Targeting secreted MDK-mediated tryptophan/kynurenine metabolism enhances DLL3 CAR T therapy for SCLC

Small cell lung cancer (SCLC) exhibits profound immunometabolic suppression that impairs antigen presentation and constrains immunotherapy efficacy. Through integrated multi-omics analyses of primary human SCLC tumors, we identified midkine (MDK) as a dominant tumor-secreted driver of immune evasion. Mechanistically, MDK activates STAT3 to induce indoleamine 2,3-dioxygenase 1 (IDO1), driving tryptophan-kynurenine metabolic reprogramming. This axis suppresses myeloid antigen presentation, reduces HLA class I expression, and impairs CD8+ T cell function, establishing a immunosuppressive tumor microenvironment (TME). We engineered DLL3-targeted CAR T cells secreting anti-MDK scFv. These dual-functional CAR T cells neutralize MDK within the TME, restore antigen presentation, alleviate metabolic suppression, and reinvigorate CD8+ T cell responses. In SCLC models, they exhibited markedly enhanced antitumor activity, improved metabolic fitness, and durable immune activation without systemic toxicity. Collectively, our findings identify MDK as a key immunometabolic regulator and support sMDK-DLL3 CAR T cells as a targeted immunotherapy for SCLC.