Background: Despite substantial progress, only a select subset of patients benefit from anti-PD-1/PD-L1 therapies. The underlying cause for these failures of immune checkpoint blockade therapy is the overwhelming, persistent and multifocal immune suppression within the tumor microenvironment. As phosphatidylserine (PS) becomes externalized to the outer leaflet of the cell’s plasma membrane within the tumor microenvironment, it serves as a signaling ligand for PS receptors on immunosuppressive myeloid-derived suppressor cells (MDSCs), regulatory T cells and M2 macrophages that can occupy up to 50% of the tumor mass. Bavituximab is a chimeric monoclonal antibody that targets and inhibits PS mediated immunosuppressive signaling, supporting immune activation and reducing levels of MDSCs, re-polarizing tumor-associated macrophages from M2 to M1 phenotype, promoting the maturation of dendritic cells (DCs) and inducing potent antitumor T-cell immunity. Methods: A combination of bavituximab and anti-PD-1 therapy was compared in syngeneic, pre-clinical models of melanoma and breast cancer. Results: Our results show that the combination induces a statistically significant activation of lymphocytes in the spleen and the tumor microenvironment as well as decreases MDSCs and PD-L1 expression. In the spleen, increases were noted in T-cells producing IFN-g and IL-2 and DCs in association with decreased MDSCs over single anti-PD-1 treatment alone. Similarly, in the tumor microenvironment, the combination treatment demonstrates increases in TILs producing IFN-g, TNFα, IL-2, Granzyme B, PD-1, increased Lag-3 positive CD8 cells, CD137 (41BB) positive CD4 cells as well as a decrease in MDSCs and PD-L1 expressing TILs compared to anti-PD-1 treatment alone. Conclusions: Our pre-clinical results support the use of bavituximab as an immunomodulatory treatment in PD-1 sensitive and anti-PD-1 resistant/unresponsive tumors. This effect involves enhancing the activation of CD8+ TIL correlating with increased immune stimulatory components in the spleen and the tumor microenvironment.