Mitochondrial Localized In Situ Self‐Assembly Reprogramming Tumor Immune and Metabolic Microenvironment for Enhanced Cancer Therapy

Abstract The inherent immune and metabolic tumor microenvironment (TME) of most solid tumors adversely affect the antitumor efficacy of various treatments, which is an urgent issue to be solved in clinical cancer therapy. In this study, a mitochondrial localized in situ self‐assembly system is constructed to remodel the TME by improving immunogenicity and disrupting the metabolic plasticity of cancer cells. The peptide‐based drug delivery system can be pre‐assembled into nanomicelles in vitro and form functional nanofibers on mitochondria through a cascade‐responsive process involving reductive release, targeted enrichment, and in situ self‐assembly. The organelle‐specific in situ self‐assemblyeffectively switches the role of mitophagy from pro‐survival to pro‐death, which finally induces intense endoplasmic reticulum stress and atypical type II immunogenic cell death. Disintegration of the mitochondrial ultrastructure also impedes the metabolic plasticity of tumor cells, which greatly promotes the immunosuppresive TME remodeling into an immunostimulatory TME. Ultimately, the mitochondrial localized in situ self‐assembly system effectively suppresses tumor metastases, and converts cold tumors into hot tumors with enhanced sensitivity to radiotherapy and immune checkpoint blockade therapy. This study offers a universal strategy for spatiotemporally controlling supramolecular self‐assembly on sub‐organelles to determine cancer cell fate and enhance cancer therapy.