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

Abstract 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.