A neutrophil-tumor cascade-targeting Trojan horse for heterobifunctional prodrug delivery to enhance cGAS-STING cancer immunotherapy

BACKGROUND: Since the discovery of the cGAS-STING pathway, attempts to utilize it as an anti-tumor immunotherapy have attracted significant research interest and investment. However, relevant clinical translation remains hindered by immune evasion and systemic toxicity. RESULTS: We introduce BMSA, a first-in-class STING-PD-L1 heterobifunctional prodrug in which the PD-L1 inhibitor BMS-1 and the STING agonist MSA-2 are bridged by a tumor-cleavable linker. BMSA executes glutathione-triggered extracellular release of BMS-1 and intracellular esterase-mediated liberation of MSA-2, synchronizing dual immune signals at their respective sites of action. To confine activation to the tumor, we encapsulated BMSA into neutrophil-hitchhiking nanoparticles (T-NPs). After tail intravenous injection, T-NPs hijacked circulating neutrophils, accumulated at irradiated tumors via X-ray-induced inflammation, and exposed the fibrin-binding peptide CREKA through MMP-2/9 cleavage, producing markedly intratumoral accumulation while minimizing systemic exposure. CONCLUSION: This "Neutrophil-Tumor" cascade delivered heterobifunctional immunomodulation drugs with spatial and temporal precision, offering a translatable solution to the toxicity-efficacy dilemma that currently constrains STING-based cancer therapy.