DCX+ cells cripple systemic spleen immunity and promote tumor progression

• DCX + cells in human and mice with cancer show distinct distribution pattern. • Human cancer-associated DCX + cells might not be NPCs. • Mice DCX deficiency rescues spleen immunity during carcinogenesis. • DCX is required for sympathetic nerves-CD8 + T cells interaction in mice spleen. The neuronal microtubule-associated protein doublecortin (DCX), traditionally known for its expression in neural precursor cells and its critical roles in neurogenesis and neuronal migration, has recently emerged as a potential player in cancer progression. However, its specific functions in tumor immunity remain largely unexplored. Here, we reveal a distinct central and peripheral distribution of DCX + cells in human and murine cancers. In non-neurological solid tumors of human, DCX + cells, as new tumor stromal components, may lack neuronal maturation capacity and exhibited a dopaminergic phenotype (NeuN − /CD45 − /c-Kit − /CD31 + /TH + /DAT + ), and localized within highly invasive stromal microenvironments. Their presence correlated with postoperative tumor recurrence and reduced circulating CD8 + T cells. In 4NQO-induced murine tumor models, DCX knockdown delayed tumor progression and restored systemic antitumor immunity, characterized by diminished immunosuppressive IRF4 + cDC2 cells and attenuated CD8 + T cell exhaustion in the spleen. Notably, DCX was absent in murine tumor tissues and spleen, suggesting that DCX-mediated systemic immune regulation exclusively involved brain DCX + cells, which functionally connected to peripheral sympathetic innervation of ADRB2 + splenic immune cells. Depletion of DCX + cells downregulated splenic neurotrophins, including PGF, FGF2, GDF15, and BMPs. Even under non-tumor conditions, DCX deficiency disrupted direct sympathetic nerve-CD8 + T cell interactions, unleashing CD8 + T cell activation and intrasplenic migration. Although mechanistic differences may exist between species, our findings identify DCX + cells as a novel brake on T cell activation, bridging neural and immune regulation in cancer.