Combination therapy with lipid prodrug liposomes reshapes disease-associated neutrophils to promote the cancer-immunity cycle

Neutrophils play a critical role in the cancer-immunity cycle and are associated with poor clinical outcomes. Recent research has primarily focused on the targeted delivery, phenotypic reversal, and reprogramming of tumor-associated neutrophils, while the impact of disease-associated neutrophils (DANs) on antitumor therapy remains understudied. Since liposomes, as drug delivery carriers, possess excellent biocompatibility and stability, making them particularly suitable for combination therapy, we optimized the formulation of asymmetrically branched polyethylene glycol-modified mitomycin C lipid prodrug liposomes (PEG_{2,5 K}@MLP-L) and prepared hyaluronic acid and sialic acid ester stearate-co-modified dexamethasone palmitate liposomes (HA*SAS@DXP-L) to study DANs in normal, obese, aged, and septic mice. An increase in mitochondria and lysosomes in Ly-6G⁺CXCR2^high DANs accelerated drug clearance, reduced CD3⁺CD8⁺ T cell activity in tumor-draining lymph nodes, and decreased CD8⁺ T cell infiltration in tumors. As the proportion of DANs increased, the efficacy of PEG_{2,5 K}@MLP-L decreased. Combination therapy with PEG_{2,5 K}@MLP-L and HA*SAS@DXP-L can reshape DANs, promote the cancer-immunity cycle, and enhance treatment efficacy. This study identifies key characteristics and functions of DANs and presents a promising strategy for improving clinical outcomes.