Transient T cell therapies.

In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.

This review highlights key engineering strategies enabling in vivo CAR T-cell generation, summarizes emerging clinical research and development, and discusses future opportunities for expanding in vivo CAR T-cell therapies as scalable immunotherapy platforms.

In vivo CAR‑T therapy: recent progress and future directions

CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.

A three-layer mechanistic framework is presented that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting preconfigures functional trajectories.

In vivo CAR T cells on the highway: a roadmap for the next decade.

INTRODUCTION Chimeric antigen receptor (CAR) T cell therapy has shown efficacy in the treatment of hematological malignancies. However, the application to a broader patient population is still limited by the complex logistics in coordinating the lymphodepleting chemotherapy and the labor-, time-, and cost-intensive ex vivo manufacturing of patients' CAR T cells in specialized centers. By combining recent advances in lipid nanotechnology, RNA chemistry, and viral particle targeting, engineering CAR T cells in the patient's blood stream is becoming an emerging option that may overcome current limitations. Advanced pre-clinical and early clinical studies support this approach by demonstrating successful engineering of CAR T cells in vivo and producing some anti-tumor responses in clinical trials. AREAS COVERED We review delivery strategies using viral and non-viral vectors, summarize the translation into clinical application, and outline strategies for optimization. We further discuss current challenges with respect to targeting specificity, genomic safety, pharmacokinetics, host immune responses, and regulatory oversight. EXPERT OPINION Although still in its infancy, in vivo genetic engineering shows promise for CAR T cell therapy in a wide range of cancer patients. It also has the potential to reprogram patients' immunity in autoimmunity, chronic infections, and regenerative medicine.

In-vivo CAR-T Cell Engineering: A Narrative Review of Emerging Delivery Strategies and Their Potential Future Impact on Accessibility

If in-vivo CAR-T therapy approaches continue to mature, they may offer a more scalable, cost-effective, and accessible alternative to traditional ex vivo CAR-T therapy, though this remains a projected rather than demonstrated benefit.

Reprogramming CAR-T Cell Therapy for Solid Tumors: Combination Strategies to Overcome Resistance

The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.