Academic Journal
Reprogramming CAR T cells across genetic, epigenetic, metabolic and microenvironmental axes to improve efficacy and safety in cancer and autoimmune disease.
| Title: | Reprogramming CAR T cells across genetic, epigenetic, metabolic and microenvironmental axes to improve efficacy and safety in cancer and autoimmune disease. |
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| Authors: | Scherlinger M; Rheumatology Department, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Strasbourg University Hospital, Strasbourg, France.; UMR Inserm 1109 Immuno-Rhumatologie Moléculaire, Centre de recherche en biomédecine de Strasbourg (CRBS), Strasbourg, France. |
| Source: | Frontiers in immunology [Front Immunol] 2026 Apr 07; Vol. 17, pp. 1806459. Date of Electronic Publication: 2026 Apr 07 (Print Publication: 2026). |
| Publication Type: | Journal Article; Review |
| Language: | English |
| Journal Info: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| MeSH Terms: | Autoimmune Diseases*/therapy , Autoimmune Diseases*/immunology , Autoimmune Diseases*/genetics , Autoimmune Diseases*/metabolism , Neoplasms*/therapy , Neoplasms*/immunology , Neoplasms*/genetics , Neoplasms*/metabolism , Immunotherapy, Adoptive*/methods , Immunotherapy, Adoptive*/adverse effects , Receptors, Chimeric Antigen*/immunology , Receptors, Chimeric Antigen*/genetics , Receptors, Chimeric Antigen*/metabolism , T-Lymphocytes*/immunology , T-Lymphocytes*/metabolism , Epigenesis, Genetic* , Cellular Reprogramming*, Tumor Microenvironment/immunology ; Humans ; Animals ; Metabolic Reprogramming |
| Abstract: | CAR T-cell therapy has delivered durable remissions in several hematologic cancers, yet activity in solid tumors and extension to immune-mediated diseases remain constrained by recurring failure modes: imperfect antigen specificity, inadequate trafficking, progressive dysfunction under chronic stimulation, and toxic inflammatory syndromes. Early reports of CAR-based immune "resets" in refractory autoimmune disease amplify both promise and stakes, because acceptable risk is lower than in cancer and "on-target" effects may still be clinically unacceptable if they create long-term immunodeficiency. This review treats CAR T optimization as multi-layer reprogramming across genetic circuitry, epigenetic state, metabolism, and the tissue microenvironment. We argue that many celebrated single-layer upgrades (stronger signaling, checkpoint deletion, constitutive cytokine armoring) often trade one failure mode for another. Instead, the most credible path to simultaneously improving efficacy and safety is disciplined, failure-mode-driven design: (i) programmable antigen logic and titratable activation to reduce off-tissue damage; (ii) epigenetic programming that preserves renewable functional states without removing essential restraints; (iii) metabolic rewiring evaluated under physiologic stress conditions; and (iv) microenvironment-aware strategies that prioritize access and local control over brute-force potency. (Copyright © 2026 Scherlinger.) |
| Competing Interests: | MS has received consultancy fees unrelated to this topic from Abbvie, Amgen, AstraZeneca, Biogen, BMS, Fresenius, Galapagos, GSK, Nordic Pharma, Novartis, Roche, Sandoz. |
| Contributed Indexing: | Keywords: CAR T cells; CAR-Treg; autoimmunity; exhaustion; genome editing; immunometabolism; safety switches; tumor microenvironment |
| Substance Nomenclature: | 0 (Receptors, Chimeric Antigen) |
| Entry Date(s): | Date Created: 20260423 Date Completed: 20260715 Latest Revision: 20260715 |
| Update Code: | 20260716 |
| PubMed Central ID: | PMC13096093 |
| DOI: | 10.3389/fimmu.2026.1806459 |
| PMID: | 42023226 |
| Database: | MEDLINE |
| ISSN: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2026.1806459 |