Based on these data, we hypothesized that blocking the SIRPα/CD47 inhibitory innate immune checkpoint with evorpacept and providing a pro-phagocytic (“eat me”) opsonizing signal with pembrolizumab would overcome resistance to single-agent anti–PD-1 antibody in patients with refractory MSS colorectal cancer by enhancing macrophage activation, generating synergistic innate and adaptive antitumor immunity, and reversing the immunosuppressive TME. This evidence concerns the gene SIRPA and colorectal cancer.