Therapeutic cancer vaccines remain constrained by insufficient intracellular antigen trafficking and weak activation of innate immunity. Here, we report an immunoactive dendrimer-based nanovaccine platform that integrates efficient antigen cytosolic transport with intrinsic stimulation of innate immunity. Through screening a library of thiourea-modified dendrimers, we identify a naphthyl-functionalized polymer (D15) that forms stable antigen nanocomplexes via noncovalent interactions, enabling rapid endosomal escape and efficient cytosolic antigen release in dendritic cells. Mechanistic investigations demonstrated that D15 triggered STING-associated signaling in a cGAS-independent manner, likely related to endosomal membrane perturbation, thereby promoting type I interferon secretion and dendritic cell activation. Owing to its modular structure, D15 also enabled flexible incorporation of additional immunoadjuvants. Incorporation of CpG enhanced lymph node dendritic cell activation and antigen presentation, whereas loading of cGAMP further potentiated STING signaling and intratumoral immune responses. Both CpG- and cGAMP-adjuvanted D15 nanovaccines elicit potent antitumor immune responses in melanoma-bearing mice. Moreover, combination with PD-1 blockade markedly improved tumor suppression, cytotoxic T-cell infiltration, and survival outcomes. Collectively, this work establishes D15 as a multifunctional immunoactive nanocarrier with considerable potential for the construction of next-generation cancer nanovaccines.
Ren et al. (2026) studied this question.