VTCN1 (B7-H4) is an immune checkpoint molecule that negatively regulates T cell-mediated immunity. Structurally, it contains a V-set domain and localizes to the plasma membrane, where it inhibits T cell activation, proliferation, and cytokine production 1. Mechanistically, VTCN1 suppresses CD8+ T cell function, possibly through Eomes overexpression, and its expression on tumor-associated myeloid cells correlates with T cell exhaustion 2. In cancer, VTCN1 represents a critical immune evasion mechanism, particularly in triple-negative breast cancer (TNBC) and immune-cold tumors, where it inversely correlates with PD-L1 expression [PMID:25208879; 36]. Progesterone upregulates VTCN1 in breast cancer and placental cells through the PR-P300-BRD4 axis, linking female hormones to onco-fetal immune tolerance 1. Post-translational modifications regulate VTCN1 stability: palmitoylation by ZDHHC3 prevents lysosomal degradation and maintains immunosuppression, while glycosylation inhibition promotes ubiquitination-dependent degradation [PMID:40341398; 36]. Clinically, elevated VTCN1 associates with worse outcomes in small cell lung cancer 4. Therapeutic strategies include VTCN1-targeted antibody-drug conjugates (XMT-1660), CDK4/6 inhibitors promoting B7-H4 degradation, glycosylation inhibitors, and combinatorial PD-1/VTCN1 blockade, demonstrating superior anti-tumor efficacy [PMID:37294948; 5; 36].