Inflammation is a key etiologic component in atherogenesis. Previously we demonstrated that adeno-associated virus (AAV) 2/8 gene delivery of Netrin1 inhibited atherosclerosis in the low density lipoprotein receptor knockout mice on high-cholesterol diet (LDLR-KO/HCD). One important finding from this study was that FOXP3 was strongly up-regulated in these Netrin1-treated animals, as FOXP3 is an anti-inflammatory gene, being the master transcription factor of regulatory T cells. These results suggested that the FOXP3 gene might potentially be used, itself, as an agent to limit atherosclerosis. To test this hypothesis AAV2/8 (AAV)/hFOXP3 or AAV/Neo (control) gene therapy virus were tail vein injected into the LDLR-KO/HCD animal model. It was found that hFOXP3 gene delivery was associated with significantly lower HCD-induced atherogenesis, as measured by larger aortic lumen cross sectional area, thinner aortic wall thickness, and lower aortic systolic blood velocity compared with Neo gene-HCD-treated controls. Moreover these measurements taken from the hFOXP3/HCD-treated animals very closely matched those measurements taken from the normal diet (ND) control animals. These data strongly suggest that AAV/hFOXP3 delivery gave a robust anti-atherosclerosis therapeutic effect and further suggest that FOXP3 be examined more stringently as a therapeutic gene for clinical use.

The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), defined as a tumour’s capacity to be recognised by the immune system and respond to immunotherapy. Tumours with intact antigen presentation pathways are more likely to generate effective antitumour responses, whereas APM defects promote immune escape and therapeutic resistance. Cancer cells frequently evade immune detection through altered antigen processing or reduced expression of major histocompatibility complex (MHC) class I molecules, limiting tumour antigen presentation to cytotoxic T lymphocytes. These alterations are increasingly recognised as determinants of response to immune checkpoint inhibitors and potential predictive biomarkers. APM defects may be reversible or irreversible. Interferon-mediated signalling can restore MHC class I expression and T-cell cytotoxicity in some tumours, whereas permanent genomic alterations affecting human leukocyte antigen (HLA) class I genes, β2-microglobulin (β2-m), or interferon-γ (IFN-γ) pathway components can severely impair antigen presentation. Emerging evidence highlights four mechanistic levels of APM perturbation: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. Each contributes to distinct patterns of immune evasion. This review examines how MHC class I alterations influence CIR and contribute to immune evasion and immunotherapy resistance in gastrointestinal malignancies, while discussing therapeutic strategies to restore or bypass APM deficiencies.

