Immunotherapies harness the power of the immune system, broadly, to identify, suppress, or otherwise control disease progression. Potent immune checkpoints, such as PD-1/PD-L1, CTLA4, and here, CD47-SIRPα restrain immunity in normal regulation to protect healthy ‘self’ cells, yet can become dysregulated in the progression of diseases. Antibody-based blockade of such checkpoints has emerged as a powerful tool to retrain and re-energize immune surveillance, but significant barriers to efficacy and safety remain. CD47-SIRPα is the macrophage immune checkpoint that enables macrophages, a first line of defense in innate cellular immunity, to discriminate ‘self’ vs. ‘foreign’, which many cancers utilize to evade clearance. Consequently, CD47 is now a clinical target for antibody-based blockade in early and late phase clinical trials in many liquid tumors and some solid tumors. However, clinically targeting a ubiquitously expressed surface marker presents numerous challenges, including a large antigen sink, on-target but off-tumor clearance, and mass permeation of solid tissues that are yet to be answered (Chapter 1 and Chapter 4). Here, we demonstrate that efficacy of molecular and cell-based therapies targeting CD47-SIRPα requires complete ablation of signaling and a pro-phagocytic signal to drive tumor-specific macrophage phagocytosis in solid tumors (Chapter 2). We further delineate and provide evidence for a novel phenomenon of “cooperative phagocytosis” in these tumors, whereby macrophages that are maximally activated along the CD47-SIRPα paradigm, work together to disrupt solid tumor adhesions and durably eliminate tumoroids in vitro and tumors in vivo (Chapter 3). Finally, we highlight a significant role for macrophages as potent immune effectors to clear tumors and induce a de novo, endogenous antibody response that strengthens macrophage phagocytosis and cooperativity with high tumor antigen-binding and -specificity (Chapter 3). These results position macrophages as potent immune effectors in solid tumors with the potential to overcome long-standing challenges in immuno-oncology (Chapter 5).