AbstractTherapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials.Significance:Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti–PD-1/PD-L1 agents.