Engineering Endogenous Tumor‐Associated Macrophage‐Targeted Biomimetic Nano‐RBC to Reprogram Tumor Immunosuppressive Microenvironment for Enhanced Chemo‐Immunotherapy

Abstract

Immunotherapy has shown encouraging results in various cancers, but the response rates are relatively low due to the complex tumor immunosuppressive microenvironment (TIME). The presence of tumor‐associated macrophages (TAMs) and tumor hypoxia correlates significantly with potent immunosuppressive activity. Here, a hemoglobin–poly(ε‐caprolactone) (Hb–PCL) conjugate self‐assembled biomimetic nano red blood cell (nano‐RBC) system (V(Hb)) is engineered to deliver chemotherapeutic doxorubicin (DOX) and oxygen for reprogramming TIME. The Hb moiety of V(Hb)@DOX can bind to endogenous plasma haptoglobin (Hp) and specifically target the M2‐type TAMs via the CD163 surface receptor, and effectively kill the cells. In addition, the O2 released by the Hb alleviates tumor hypoxia, which further augments the antitumor immune response by recruiting fewer M2‐type macrophages. TAM‐targeting depletion and hypoxia alleviation synergistically reprogram the TIME, which concurrently downregulate PD‐L1 expression of tumor cells, decrease the levels of immunosuppressive cytokines such as IL‐10 and TGF‐β, elevate the immunostimulatory IFN‐γ, enhance cytotoxic T lymphocyte (CTL) response, and boost a strong memory response. The ensuing TAM‐targeted chemo‐immunotherapeutic effects markedly inhibit tumor metastasis and recurrence. Taken together, the engineered endogenous TAM‐targeted biomimetic nano‐RBC system is a highly promising tool to reprogram TIME for cancer chemo‐immunotherapy.

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

“…TAM depletion and hypoxia alleviation with TAM-targeted biomimetic nano-RBC system synergistically reprogram the immunosuppressive TME 2. This system downregulates PD-L1 expression of tumor cells, decreases immunosuppressive cytokines and increases the immunostimulatory IFN-γ and boost CTL response [ 246 ] Sunitinib Downregulation Melanoma and NSCLC Anti-CTLA-4 therapy 1. Sunitinib modulates the expression of tumor PD-L1 via p62, which binds to PD-L1 and specifically enhances its translocation into autophagic lysosomes for degradation 2.…”

Identification of Prognostic Biomarker and Immune Infiltration of CDH23 in Acute Myeloid Leukemia

“…[31,32,33] Among the cell types in the TME, immune cells such as macrophages, natural killer cells, neutrophils, dendritic cells, and myeloid derived suppressor cells, play signi cant roles in tumor progression. [34,35,36,37,38,39,40,41,42] In this study,…”

Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment

“…Various strategies for delivering O 2 to the hypoxic TME have been reported, such as using certain oxygen carriers for transporting O 2 to tumor sites or generating O 2 from endogenous hydrogen peroxide in situ using nanocatalysts (131)(132)(133)(134). Recently, a TAM-targeted biomimetic nano red blood cell system was designed for precise O 2 delivery and M2-like TAM depletion within the TME (135). This nanosystem alleviated tumor hypoxia and markedly enhanced chemoimmunotherapeutic effects.…”