecosystems.

Alex Zhavoronkov, Chuen Yan Leung.

The escalating cost, extended timelines, and low success rates in pharmaceutical research demand a rethinking of biotechnology R&D infrastructure to more efficiently discover and deliver novel therapeutics to an increasingly aging population. We introduce the concept of the AI-Integrated Biotechnology Hub, a purpose-built research ecosystem uniting residential, commercial, clinical, and research facilities under a central, AI-driven operating system. The hub functions as a multi-sided platform that unites health data collection, smart living environments, and federated learning to enable secure, privacy-preserving biomedical and longevity research. By integrating real estate, biotechnology facilities, research hospitals, and community services, the model maximizes data utility, accelerates drug discovery, and enhances resident well-being. Transparency, accountability, and ethical stewardship are critical pillars of governance, enacted through dynamic consent, data trusts, and multi-stakeholder oversight. Designed to be scalable across urban and vertical architectures, this paradigm represents a potential approach that may enable more efficient research workflows to improve healthspan, foster innovation, and reshape the economics of global drug development.

DOI: https://doi.org/10.14336/AD.2025.1313
Front Immunol. 2025 ;16 1690374

Unveiling the interplay between microbiota and PD1/PD-L1 axis in tumor immunity and immunotherapy.

Qiguang Lu, Jiasheng Wu, Xiaoyan Yu, Juanjuan Qian, Zhengwei Song.

  Microbial communities across diverse body sites critically shape host immunity and tumor responses. Within this framework, the PD-1/PD-L1 axis emerges as a central pathway governing tumor immune evasion and resistance to therapy. Recent evidence reveals that microbiota-from the gut, lungs, and elsewhere-significantly influence PD-1/PD-L1 signaling, thereby altering immune checkpoint blockade efficacy. This review synthesizes current understanding of the microbiota-PD-1/PD-L1 interplay, examining how microbial composition and metabolites impact immune cell activity, the tumor microenvironment, and immunotherapy outcomes. We detail mechanisms through which microbiota regulate PD-1/PD-L1 expression, fostering immune tolerance and tumor progression while modulating therapeutic responses. The translational potential of microbiota-targeted strategies to enhance PD-1/PD-L1 therapy and overcome resistance is discussed. Integrating microbiota modulation with existing immunotherapies offers promising avenues for precision cancer treatment. Advancing these concepts into clinical practice will require future research to establish microbiome-based interventions as transformative tools in oncology.

Keywords:  PD1/PD-L1 axis; cancer immunotherapy; microbiota; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1690374
Int J Nanomedicine. 2025 ;20 14643-14665

Crosstalk Between Extracellular Vesicles and Regulatory T Cells Across Cancers: From Interaction to Therapeutic Potential.

Di Liu, Zhixiong Hao, Guangpeng He, Ye Huang.

  Regulatory T cells (Treg cells) play a crucial role in maintaining immune tolerance and regulating immune responses, especially in cancer, where their immunosuppressive function is highly significant. Treg cells accumulate in the tumor microenvironment (TME), interact with tumor cells and other immune cells, and suppress anti-tumor immunity through various mechanisms, including secretion of immunosuppressive cytokines, direct contact with target cells, and depletion of key nutrients and signaling molecules. Regulating Treg cells has become a novel approach for enhancing cancer immunotherapy. Extracellular vesicles (EVs) are small vesicles with a lipid bilayer membrane secreted by all cells and play an important role in tumor biology as communication mediators by transmitting proteins, RNA, and other bioactive molecules in TME. In the past years, an increasing amount of research has uncovered the effects of EVs on Treg in TME, greatly enriching our understanding of Treg in tumor progression. Additionally, due to the potential of EVs as "natural nanoparticles" for drug and gene delivery, targeting Treg via an EV-delivery system has become a hotspot. Therefore, we comprehensively summarized the updates on the effects of EVs on Treg in TME and EV-related therapy for tumor treatment.

Keywords:  extracellular vesicle; immunotherapy; regulatory T cells; tumor microenvironment

DOI:  https://doi.org/10.2147/IJN.S562593
Proc Natl Acad Sci U S A. 2025 Dec 23. 122(51): e2522020122

Platelet-engineered CAR-T cells as adjuvant therapy after cancer surgery.

Yixin Wang, Edikan Ogunnaike, Huan Yang, Sichen Yuan, Rachel Hong, Allie Barrett, Emem Ebong, Bo Liu, Gianpietro Dotti, Quanyin Hu.

