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Our evolving understandings of cell-material interactions provide insights for using polymers to modulate cell behaviour that may lead to therapeutic applications. It is known that in certain cancers, myeloid-derived suppressor cells (MDSCs) play vital roles in promoting tumour progression, chiefly because of their ‘alternatively activated’ (or M2) phenotype that orchestrates immunosuppression. In this study, we demonstrated that two cationic polymers – cationic dextran (C-dextran) and polyethyleneimine (PEI) – could directly remodel these cells into an anti-tumour, ‘classically activated’ (or M1) phenotype, thereby stimulating these cells to express tumouricidal cytokines, reactivating the T cell functions, and prolonging the lifespan of the mice model. Our investigations with knock-out mice further indicate that the functions of these cationic polymers require the involvement of toll-like receptor 4-mediated signalling. Taken together, our study suggests that these cationic polymers can effectively and directly re-polarize MDSCs from an immunosuppressive characteristic to an anti-tumour phenotype, leading to successful restoration of immune surveillance in the tumour microenvironment and elimination of tumour cells. Our findings may have immediate impact on further development of polymer-based therapeutics for cancer immunotherapy.

Both tumor associated macrophages (TAMs) and tumor infiltrating dendritic cells (TIDCs) are important components in the tumor microenvironment that mediate tumor immunosuppression and promote cancer progression. Targeting these cells and altering their phenotypes may become a new strategy to recover their anti-tumor activities and thereby restore the local immune surveillance against tumor. In this study, we constructed a nucleic acid delivery system for the delivery of let-7b, a synthetic microRNA mimic. Our carrier has an affinity for the mannose receptors on TAMs/TIDCs and is responsive to the low-pH tumor microenvironment. The delivery of let-7b could reactivate TAMs/TIDCs by acting as a TLR-7 agonist and suppressing IL-10 production in vitro. In a breast cancer mouse model, let-7b delivered by this system efficiently reprogrammed the functions of TAMs/TIDCs, reversed the suppressive tumor microenvironment, and inhibited tumor growth. Taken together, this strategy, designed based upon TAMs/TIDCs-targeting delivery and the dual biological functions of let-7b (TLR-7 ligand and IL-10 inhibitor), may provide a new approach for cancer immunotherapy.

Tumor necrosis factor-alpha (TNF-α) plays a central role in the pathogenesis of inflammatory bowel disease (IBD). Anti-TNF-α therapies have shown protective effects against colitis, but an efficient tool for target suppression of its secretion - ideally via oral administration - remains in urgent demand. In the colon tissue, TNF-α is mainly secreted by the colonic macrophages. Here, we report an orally-administrated microspheric vehicle that can target the colonic macrophages and suppress the local expression of TNF-α for IBD treatment. This vehicle is formed by cationic konjac glucomannan (cKGM), phytagel and an antisense oligonucleotide against TNF-α. It was given to dextran sodium sulfate (DSS) colitic mice via gastric perfusion. The unique swelling properties of cKGM enabled the spontaneous release of cKGM& antisense nucleotide (ASO) nano-complex from the phytagel scaffold into the colon lumen, where the ASO was transferred into colonic macrophages via receptor-mediated phagocytosis. The treatment significantly decreased the local level of TNF-α and alleviated the symptoms of colitis in the mice. In summary, our study demonstrates a convenient, orally-administrated drug delivery system that effectively targets colonic macrophages for suppression of TNF-α expression. It may represent a promising therapeutic approach in the treatment of IBD.