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

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 (FucSSeDHA (FSSeD)-CFZs) induce immunogenic cell death, inhibit hypoxia-inducible factor-1 & alpha; 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. Fucoidan-selenylsulfide-docosahexaenoic acid-chemotherapeutic drug carfilzomibs (FSSeD-CFZs) downregulate hypoxia-inducible factor-1 & alpha; for reducing M2 tumor-associated macrophages (TAMs) and promote M1 macrophage polarization, which increases the mature and tumor antigen presentation of dendritic cells to enhance immunogenic-cell-death-induced immunoreaction. Therefore, FSSeD-CFZs rescue TAM-hijacked immune response to enhance metastatic cancer treatments.image