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Targeted modulation of the immune system against tumors can achieve responses in otherwise refractory cancers, which has spurred efforts aimed at optimizing such strategies. To this end, we have previously investigated cancer immunotherapy approaches using recombinant adenovirus vectors, as well as via modulation of the self-ligand receptor SLAMF7. Here, we present a gene transfer-based immunotherapy approach using targeted expression of a SLAMF7-Fc fusion construct directly into tumors at high concentrations via a recombinant adenoviral vector (Ad-SF7-Fc). Using multiple murine cancer models, we show that Ad-SF7-Fc can induce tumor control via augmentation of innate immunity; specifically, induction of type I interferons and activation of dendritic cells (DCs) and macrophages. Analogously, we find that modulating SLAMF7 signaling via an adenoviral vector expressing its intracellular adaptor, EAT-2, is also capable of inducing tumor control. Finally, we employ a novel in vivo prediction approach and dataset integration with machine learning to dissect how Ad-SF7-Fc modulates cell-type-specific responses in the tumor microenvironment to achieve tumor control. Thus, our novel combinatorial cancer immunotherapy highlights the benefit of multimodal immune modulation and lays a framework for combination with complementary approaches capable of inducing adaptive immune responses., Competing Interests: The authors declare no conflicts of interest exist., (© 2021 The Authors.)