Despite remarkable clinical efficacy of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits for triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that Cop1 functions through proteasomal degradation of the C/ebpδ protein. The Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment. Display omitted •In vivo CRISPR screens identify new immune targets regulating the tumor microenvironment•Cop1 knockout in cancer cells enhances anti-tumor immunity•Cop1 modulates chemokine secretion and macrophage infiltration into tumors•Cop1 targets C/ebpδ degradation via Trib2 and influences ICB response Large-scale in vivo CRISPR screens reveal that Cop1 knockout in cancer cells stabilizes C/ebpδ protein, suppressing macrophage infiltration and enhancing anti-tumor immunity.