Nano‐Regulator Inhibits Tumor Immune Escape via the “Two‐Way Regulation” Epigenetic Therapy Strategy

• Published in: Advanced science 2024-03, Vol.11 (9), p.e2305275-n/a
• Main Authors: Liang, Shuang, Liu, Meichen, Mu, Weiwei, Gao, Tong, Gao, Shuying, Fu, Shunli, Yuan, Shijun, Liu, Jinhu, Liu, Yongjun, Jiang, Dandan, Zhang, Na
• Format: Article
• Language: English
• Subjects: Antigens; DNA methylation; epigenetic regulation; Epigenetics; Immunotherapy; Ligands; nano‐regulator; NMR; Nuclear magnetic resonance; Polyethylene glycol; Proteins; tumor immune escape; two‐way regulation
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202305275

Tumor immune escape caused by low levels of tumor immunogenicity and immune checkpoint‐dependent suppression limits the immunotherapeutic effect. Herein, a “two‐way regulation” epigenetic therapeutic strategy is proposed using a novel nano‐regulator that inhibits tumor immune escape by upregulating expression of tumor‐associated antigens (TAAs) to improve immunogenicity and downregulating programmed cell death 1 ligand 1 (PD‐L1) expression to block programmed death‐1 (PD‐1)/PD‐L1. To engineer the nano‐regulator, the DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) and the bromodomain‐containing protein 4 (BRD4) inhibitor JQ1 are co‐loaded into the cationic liposomes with condensing the toll‐like receptor 9 (TLR9) agonist cytosine‐phosphate‐guanine (CpG) via electrostatic interactions to obtain G‐J/ZL. Then, asparagine–glycine–arginine (NGR) modified material carboxymethyl‐chitosan (CMCS) is coated on the surface of G‐J/ZL to construct CG‐J/ZL. CG‐J/ZL is shown to target tumor tissue and disassemble under the acidic tumor microenvironment (TME). Zeb upregulated TAAs expression to improve the immunogenicity; JQ1 inhibited PD‐L1 expression to block immune checkpoint; CpG promote dendritic cell (DC) maturation and reactivated the ability of tumour‐associated macrophages (TAM) to kill tumor cells. Taken together, these results demonstrate that the nano‐regulator CG‐J/ZL can upregulate TAAs expression to enhance T‐cell infiltration and downregulate PD‐L1 expression to improve the recognition of tumor cells by T‐cells, representing a promising strategy to improve antitumor immune response. The “two‐way regulation” epigenetic therapy strategy via designing an integrated nano‐regulator is proposed to inhibit tumor immune escape, which can upregulate tumor‐associated antigens (TAAs) expression to enhance T‐cell infiltration and downregulate PD‐L1 expression to improve the recognization of T‐cells to tumor cells, thus inhibiting tumor immune escape and activating antitumor immune response.