Cancer immunotherapy shows promising potential in future cancer treatment but unfortunately is clinically unsatisfactory due to the low therapeutic efficacy and the possible severe immunotoxicity. Here we show a combined magnetic hyperthermia therapy (MHT) and checkpoint blockade immunotherapy for both primary tumor ablation and mimetic metastatic tumor inhibition. Monodispersed, high-performance superparamagnetic CoFe2O4@MnFe2O4 nanoparticles were synthesized and used for effective MHT-induced thermal ablation of primary tumors. Simultaneously, numerous tumor-associated antigens were produced to promote the maturation and activation of dendritic cells (DCs) and cytotoxic T cells for effective immunotherapy of distant mimetic metastatic tumors in a tumor-bearing mice model. The combined MHT and checkpoint blockade immunotherapy demonstrate the great potentials in the fight against both primary and metastatic tumors.

The innate immune system plays a key role in protecting the human body from tumors, which, unfortunately, is largely counteracted by their immune‐suppression function. Such an immune suppression has been reported to be induced by the immunosuppressive microenvironment, including the exhausted cytotoxic T lymphocytes (CTLs) and tumor‐promoting M2‐polarized macrophages. Here, a novel tumor‐immunotherapeutic modality based on the nanocatalytic innate immunity activation by tumor‐specific mitochondrial DNA (mtDNA) oxidative damage is proposed. In detail, a nanocatalytic medicine, Fe2+–Ru2+‐loaded mesoporous silica nanoparticle named as MSN‐Ru2+/Fe2+ (MRF), is constructed to induce oxidative damage in the mtDNA of tumor cells. Such an oxidative mtDNA is able to escape from the tumor cells and acts as an immunogenic damage‐associated molecular pattern to M1‐polarize tumor‐associated macrophages (TAMs), resulting in the reactivated immunoresponse of macrophages against cancer cells, and the subsequent inflammatory response of innate immunity. Most importantly, the treatment strategy based on regulating the innate immune response of TAMs not only stops the primary tumor progression, but also almost completely inhibits the growth of distant tumors in the periods of treatments.