The JAK1 inhibitor golidocitinib boosts therapeutic potency of DLL3-targeted CAR-T therapy for small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy with limited effective therapeutic options. DLL3-targeted CAR-T therapy shows promising anti-tumor potential but is often restricted by T-cell exhaustion, which impairs its long-term efficacy. In the present study, we found that golidocitinib, a highly selective JAK1 inhibitor, induces apoptosis in SCLC cells in vitro via inhibiting STAT3 phosphorylation and regulating apoptosis‑associated genes. It also reduced the expression of exhaustion markers in anti-DLL3 CAR-T cells, promoted the formation of memory T cell phenotypes, and enhanced CAR-T cell persistence both in vitro and in vivo. When combined with anti-DLL3 CAR-T therapy, golidocitinib significantly augmented anti-tumor efficacy in both in vitro cytotoxicity assays and in vivo models, without obvious organ toxicity. These findings collectively demonstrate the dual anti-tumor effects of golidocitinib, thus providing a novel and promising strategy for SCLC treatment.