Engineered CAR-T cells induce long-lasting remission in rheumatoid arthritis with a single infusion

For the 18 million people living with rheumatoid arthritis, disease management currently means a lifetime of injections—a reality that new research from Tsinghua University may soon begin to change. Current first-line biologics targeting tumor necrosis factor (TNF)—including adalimumab (Humira), long among the world’s best-selling drugs—require injections every two weeks, potentially for decades. Prolonged use drives anti-drug antibody (ADA) formation in many patients, eroding therapeutic benefit and causing secondary treatment failure. Chronic TNF blockade also heightens infection risks, including latent tuberculosis reactivation. Emerging targeted protein degradation (TPD) technologies, such as LYTACs and KineTACs, offer promising alternatives. Yet, all rely on the host’s endogenous degradation machinery and require repeated dosing—making them poorly suited to chronic disease management.

A research team led by Professor Min Peng at Tsinghua University has now developed a fundamentally different approach. Published in hLife, the study reports engineered CAR-T cells—termed TNFR1T_IF cells—that specifically capture and degrade soluble TNF through receptor-mediated endocytosis, functioning as a self-renewing, living cellular drug. A single infusion of TNFR1T_IF cells prevented and treated all stages of RA in human TNF-transgenic mice, lowering serum human TNF to near wild-type levels and matching the efficacy of repeated high-dose adalimumab—without redosing or ADA risk.

“Existing anti-TNF biologics rely on neutralization rather than degradation, while all current targeted protein degradation tools borrow the host’s endogenous protein degradation machinery—an approach that can introduce unpredictable side effects and fundamentally limits durability,” said Professor Min Peng, corresponding author and researcher at Tsinghua University’s Institute for Immunology. “By recruiting an exogenous cellular platform—CAR-T cells—to perform the degradation, we bypass this limitation entirely. Our vision is a one-time intervention that provides years of sustained benefit for patients with chronic inflammatory disease.”

The TNFR1 CAR was constructed by fusing the mouse TNFR1 ectodomain (amino acids 1–212) with CD28 co-stimulatory and CD3ζ signaling domains. To overcome a key translational barrier—conventional CAR-T cells’ failure to expand without lymphodepleting preconditioning—the team co-deleted Bcor and Zc3h12a via CRISPR-Cas9. The resulting TNFR1T_IF cells expanded robustly and maintained stable levels in peripheral blood for more than one year in fully immunocompetent mice, with no conditioning regimen required. Their persistence proved strictly TNF-dependent, as expansion was abolished in TNF-knockout animals. Twelve-month safety monitoring revealed no disruption of endogenous T cell homeostasis, organ integrity, or antibacterial immunity. A pharmacological safety switch—anti-Thy1.1 depleting antibody—efficiently eliminated TNFR1T_IF cells in vivo, providing a controllable fail-safe mechanism for potential clinical translation.

This work marks a conceptual shift in the targeting scope of CAR-T cell therapy, extending it from cell-surface antigens to soluble extracellular proteins. The platform is broadly applicable: other disease-relevant cytokines (IL-1β, IL-4, IL-17) and extracellular aggregates, such as amyloid-β in Alzheimer’s disease, are natural candidates. The team envisions adapting the safety switch to the clinical setting by substituting FDA-approved surface markers, such as truncated EGFR or CD20, targetable by cetuximab or rituximab, respectively.

This work was conducted at the State Key Laboratory of Molecular Oncology, Institute for Immunology, and School of Basic Medical Sciences, Tsinghua University, Beijing, China, in collaboration with Shanxi Medical University. Support was provided by the National Natural Science Foundation of China (Grant Nos. T2495270 and 82350108), the Tsinghua University DUSHI Program (Grant No. 52302102323), the Tsinghua-Peking Center for Life Sciences, and the SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine.

About Author: 

Professor Min Peng is a principal investigator and Associate Professor at the State Key Laboratory of Molecular Oncology, Institute for Immunology, and School of Basic Medical Sciences, Tsinghua University. His laboratory focuses on T cell biology, engineered immune cell therapy, and cellular approaches to chronic inflammatory disease. His work has been published in Nature Immunology, Journal of Experimental Medicine, Journal of Clinical Investigation, Cell Reports, and hLife, among others.

DOI Link:

https://doi.org/10.1016/j.hlife.2026.05.003