## 5 Conclusions  
CD47 is a promising, emerging target for clinical cancer therapeutics but its efficacy remains a challenge. Pro-phagocytic signals are required in combination with deep disruption of CD47 inhibitory signaling. The clinical success of CD47-based therapeutics depends on macrophage activation, not just inhibition of \"don't eat me\" signals. We demonstrate this strategy in two different models of metastasis by CD47 deletion and by adoptive transfer of SIRP\(\upalpha\)-blocked marrow cells in combination with tumor-opsonizing IgG. While advancing our understanding of phagocytosis and CD47's role in solid tumors, further efforts might seek to: (i) maximize CD47-SIRP\(\upalpha\) disruption, (ii) increase the numbers of phagocytic effector cells [40], and (iii) provide additional pro-phagocytic signals (e.g., another tumor-specific monoclonal antibody, bispecific antibodies, some chemotherapeutic, etc.) that are suppressed by CD47-SIRP\(\upalpha\). **Supplementary Materials:** The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/cancers14081930/s1](https://www.mdpi.com/article/10.3390/cancers14081930/s1)]([https://www.mdpi.com/article/10.3390/cancers14081930/s1](https://www.mdpi.com/article/10.3390/cancers14081930/s1)). Figure S1: Cell surface marker expression levels in B16F10 lines. Figure S2: Wild-type B16F10 metastases do not respond to low or high doses of anti-Tyrp1. Figure S3: Combination anti-CD47 and anti-Tyrp1 fails to affect tumor area of primary wild-type B16F10 tumors. Figure S4: Computed tomography (CT) imaging of B16F10 lung metastases (CD47 KO). Figure S5: Melanin and nuclei of tumor and lung tissue in embedded lung sections. Figure S6: Marker-free analysis of immune infiltrate in treated CD47 KO lung tumor nodules. Figure S7: Tumor masses on lungs (related to Main Figure 2). Figure S8: Tumor growth in APB-treated mice. Figure S9: Pre-feeding bone marrow-derived macrophages with non-tumor targets can affect on-target tumor cell phagocytosis. **Author Contributions:** Conceptualization, J.C.A. and D.E.D. ; methodology, J.C.A. and D.E.D. ; validation, J.C.A. and D.E.D. ; formal analysis, J.C.A., M.P.T., and D.E.D. ; investigation, J.C.A., L.J.D., W.Z., B.H.H., J.Y.L., X.J., and J.I. ; resources, D.E.D. ; data curation, J.C.A. ; writing--original draft preparation, J.C.A. ; writing--review and editing, J.C.A., L.J.D. and D.E.D. ; visualization, J.C.A. andL.J.D. ; supervision, D.E.D. ; project administration, D.E.D. ; funding acquisition, D.E.D. All authors have read and agreed to the published version of the manuscript. The National Institutes of Health supported this work under R01-HL124106, U01-CA254886, U54-CA193417 (to D.E.D.) and F32-CA228285 (to L.J.D.). J.C.A., B.H.H., and M.P.T. were supported by the National Science Foundation Graduate Research Fellowship Program (DGE-1845298). Funding was also provided by the National Science Foundation (Materials Science and Engineering Center award DMR-1720530 and DMR-1120901; as well as Grant Agreements CMMI 1548571 and 154857), Pennsylvania Department of Health Grant HRFF 4100083101. The animal study protocol was approved by the Institutional Review Board (or Ethics Committee) of the University of Pennsylvania (IACUC-approved protocols #803177 and #804455 with most recent dates of approval of 09/24/2021 and 06/20/2021). Not applicable. Data Availability Statement:Data are openly available at [[https://doi.org/10.6084/m9.figshare.19358786](https://doi.org/10.6084/m9.figshare.19358786)]([https://doi.org/10.6084/m9.figshare.19358786](https://doi.org/10.6084/m9.figshare.19358786)) (accessed on 30 January 2022).