Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles

Abstract

The combination of an immuno-metabolic adjuvant and immune checkpoint inhibitors holds great promise for effective suppression of tumor growth and invasion. In this study, a pH-responsive co-delivery platform was developed for metformin (Met), a known immuno-metabolic modulator, and short interfering RNA (siRNA) targeting fibrinogen-like protein 1 mRNA (siFGL1), using a hybrid biomimetic membrane (from macrophages and cancer cells)-camouflaged poly (lactic-co-glycolic acid) nanoparticles. To improve the endo-lysosomal escape of siRNA for effective cytosolic siRNA delivery, a pH-triggered CO2 gas-generating nanoplatform was developed using the guanidine group of Met. It can react reversibly with CO2 to form Met-CO2 for the pH-dependent capture/release of CO2. The introduction of Met, a conventional anti-diabetic drug, promotes programmed death-ligand 1 (PD-L1) degradation by activating adenosine monophosphate-activated protein kinase, subsequently blocking the inhibitory signals of PD-L1. As a result, siFGL1 delivery by the camouflaged nanoparticles of the hybrid biomimetic membrane can effectively silence the FGL1 gene, promoting T-cell-mediated immune responses and enhancing antitumor immunity. We found that a combination of PD-L1/programmed death 1 signaling blockade and FGL1 gene silencing exhibited high synergistic therapeutic efficacy against breast cancer in vitro and in vivo. Additionally, Met alleviated tumor hypoxia by reducing oxygen consumption and inducing M1-type differentiation of tumor-related macrophages, which improved the tumor immunosuppressive microenvironment. Our results indicate the potential of hybrid biomimetic membrane-camouflaged nanoparticles and combined Met-FGL1 blockade in breast cancer immunotherapy.

Implication of the hepatokine, fibrinogen-like protein 1 in liver diseases, metabolic disorders and cancer: The need to harness its full potential

“…Intriguingly, when FGL1/LAG3 and PD-1/PD-L1 axes were simultaneously inhibited, the therapeutic effect was significantly improved, evidenced by a longer lifespan and reduced tumor burden in mice [42]. In addition, the combination of PD-1/PD-L1 signaling blockade and FGL1 gene silencing showed a high synergistic effect in the treatment of breast cancer [46]. Together, the FGL1/LAG3 and PD-1/PD-L1 axes might be independently targeted in treating cancers though synergism of the two yields better therapeutic outcomes.…”

“…Oxysophocarpine is a known alkaloid with demonstrable anti-HCC properties both in vivo and in vitro by reducing FGL1 expression and sensitizing CD8+ T cells to LAG3 immunotherapy [45]. Blockade of the FGL1/LAG3 axis with concurrent administration of metformin can enhance T-cell-mediated immune response, improve the tumor microenvironment immunosuppression, and enhance general anti-tumor immunity [46].…”

Fibrinogen-like protein 1 (FGL1): the next immune checkpoint target

“…org/). The regulatory effect of FGL1 on the TME was further demonstrated in a breast cancer model constructed using biomimetic nanomaterials designed to deliver a short interfering RNA targeting FGL1 [185]. Moreover, FGL1 was shown to be closely associated with tumor cell invasion and metastasis via acquisition of the EMT phenotype, which was underlined by bidirectional crosstalk between tumor cells and the surrounding TME [93,94].…”

“…As a major LAG3 functional ligand independent of MHC-II, FGL1 is positively correlated with MDSC and Treg populations and negatively correlated with CD8 + T cells as determined by analysis of the TIMER database ( http://timer.cistrome.org/ ). The regulatory effect of FGL1 on the TME was further demonstrated in a breast cancer model constructed using biomimetic nanomaterials designed to deliver a short interfering RNA targeting FGL1 [ 185 ]. Moreover, FGL1 was shown to be closely associated with tumor cell invasion and metastasis via acquisition of the EMT phenotype, which was underlined by bidirectional crosstalk between tumor cells and the surrounding TME [ 93 , 94 ].…”

Tumor microenvironment-activated cancer cell membrane-liposome hybrid nanoparticle-mediated synergistic metabolic therapy and chemotherapy for non-small cell lung cancer

“…A549 cell membrane material was prepared as previously described [ 41 , 66 ]. Briefly, human A549 cells were harvested, washed with PBS, and centrifuged.…”