  Surgery remains the mainstay treatment for many kinds of solid tumors, while tumor recurrence frequently occurs. Adjuvant therapy can reduce the risk of recurrence and improve the prognosis of surgery. Chimeric antigen receptor (CAR)-T cell therapy can be leveraged as an alternative adjuvant therapy to clear residual cancer cells and prevent tumor recurrence. However, systemic administration of CAR-T often results in insufficient tumor infiltration and side effects to normal organs. Given that platelets can preferentially accumulate at postsurgical wounds, we proposed that conjugating platelets to CAR-T cells may enhance the accumulation of the CAR-T cells within the surgical bed after the resection of solid tumors. In this study, we conjugated platelets to B7-H3.CAR-T cells via click chemistry. In postsurgical human pancreatic cancer mouse models, platelet-CAR-T cells showed enhanced tumor infiltration and elevated antitumor cytokine levels, resulting in superior suppression effects on tumor recurrence, compared with CAR-T cells. Additionally, platelet-CAR-T cells showed enhanced efficacy in inhibiting metastasis and prolonging the survival time of the mice in postsurgical triple-negative breast cancer (TNBC) models. Mechanistic studies revealed that platelet activation could improve the CAR-T cell activity and persistence, as evidenced by an upregulation of genes associated with T cell infiltration and a downregulation of genes related to T cell exhaustion. Finally, we further validated the biosafety profile and efficacy of platelet-CAR-T in a postsurgical patient-derived xenograft TNBC-bearing humanized mouse model. The results suggested that the CAR-T cell strengthened by platelet engineering is a promising adjuvant therapy against postsurgical tumor recurrence.

Keywords:  CAR-T cell therapy; click chemistry; platelet

DOI:  https://doi.org/10.1073/pnas.2522020122
Crit Rev Oncol Hematol. 2025 Dec 13. pii: S1040-8428(25)00473-1. [Epub ahead of print]218 105085

Phage therapy in cancer treatment: Mechanisms, emerging innovations, and translational progress.

Chou-Yi Hsu, Djamila Polatova, Rania Hameed Hamad, Pareshkumar N Patel, Muhammad Akram, Gunjan Singh, Vimal Arora, Priya Priyadarshini Nayak, Munthar Kadhem, Hamza Fadhel Hamzah.

  Bacteriophage therapy has re-emerged as a rapidly advancing field in oncology, bridging antimicrobial precision with tumor-targeted biotherapy. Beyond infection control, phages are now recognized as programmable biological systems capable of eradicating multidrug-resistant (MDR) pathogens, modulating tumor-associated microbiota, activating immune responses, and delivering therapeutic genes or drugs. Preclinical evidence shows that phages can selectively eliminate Fusobacterium nucleatum in oral squamous cell carcinoma, restore microbial balance in colorectal cancer, and enhance immune infiltration via cytokine or antigen display. Engineered constructs including GM-CSF-expressing and MAGE-A1-displaying phages, λ-phage ASPH vaccines, and PEGylated nanocarriers delivering MEG3 or TRAIL have demonstrated strong anti-tumor efficacy across melanoma, hepatocellular, and colorectal cancer models. Additionally, CRISPR-Cas-armed phages precisely remove resistance genes such as bla-CTX-M and mecA, while AI-driven selection pipelines enable data-guided design of personalized phage cocktails. These advances represent a paradigm shift from empirical antibacterial use toward mechanistically engineered, multifunctional phage platforms that integrate microbiome modulation, immune activation, and nanocarrier-mediated gene delivery. Although challenges such as immune clearance, bacterial resistance, and regulatory complexity remain, the convergence of AI, CRISPR, and synthetic biology is accelerating the evolution of phage therapy into a clinically viable precision-oncology strategy. In this context, bacteriophages emerge not merely as antibacterial agents but as intelligent, patient-specific nanomedicines poised to redefine therapeutic boundaries in cancer treatment.

Keywords:  Cancer immunotherapy; Engineered bacteriophages; Multidrug-resistant infections; Phage therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.critrevonc.2025.105085
Comput Struct Biotechnol J. 2025 ;28 592-608

Advancing rare disease therapeutics through digital twins: Opportunities in drug development and precision dosing.

Charlotte Maria Ursula Dette, Veronika Alberg, Simeon Rüdesheim, Dominik Selzer, Fatima Zahra Marok, Nicola Luigi Bragazzi, Laura Maria Fuhr, Søren Brunak, Ewan R Pearson, Tobias Zahn, Dimitra Kiritsi, Matthias Schwab, Thorsten Lehr.

