In Situ Vaccination with Mitochondria‐Targeting Immunogenic Death Inducer Elicits CD8(+) T Cell‐Dependent Antitumor Immunity to Boost Tumor Immunotherapy

In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria‐targeting modification of fenofibric acid (FFa), a lipid‐lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria‐targeting FFa (Mito‐FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS‐STING‐dependent type I interferon (IFN‐I) secretion. The synchronous CRT exposure and IFN‐I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross‐priming of CD8(+) T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito‐FFa injection turns immune‐cold tumors into hot ones and elicits systemic tumor‐specific CD8(+) T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD‐L1 blockade and good bio‐safety of i.t. Mito‐FFa administration suggest the great translational potential of Mito‐FFa in tumor immunotherapy.