9KMC

Cryo-EM structure of the heterotrimeric interleukin-2 receptor in complex with interleukin-2 and anti-CD25 Fab S417

Summary for 9KMC

• Entry DOI: 10.2210/pdb9kmc/pdb
• EMDB information: 62427
• Descriptor: Interleukin-2 receptor subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose, Interleukin-2 receptor subunit beta, ... (10 entities in total)
• Functional Keywords: cytokine, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 146775.96

Authors

Katsura, K.,Matsumoto, T.,Shirouzu, M. (deposition date: 2024-11-15, release date: 2025-11-19, Last modification date: 2026-02-18)

Primary citation

Itoh-Nakadai, A.,Liang, M.,Shindo, M.,Bibi, C.,Tomizawa-Murasawa, M.,Fujiki, S.,Kaneko, A.,Kanamaru, E.,Hashimoto, M.,Kajita, H.,Ando, Y.,Kojima, M.,Moody, J.,Iwasaki, M.,Takagi, S.,Nakagawa, R.,Agrawal, S.,Amitani-Iijima, H.,Sato, K.,Sorimachi, Y.,Suzuki, N.,Fukami, T.,Hanada, K.,Morita, S.,Katsura, K.,Matsumoto, T.,Kobayashi, M.,Kato, M.,Negishi, Y.,Shirouzu, M.,Najima, Y.,Takubo, K.,Hon, C.C.,Uchida, N.,Taniguchi, S.,Momozawa, Y.,Carninci, P.,Shultz, L.D.,Saito, Y.,de Hoon, M.,Shin, J.W.,Ishikawa, F.
CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.
Nat Commun, 17:101-101, 2026

PubMed Abstract: Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B-cell malignancies, but its success in acute myeloid leukemia (AML) remains limited. Durable responses depend on the formation of long-lived memory T cells, whereas T cell exhaustion contributes to non-response and relapse. In patients with AML who achieved remission after cord blood transplantation, we here first observe enrichment of memory T cells with high expression of the chemokine receptor CXCR4. Next, we show that engineering CAR-T cells to co-express CXCR4 enhances their persistence and anti-leukemic activity in patient-derived xenograft models. Using single-cell profiling and metabolic analysis, we find that CXCR4 promotes memory-associated transcriptional programs, reduces exhaustion, and supports oxidative metabolism. These effects are observed with CAR-T cells targeting CD25 or CD96 as AML-associated targets. Our results indicate that CXCR4 strengthens CAR-T cell memory and durability, offering a strategy to improve immunotherapy outcomes in AML and beyond.

PubMed: 41587986
DOI: 10.1038/s41467-025-67745-x

Experimental method

ELECTRON MICROSCOPY (2.97 Å)