Metasta3c renal cell carcinomas using autologous T cells engineered to express MOv-γ and scFv(G250) chimeric receptors, respec3vely. Although these treatments were well tolerated, they did not reduce tumor burden, likely due to the limited in vivo persistence of the infused CAR-T cells.T-cell ac3va3on requires two signals: an3gen recogni3on through the TCR-pep3de-MHC (pMHC) interac3on and co-s3mula3on via receptors such as CD28. To address this limita3on, Dr. Michel Sadelain's group at MSKCC developed a chimeric receptor incorpora3ng both CD3ζ and CD28 signaling domains, thereby providing dual ac3va3on signals that enhanced an3gen-dependent prolifera3on, IL-2 secre3on, and cytotoxic ac3vity in vitro (Mitra et al., 2023). Second-genera3on CD19 CAR-T cell therapy has since revolu3onized the treatment of B-cell malignancies. However, in chronic lymphocy3c leukemia (CLL), response rates and durability remain inferior to those observed in other indolent B-cell lymphomas. In 2024, Derigs et al. reported early clinical results from the HD-CAR-1 trial, evalua3ng academically manufactured third-genera3on CAR-Ts in pa3ents with relapsed/refractory CLL (Derigs et al., 2024). Third-genera3on an3-GD2 CAR-T cells (GD2-CART01) showed promising efficacy in children with high-risk metasta3c, relapsed, or refractory neuroblastomas in a phase 1/2 trial. The Locatelli et al. (Locatelli et al., 2025) final report results from 54 children, confirming that GD2-CART01 can induce durable remissions in this popula3on. This Research Topic aimed to tackle the key challenges in developing sustainable and cost-effective CAR-T cell therapies. Its main objectives were to identify promising strategies for reducing manufacturing costs, automate production processes to minimize human error, and enhance the therapeutic efficacy of CAR-T cells. The research also sought to explore how to lower CAR immunogenicity, improve infiltration into the tumor microenvironment, and prevent antigen escape. By addressing these critical areas, the work aimed to advance the field toward more effective, accessible, and safer cancer treatments.In their manuscript, Harer et al. (Harrer et al., 2023) discussed upcoming strategies and current challenges in designing CARs for recognition of antigen low cancer cells, aiming at augmenting sensitivity and finally therapeutic efficacy while reducing the risk of tumor relapse. Specifically, CAR-T cells are engineered "living drugs" designed to recognize specific tumor an3gens and eliminate malignant cells through targeted immune ac3va3on. Despite their success in trea3ng B cell malignancies, many pa3ents experience relapse due to an3gen loss or T cell exhaus3on, which limits long-term efficacy. To overcome these challenges, current research focuses on developing next-genera3on CARs with enhanced an3gen sensi3vity, enabling the detec3on and elimina3on of cancer cells expressing low levels of target an3gens. Cancer cells can evade CAR-T cell therapy by reducing the expression of target an3gens, rendering them invisible to immune aqack and leading to tumor relapse. Although enhancing CAR-T cell sensi3vity to low an3gen levels could address this issue, it also raises significant safety concerns, as many tumor-associated an3gens are shared with healthy 3ssues, increasing the risk of on-target off-tumor toxicity. Consequently, ongoing research focuses on balancing efficacy and safety through strategies such as logic-gated CAR designs, coopera3ve targe3ng approaches, and the careful selec3on of tumor-selec3ve an3gens to minimize adverse effects while maximizing therapeu3c benefits. CAR-T cell therapy has made remarkable strides in trea3ng hematological malignancies. However, the widespread adop3on of CAR-T cell therapy is hindered by several challenges. Li et al. (Li et al., 2024) comprehensively examined the clinical challenges of CAR-T cell therapy and outlined strategies to overcome them, aiming to chart pathways beyond its current Achilles' heels. CAR T cell therapies have achieved remarkable success in trea3ng hematologic cancers, yet their broader use remains limited by high costs, long manufacturing 3mes, safety issues, and variable efficacy. Advancements in gene edi3ng technologies and delivery systems are essen3al to overcome these barriers and redefine the development of next-genera3on CAR-T cells. As these tools con3nue to evolve, they hold the promise of crea3ng safer, more potent, and more accessible CAR-T cell therapies, transforming them into rou3ne and affordable treatment op3ons for a wider range of pa3ents. Although CAR-T cell therapy remains one of the most innova3ve immunotherapeu3c approaches with remarkable clinical success, its broader applica3on is limited by lengthy manufacturing 3mes, high costs, and pa3ent-to-pa3ent variability (Chen et al., 2024). Despite notable advances in the development of universal CAR T (U-CAR T) cells, a stable and standardized cell bank has yet to be achieved. Mohammad et al. (Mohammad et al., 2024) systema3cally reviewed and evaluated the efficacy of modular (universal) CAR T-cell plasorms in xenograt mouse models. Across 33 studies encompassing 15 dis3nct plasorm designs, modular CAR-T cells were shown to significantly reduce tumor burden and improve survival compared to nega3ve controls, achieving outcomes comparable to conven3onal CAR-T cell therapies. Overall, these findings suggest that modular CAR T-cell plasorms are effec3ve and represent a promising, flexible, and controllable approach for next-genera3on cancer immunotherapy. Select pa3ents with relapsed/refractory aggressive B cell lymphoma may benefit from bridging radia3on (bRT) prior to an3-CD19-directed CAR-T. Manzar et al. (Manzar et al., 2025) evaluated 51 adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received bridging radia3on therapy (bRT) prior to an3-CD19 CAR-T cell therapy. Just over half (51%) received comprehensive bRT to all disease...

Background: Bladder cancer (BLCA) remains a prevalent and complex malignancy characterized by significant heterogeneity. Treatment strategies are diverse, based on patient characteristics and cancer stage. Early identification of biomarkers is crucial for improving diagnosis, staging, and treatment planning. These biomarkers offer valuable insights into lesion features, tumor differentiation, and disease progression, thereby playing a pivotal role in the personalized management of BLCA. Objective: This study investigated the expression of cancer-testis antigens SPEF1 and SPEF2 in BLCA using comprehensive bioinformatic analyses to assess their potential as biomarkers. Methods: The UALCAN database, based on The Cancer Genome Atlas datasets, was employed to compare SPEF1 and SPEF2 expression levels in normal bladder tissues and BLCA samples. In addition, the Kaplan–Meier Plotter, OncoDB, and TIMER 2.0 platforms were utilized to evaluate the prognostic and immunotherapeutic relevance of these antigens. Results: The findings suggest that SPEF1 and SPEF2 are integral to various biological processes driving BLCA onset and progression. Both genes appear to facilitate BLCA cell progression and migration, contributing to poor prognosis through specific pathways and by altering tumor microenvironment. Notably, SPEF1 expression was significantly upregulated in BLCA tissues compared to normal tissues. Conversely, higher SPEF2 expression was associated with longer overall survival and positively correlated with immunotherapeutic targets. Conclusion: Although these results were derived from in silico analyses, they offer insights into the potential roles of SPEF1 and SPEF2 as biomarkers. Further studies are warranted to validate these biomarkers in retrospective patient cohorts to establish their clinical utility.