The progress of antitumor immunotherapy is usually limited by tumor-associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2-like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA-ION-R837 @ M (PIR @ M) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe 3 O 4 NPs and Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)- treated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIR @ M can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe 3 O 4 NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe 3 O 4 NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species-induced NF-κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe 3 O 4 NPs and R837.
Cancer immunotherapy has already become a critical hallmark in clinical cancer therapy, especially through tumor associated macrophages (TAMs) polarization. Because multidrug resistance (MDR) hinders the efficiency of chemotherapy, immunotherapy was also incorporated in regulation of MDR. Herein, Au nanocages encapsulated with doxorubicin (Dox) by the phase change material were fabricated with a layer consisting of calcium and ferrous carbonates (FeCaC), and achieved DP [email protected] NPs could reprogram TAMs from immunosuppressive M2 to immunostimulatory M1 based on the intrinsic property of FeCaC shell. Nitric oxide (NO) could be produced by M1 TAMs to inhibit P-glycoprotein (P-gp) expression. Then, FeCaC shell of DP [email protected] NPs could be degraded at the acidic condition and NIR laser irradiation would further facilitate to thermally release Dox. A series of in vitro and in vivo assessments confirmed DP [email protected] NPs could realize the immunotherapy-mediated highly efficient chemotherapy of MDR cancer.
Liu Yu,Shang Wenting,Liu Heng,Hui Hui,Wu Jun,Zhang Wei,Gao Pengli,Guo Kunxiong,Guo Yanli,Tian Jie
Pro-tumoral and immunosuppressive M2-like tumor-associated macrophages (TAMs) contribute to tumor progression, recurrence and distal metastasis. However, current TAMs-modulating therapeutic strategies often encounter challenges including insufficient immune activation, weak antigen presentation ability and unsatisfactory antitumor immune performance. Herein, cyclic RGD peptide functionalized and manganese doped eumelanin-like nanocomposites (RMnMels) are reported for combined hyperthermia-immunotherapy against PC3 prostate cancer. The RMnMels could promote M2-to-M1 macrophage repolarization via scavenging multiple reactive oxygen species and remodeling the immunosuppressive tumor microenvironment. Following near-infrared light irradiation, RMnMels-mediated thermal ablation not only could destroy tumor cells directly, but also elicit the release of damage associated molecular patterns and tumor-associated antigens, provoking robust tumor immunogenicity and strong antitumor immune responses. The results showed that RMnMels could effectively scavenge reactive oxygen species and promote M2-to-M1 macrophage repolarization both in vitro and in vivo. Synergistically enhanced anti-tumor therapeutic efficacy was achieved following single administration of RMnMels plus single round of laser irradiation, evidenced by decreased primary tumor sizes and decreased number of distant liver metastatic nodules. The as-developed RMnMels may represent a simple and high-performance therapeutic nanoplatform for immunomodulation and enhanced antitumor immune responses.Graphical Abstract
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