TAM‐Hijacked Immunoreaction Rescued by Hypoxia‐Pathway‐Intervened Strategy for Enhanced Metastatic Cancer Immunotherapy

Abstract Immunotherapy is regarded as a prospective strategy against metastatic cancer. However, tumor‐associated macrophages (TAMs), which accumulate in hypoxic tumor microenvironment, reduce the effectiveness of immunotherapy by blocking or “hijacking” the initiation of the immune response. Here, a novel tumor‐targeted nanoplatform loaded with hypoxia‐pathway‐intervened docosahexaenoic acid (DHA) and chemotherapeutic drug carfilzomib (CFZ) is developed, which realizes the rescue of TAM‐hijacked immune response and effective metastatic cancer immunotherapy. DHA is conjugated to fucoidan (Fuc) via a reduction cleavable selenylsulfide bond (SSe) for micelle preparation, and CFZ is encapsulated in the hydrophobic cores of micelles. The functionalized nanoplatforms (Fuc─SSe─DHA (FSSeD)–CFZs) induce immunogenic cell death, inhibit hypoxia‐inducible factor‐1α expression, and improve immunosuppression by TAM suppression. FSSeD–CFZs enhance immune response against primary tumor development and metastasis formation. In brief, the novel rescue strategy for TAM‐hijacked immunoreaction by inhibiting hypoxia pathway has the potential and clinically translational significance for enhanced metastatic cancer immunotherapy.