• SRC and TOPK are overexpressed and positively correlated in LUSC, correlating with poor patient survival.
• A positive feedback loop between SRC and TOPK promotes LUSC tumorigenicity by phosphorylating RB1 and inhibiting its tumor suppressor function.
• Targeting SRC and TOPK synergistically induces apoptosis in LUSC cells and shows efficacy in vivo, suggesting a novel therapeutic strategy.
• This study identifies the SRC-TOPK-RB1 axis as a promising precise therapeutic target for LUSC, addressing the current lack of targeted therapies.