Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers

Abstract

Cancer immunotherapy utilizing cytotoxic T lymphocytes has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondrial content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8⁺ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8⁺ T cells but also increases the susceptibility of cancer cells to CD8⁺ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumour therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T cell therapy, CAR-T cell therapy and tumour-vaccine-based immunotherapy.