Carboxymethylated Alginate-Resiquimod Micelles Reverse the Immunosuppressive Tumor Microenvironment and Synergistically Enhance the Chemotherapy and Immunotherapy for Gastric Cancer

Due to the intrinsic weak immunogenicity of tumor cellsand thequantitatively and functionally different populations of immune cells,immunosuppression has become the major obstacle for cancer immunotherapy.In this study, the biocompatible alginate was chemically modifiedwith the carboxyethyl linker to facilitate the esterification reactionof the resultant carboxymethylated alginate (CMA) and resiquimod (R848),the agonist of Toll-like receptor 7/8 (TLR7/8a). In aqueous solution,the hydrophilic CMA and the hydrophobic R848 formed stable nanomicelles(CMA-R848) by self-assembling. After combined administration of CMA-R848and cisplatin (Cis) in a gastric cancer (GC) model, the long-circulatingCMA-R848 micelle reached the mild acidic tumor microenvironment (TME);the ester bonds were quickly cleaved by the ubiquitous esterase andreleased the single molecule of R848. In vitro and in vivo results demonstrated that the released R848 efficientlypromoted co-stimulatory molecules' expression of dendriticcells (DCs), enhanced the antigen uptake and cross-presentation, andprimed the cytotoxic T lymphocytes' (CTLs) infiltration andkilling effects, thereby reprogramming the "cold tumor"into the "hot tumor". In addition, the ex vivo tumor sections revealed that the released R848 effectively repolarizedthe M2-like tumor-associated macrophages (TAMs) into M1-like macrophages,exerted synergistic antitumor activity, reduced the tumor burden,and prolonged the overall survival duration of the GC animal model.Our study provided a targeting therapeutic strategy overcoming thelimitations of R848 in vivo, and enhanced the efficacyof GC chemotherapy and immunotherapy by TME modulation.