Authors
Miao Tian, Teizo Yoshimura, Kun Zhao, Chunning Li, Tong Gao, Ziyi Wang, Masayoshi Fujisawa, Toshiaki Ohara, Akihiro Matsukawa
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77909. Sep 27, 2026. Epub Sep 27, 2026.
Abstract
Activation of the RAS/RAF/ERK pathway is crucial for adaptive immunity. Here, we provide evidence that Sprouty-related EVH1 domain containing 2 (SPRED2), an endogenous inhibitor of this pathway, negatively regulates CD8+ T cell-mediated antitumor immunity in breast cancer. In EO771 and 4T1 mouse models, Spred2-/- mice exhibit reduced tumor growth, with lower endpoint lung metastatic burden in the 4T1 model, accompanied by increased T-cell infiltration and activation. Spred2-/- T cells show enhanced cytokine expression, proliferation, survival, in vitro cytotoxicity, and memory-like phenotypes, particularly among CD8+ T cells. Adoptive transfer of Spred2-/- CD8+ T cells into tumor-bearing wild-type hosts similarly reduces endpoint lung metastatic burden. MEK inhibition with U0126 attenuates increased interferon-gamma and granzyme B expression in Spred2-/- CD8+ T cells. Transcriptomic analyses reveal an inverse correlation between SPRED2 expression and antitumor CD8+ T cell states in both humans and mice. In tumor-infiltrating T cells from patients with breast cancer, SPRED2low T cells show enriched effector and cytotoxicity programs and are associated with "immune-hot" tumors, whereas survival associations vary with CD8+ T cell context. Collectively, these findings suggest that SPRED2 functions as a cell-intrinsic negative regulator of CD8+ T-cell activation and highlight its potential as a therapeutic target to enhance T cell-based cancer immunotherapy.
PMID:
42801625
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.
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