A triple combination strategy for nasopharyngeal carcinoma: Aptamer-guided liposomal chemotherapy, engineered NK cells, and Fc-enhanced PD-L1 antibody therapy

作者：Chaoyan Yao, Lei Wang, Weidong Liu, Ning Shi, Ziling Liao, Yang Fu, Jinhao Ouyang, Xuan Lei, Qianping Huang, Siyu Li, Yihua Zhouyang, Pinnan Zhao, Jie Wang, Hongjuan Xu, Wenhu Zhou, Xingjun Jiang, Xiang Gao, Caiping Ren, Longlong Luo · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.10.007 · 被引用次数：2 · 研究领域：RNA Interference and Gene Delivery、CAR-T cell therapy research、Immune Cell Function and Interaction

The effective treatment of nasopharyngeal carcinoma (NPC) is challenged by an immunosuppressive tumor microenvironment (TME) and insufficient immune effector cell activation. Herein, we design a synergistic tri-modal therapeutic strategy to overcome these barriers. This platform integrates: (1) a CD109-targeted liposomal doxorubicin (S3-Lip-DOX) for precise chemotherapy and induction of immunogenic cell death (ICD); (2) non-genetically engineered natural killer (NK) cells armed with dual aptamers (targeting CD109 and PD-L1) via bio-orthogonal chemistry for enhanced tumor recognition (S3-P-NK); and (3) an Fc-engineered anti-PD-L1 antibody (Atezolizumab/IgG1) that restores antibody-dependent cellular cytotoxicity (ADCC). Crucially, we uncovered a key mechanistic synergy: S3-Lip-DOX treatment, as a stress-adaptive response, upregulates PD-L1 expression on NPC cells. This finding provides a compelling rationale for the integration, turning a potential immune escape mechanism into a therapeutic vulnerability. The complete regimen, comprising S3-Lip-DOX, S3-P-NK, and Atezolizumab/IgG1, demonstrated potent synergistic antitumor effects in vitro and in vivo . This triple-combination therapy not only achieved significant tumor regression but also robustly reprogrammed the innate tumor microenvironment, evidenced by enhanced dendritic cell (DC) maturation and pro-inflammatory macrophage activation. This work establishes a mechanism-driven, modular therapeutic platform that effectively ...