SPRED2 Negatively Regulates CD8 ⁺ T Cell‐Mediated Antitumor Immunity in Breast Cancer

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, SPRED2 ^low 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.