Antiviral T cells doing double-duty to fight cancer.

The exquisite antigen specificity of T cells is one foundation of modern cancer immunotherapy. The therapeutic efficacy of checkpoint blockade, cancer vaccines, and engineered T-cell therapies, all appear to depend on T cells capable of recognizing specific antigens displayed by tumor cells. In a recent issue of Nature Immunology, Smith and colleagues challenge this paradigm by demonstrating that local activation of virus-specific memory T cells can eliminate tumors without direct tumor-cell recognition. Instead, activated T cells initiate a multicellular inflammatory response involving IFNγ, TNF, nitric oxide and recruited myeloid cells that collectively induce tumor-cell death. These findings separate the antigen specificity required for T-cell activation from that required for tumor killing and expand the role of T cells from direct cytotoxic effectors to organizers of a broader antitumor response. Together, these findings broaden the potential scope of T-cell-mediated antitumor immunity beyond the constraints of direct tumor-antigen recognition.