Liposomal Oncolytic Adenovirus Enables Efficient CAR-Independent Transduction of Tumors and Enhances NK Cell-Mediated Abscopal Responses

Effective delivery of oncolytic adenoviruses to tumors with low coxsackievirus and adenovirus receptor (CAR) expression remains a major barrier in oncolytic virotherapy. In this study, a liposome-encapsulated adenovirus serotype 5-based platform (DfA) was designed to bypass CAR-dependent transduction, presenting engaging antitumor immune responses in an innate immune, NK cell-dependent manner. The results show that DfA efficiently transduces CAR-low murine colorectal cancer cells (CT26) and triggers the release of damage-associated molecular patterns (DAMPs), including ATP, HMGB1, and calreticulin. In immunocompetent mice, intratumoral DfA treatment suppressed both local and distant tumor growth. In nude mice lacking T cells, DfA retained systemic antitumor activity, but abscopal effects were lost upon NK cell depletion, which suggests that natural killer (NK) cells are essential mediators of this response. In vitro, DfA enhanced NK92 cytotoxicity against low-CAR MCF-7 breast cancer cells, which further supports its innate immune-activating potential. Together, these findings reveal a previously unrecognized role for NK cells in mediating adenovirus-induced abscopal effects and position DfA as a clinically actionable strategy for CAR-deficient tumors.