Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers, the majority of patients with solid tumors do not respond well, but the underlying reason remains unclear. Here, we studied ovarian cancer (OvCa), a tumor type generally resistant to current immunotherapies, to investigate PD-1-independent immunosuppression. We found that PD-L1 was not highly expressed in the tumor microenvironment (TME) of human OvCa. Instead, B7-H3, another checkpoint molecule, was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells (APCs), which correlated with T-cell exhaustion in patients. Using ID8 OvCa mouse models, we found that B7-H3 expressed on tumor cells, but not host cells, had a dominant role in suppressing antitumor immunity. Therapeutically, B7-H3 blockade, but not PD-1 blockade, prolonged the survival of ID8 tumor-bearing mice. Collectively, our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8+ T cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition, particularly OvCa patients.Keywords: Antitumor immunity; B7-H3; Immune checkpoint; Ovarian cancer; T-cell exhaustion.