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.

Nanomaterials-Involved Tumor-Associated Macrophages’ Reprogramming for Antitumor Therapy

“…Therefore, HIF-1α, as an important isoform of HIF, is considered as an important target for altering hypoxic resistance of tumor and phenotype of TAMs. Jiang et al constructed a nanocarrier FSSeD-CFZs to deliver hypoxia-pathway-intervened docosahexaenoic acid (DHA) for immunosuppressive TME modulation and TAMs’ reprogramming . DHA is a HIF-1α inhibitor, which can activate peroxisome proliferator-activated receptors (PPARs) to promote the degradation of HIF-1α .…”

“…Jiang et al constructed a nanocarrier FSSeD-CFZs to deliver hypoxiapathway-intervened docosahexaenoic acid (DHA) for immunosuppressive TME modulation and TAMs' reprogramming. 162 DHA is a HIF-1α inhibitor, which can activate peroxisome proliferator-activated receptors (PPARs) to promote the degradation of HIF-1α. 163 With DHA downregulating HIF-1α, the hypoxia of TME was ameliorated, leading to significant inhibition of the anti-inflammatory function of M2-like TAMs, and then its phenotype was turned to M1 subtype.…”