The cell division cycle 34 (CDC34) is an E2 ubiquitin-conjugating enzyme that is required for proteasomal degradation of substrate proteins, and is able to stabilize proteins including the epidermal growth factor receptor to promote lung carcinogenesis. Here, we conducted a pan-cancer analysis of CDC34 in The Cancer Genome Atlas datasets, and found its high expression in breast cancer and negative association with patient outcomes. Analysis of single-cell RNA-sequencing data revealed a negative role of CDC34 in macrophage phagocytotic activity for cancer cells. CDC34 stabilized hypoxia-inducible factor 1α (HIF1α) and transcriptionally upregulated CD47 in cancer cells to evade phagocytosis by macrophages. Inhibition of CDC34 inhibited tumor growth and synergized with anti-PD-L1 antibody in murine models. CDC34 was positively associated with CD47 and negatively associated with CD8+ granzyme B+ T-cell infiltration in patient samples, and patients with co-overexpression of CDC34 and CD47 had markedly poorer prognosis compared to those with high expression of either marker alone. In pre-treatment tumor samples, non-responders to immunotherapy exhibited significantly higher CDC34 levels and reduced CD8+ T-cell infiltration compared to responders. These findings indicated that CDC34 is critical to immune evasion and could be a potential therapeutic target for those resistant to immune checkpoint inhibitors.Copyright © 2025. Published by Elsevier B.V.