Albumin‐Hitchhiking Drug Delivery to Tumor‐Draining Lymph Nodes Precisely Boosts Tumor‐Specific Immunity through Autophagy Modulation of Immune Cells

Abstract Tumor‐draining lymph nodes (TDLNs) are the first sites where tumor components reach and dendritic cells (DCs) present tumor‐associated antigens to T cells. DCs rely on autophagy to process tumor antigens into epitope peptides to form epitope‐MHC complexes. Selective delivery of autophagy‐stimulating drugs to TDLNs may be a precise strategy to boost chemotherapy‐induced antitumor immunity. Here, a multistage stimulating strategy is proposed to activate the antitumor immunity cascade by inducing immunogenic death of tumor cells and elevating antigen presentation of DCs in TDLNs. A tumor‐microenvironment‐responsive “albumin‐hitchhiking” micelle is established by self‐assembling tumor‐targeting oxaliplatin prodrug and lipophilized trehalose prodrug. This demonstrates that lipophilic modification of trehalose with a DSPE tail and the precise exposure in the tumor site enhances its binding to endogenous albumin and realizes TDLNs‐selective reflux, where it upregulates antigen processing and presentation of DCs. This study introduces an approach for targeted delivery to TDLNs and provides insights into mechanisms of autophagy in tumor‐specific immunity.