Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immunogenic due to inherent pathogen-associated molecular patterns. Here, we studied the capacity of adenovirus to overcome resistance of chicken ovalbumin-expressing B16.OVA murine melanoma tumors to adoptive ovalbumin-specific CD8⁺ T-cell (OT-I) therapy. Following intraperitoneal transfer of polyclonally activated OT-I lymphocytes, control of tumor growth was superior in mice given intratumoral adenovirus compared with control mice, even in the absence of oncolytic virus replication. Preexisting antiviral immunity against serotype 5 did not hinder the therapeutic efficacy of the combination treatment. Intratumoral adenovirus injection was associated with an increase in proinflammatory cytokines, CD45⁺ leukocytes, CD8⁺ lymphocytes, and F4/80⁺ macrophages, suggesting enhanced tumor immunogenicity. The proinflammatory effects of adenovirus on the tumor microenvironment led to expression of costimulatory signals on CD11c⁺ antigen-presenting cells and subsequent activation of T cells, thus breaking the tumor-induced peripheral tolerance. An increased number of CD8⁺ T cells specific for endogenous tumor antigens TRP-2 and gp100 was detected in combination-treated mice, indicating epitope spreading. Moreover, the majority of virus/T-cell–treated mice rejected the challenge of parental B16.F10 tumors, suggesting that systemic antitumor immunity was induced. In summary, we provide proof-of-mechanism data on combining adoptive T-cell therapy and adenovirotherapy for the treatment of cancer. Cancer Immunol Res; 3(8); 915–25. ©2015 AACR.