  Rare disease(s) (RD/RDs) are typically characterized by (i) genetically driven chronic, and life-threatening disease progression, (ii) delayed diagnoses, (iii) limited treatment options, and (iv) substantial economic burdens due to direct and indirect medical costs. Challenges in RD research include limited patient populations, sparse disease data, poorly understood pathophysiology and reduced trial funding for new exploratory therapies. In recent years, digital twin(s) (DT/DTs) are increasingly used for patient care, disease management, and resource optimization. They serve as virtual replicas of individual patients that enable simulation, prediction, and optimization of outcomes through real-time data integration and can facilitate advancements in treatment outcome and prediction of disease progression leveraging model-based personalized predictions. This review included 16 studies and focuses on how DTs are currently used in RD research by analyzing the underlying modeling techniques, including physiologically based pharmacokinetic (PBPK) modeling, population pharmacokinetic (PopPK) modeling, quantitative systems pharmacology (QSP) modeling, physiome modeling, and combined approaches. It identifies the limitations of these models that currently prevent them from qualifying as true DTs. Furthermore, this review discusses the potential advantages of DTs in drug development for new treatment strategies, disease progression modeling, and clinical decision support for RD research. Finally, it outlines the current state of DT implementation in the RD field, revealing that DT implementation remains in an early stage of development.

Keywords:  Digital twins; Orphan diseases; Orphan drug development; Rare diseases; Recessive dystrophic epidermolysis bullosa

DOI:  https://doi.org/10.1016/j.csbj.2025.11.047
Hum Vaccin Immunother. 2025 Dec;21(1): 2599632

Bacteriophages as vaccine platforms: Opportunities and challenges in translation.

Wangxue Chen, Danielle L Peters, Serena Lam, Maryam Kettal.

  Bacteriophages (phages) have recently received increased interest as versatile candidates for vaccine development. Their inherent characteristics, such as ease of genetic manipulation, high-density antigen display, intrinsic immunostimulatory properties, demonstrated human safety, and scalability in bacterial hosts, make them attractive as next-generation vaccine platforms. Additionally, their cost-effective production, stability, and existing regulatory approval for food and compassionate phage therapy provide a strong foundation for further development of phage-based vaccines. This commentary summarizes the types of phages, the strategies used, and current advances in phage-based vaccine development for viral and bacterial targets, and discusses the promises and challenges of this platform for novel vaccine development. Phage-based vaccines represent an innovative and promising platform for vaccine development to address significant medical and public health challenges, particularly in antimicrobial resistance, pandemic preparedness, and One Health. Accumulative experimental data have demonstrated that phage-based vaccines induce specific cellular, humoral, and mucosal immune responses at magnitudes comparable to those induced by other vaccine platforms. However, a better understanding of phage biology (interactions with the human immune system and microbiome), more carefully designed preclinical studies, Good Manufacturing Practice production development, the regulatory framework, and ultimately clinical trials are needed before the full potential of this platform is realized.

Keywords:  One Health; Vaccine development; bacteriophage; pandemic responses; phage vaccines

DOI:  https://doi.org/10.1080/21645515.2025.2599632
Research (Wash D C). 2025 ;8 1029

Generative Artificial Intelligence in Medical Imaging: Foundations, Progress, and Clinical Translation.

Shanshan Wang, Xuanru Zhou, Cheng Li, Shuqiang Wang, Ye Li, Tao Tan, Hairong Zheng.

Generative artificial intelligence (AI) is rapidly transforming medical imaging by enabling capabilities such as data synthesis, image enhancement, modality translation, and spatiotemporal modeling. This review presents a comprehensive and forward-looking synthesis of recent advances in generative modeling-including generative adversarial networks (GANs), variational autoencoders (VAEs), diffusion models, and emerging multimodal foundation architectures-and evaluates their expanding roles across the clinical imaging continuum. We systematically examine how generative AI contributes to key stages of the imaging workflow, from acquisition and reconstruction to cross-modality synthesis, diagnostic support, treatment planning, and prognosis prediction. Emphasis is placed on both retrospective and prospective clinical scenarios, where generative models help address longstanding challenges such as data scarcity, standardization, and integration across modalities. To promote rigorous benchmarking and translational readiness, we propose a 3-tiered evaluation framework encompassing pixel-level fidelity, feature-level realism, and task-level clinical relevance. We also identify critical obstacles to real-world deployment, including limited generalization under domain shift, risks of hallucinated or unreliable features, data scarcity and privacy concerns, as well as stringent regulatory and ethical constraints. Finally, we explore the convergence of generative AI with large-scale foundation models, highlighting how this synergy may enable the next generation of scalable, reliable, and clinically integrated imaging systems. By charting technical progress and translational pathways, this review aims to guide future research and foster interdisciplinary collaboration at the intersection of AI, medicine, and biomedical engineering.

DOI: https://doi.org/10.34133/research.1029