The clinical benefits that have been achieved for a group of cancer patients with metastatic disease on checkpoint inhibitor therapy have kindled intense interest in understanding tumor-induced escape from T lymphocyte control. Other lymphoid cells also participate in tumor control; in particular, NK cells can limit hematogenous cancer metastasis spread and are also subject to negative regulation by developing cancers. In this issue of the JCI, Li and colleagues define an unanticipated role for the stress-induced protein CD155 in cancer metastasis. The presence of CD155 on the surface of cancer cells was shown to promote tumor invasiveness, while its upregulation in tumor environment–infiltrating myeloid cells restrained antitumor immunity by impairing antitumor T lymphocytes and NK cell function. Together, these results support further exploration of strategies for targeting CD155.