Cryo‐Shocked Tumor‐Reprogrammed Sonosensitive Antigen‐Presenting Cells Improving Sonoimmunotherapy via T Cells and NK Cells Immunity

Ultrasound therapy has turned up as a noninvasive multifunctional tool for cancer immunotherapy. However, the insufficient co-stimulating molecules and loss of peptide-major histocompatibility complex I (MHC-I) expression on tumor cells lead to poor therapy of sonoimmunotherapies. Herein, this work develops a sonosensitive system to augment MHC-I unrestricted natural killer (NK) cell-mediated innate immunity and T cell-mediated adaptive immunity by leveraging antigen presentation cell (APC)-like tumor cells. Genetically engineered tumor cells featuring sufficient co-stimulating molecules are cryo-shocked and conjugated with a sonosensitizer, hematoporphyrin monomethyl ether, using click chemistry. These cells (DPNLs) exhibit characteristics of tumor and draining lymph node homing. Under ultrasound, NK cell-mediated innate immunity within the tumor microenvironment could be activated, and T cells in the tumor-draining lymph nodes (TDLNs) are stimulated through co-stimulatory molecules. In combination with programmed cell death ligand 1 (PD-L1) antibody, DPNLs extend the survival time and inhibited lung metastasis in triple-negative breast cancer (TNBC) models. This study provides an alternative approach for sonoimmunotherapy with precise sonosensitizer delivery and enhanced NK cell and T cell activation.