Genome Editing for Glioblastoma Immunotherapy: Delivery, Immune Exclusion, and Antigen Heterogeneity

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant cancers, with immunotherapy approaches facing persistent barriers to efficacy. Despite advances in checkpoint blockade, CAR-T cells, and vaccine strategies, clinical outcomes have been limited by key challenges intrinsic to GBM biology, including inefficient delivery across the blood–brain barrier, profound immune exclusion within the tumor microenvironment, and extensive antigen heterogeneity that enables immune escape. Genome editing technologies are now emerging as powerful tools to overcome these obstacles, offering precise ways to reprogram immune cells, sensitize tumors, and uncover actionable targets.This Research Topic will explore how genome editing—encompassing CRISPR-based nucleases, base editors, prime editors, and epigenome-modifying systems—can be leveraged to enhance immunotherapeutic strategies for GBM. A central focus is on improving delivery systems capable of reaching tumor cells and immune populations within the central nervous system, including viral and non-viral vectors, nanoparticle-based approaches, and cell-mediated delivery. We also highlight the need to address immune exclusion by editing tumor-intrinsic pathways and the surrounding microenvironment to promote immune infiltration, persistence, and function.Another critical theme is antigen heterogeneity, a defining feature of GBM that undermines targeted therapies. Genome editing enables both the discovery of novel tumor antigens and the engineering of immune cells with multi-targeting or adaptable recognition systems to mitigate antigen loss. In parallel, editing strategies can be used to modulate antigen presentation, enhance tumor visibility, and reduce immunosuppressive signaling.We invite submissions that develop or apply genome editing approaches to improve GBM immunotherapy, with an emphasis on mechanistic insight, translational relevance, and innovative model systems. We have a particular interest in original research articles that present new data and experimental advances, while also welcoming complementary methodological and conceptual contributions that push the field forward. Studies integrating multi-omics profiling, single-cell analyses, and functional screening are especially encouraged, as are efforts that address safety, specificity, and clinical scalability.Key themes and welcomed contributions include:1. Genome editing strategies to enhance immune cell therapies (e.g., CAR-T, TCR-T, NK cells) for GBM2. Overcoming delivery barriers, including blood–brain barrier penetration and tumor-targeted editing3. Editing tumor and microenvironmental pathways to reverse immune exclusion and immunosuppression4. Targeting antigen heterogeneity through multiplexed editing, neoantigen discovery, and adaptive targeting strategies5. Modulation of antigen presentation and immune recognition pathways6. High-throughput and single-cell approaches to map editing outcomes and immune responses in GBM models7. Advanced in vitro and in vivo models, including organoids and patient-derived systems, to evaluate edited therapies8. Safety, off-target effects, and translational considerations for clinical applicationBy bringing together advances in genome engineering and tumor immunology, this Research Topic aims to accelerate the development of next-generation therapies capable of overcoming the unique barriers posed by glioblastoma Topic editors: Hien Chi Nguyen, Cihan Tastan Source: https://www.frontiersin.org/research-topics/79451/genome-editing-for-glioblastoma-immunotherapy-delivery-immune-exclusion-and-antigen-heterogeneity