Ultrasound Visualization of Spatiotemporal Autophagy-Regulated Nanodroplets for Amplifying ICB in Melanoma via Remodeling Tumor Inflammatory Microenvironment

Immune checkpoint blockade (ICB) therapy, represented by anti-PD-1/PD-L1 antibodies, is confronted with difficulties of unsatisfied response rates owing to the prevalence of "cold" immune tumor microenvironment (TME) in most cancers. Blocking cytoprotective autophagy has emerged as a potential strategy to remodel the inflammatory TME. Nevertheless, the dual roles of autophagy in tumor progression, coupled with the poor pharmacokinetic properties of small-molecule autophagy inhibitors, significantly restrict clinical applications. To address these challenges, a low-intensity focused ultrasound (LIFU) responsive phase-change nanodroplet delivery platform (SP@Lip-PEG) is elaborately developed to deliver specific autophagy inhibitor SAR405 for activating typical tumor-resident immune cells. The PEG-modified nanodroplets effectively accumulate into the tumor site. Upon LIFU activation, SP@Lip-PEG transforms into microbubbles through acoustic droplet vaporization (ADV) effects, enabling the controlled release of SAR405 under ultrasound imaging guidance. The released SAR405 significantly triggered the upregulation of proinflammatory factors CCL5 and CXCL10 through autophagy manipulation, creating an inflammatory TME to facilitate the recruitment of natural killer (NK) cells and CD8⁺ T cells, along with promoting dendritic cell (DC) maturation and synergistically enhancing ICB efficacy. With the high specificity of SAR405 and the controllable therapeutic process under LIFU irradiation, this noninvasive, efficient, and cost-effective drug delivery vector opened new horizons for conquering the clinical dilemma of rescuing ICB response rates.