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 coordinates targeted chemotherapy with innate immunotherapy, holding significant translational potential for solid tumors.

Nasopharyngeal carcinoma (NPC)  /  Chemo-immunotherapy  /  Triple-combination therapy  /  Liposomal doxorubicin  /  Aptamer-engineered NK cells  /  ADCC  /  CD109  /  PD-L1