Spatiotemporal mapping of CD112 unveils its dichotomous role in T-cell exhaustion and ferroptosis crosstalk in cervical cancer

Abstract CD112 emerges as a novel immune checkpoint (IC) in various malignancies, its spatial biology and dual mechanisms in cervical cancer (CC) progression are unexplored. This study systematically analyzes the dual-functions of CD112 in immune evasion and metabolic adaptation in CC. Proteomics and immune checkpoint analysis were performed on 10 CC and normal tissues to explore key targets. Multiplex immunofluorescence (mIHC) on 318 CC tissue microarrays analyzed CD112/CD112R spatial distribution and prognosis. Tumor cell and T cell co-culture models and immunocompetent murine models were used to validate effects of anti-CD112 mAb±anti-PD-1 treatment. CD112 expression in the infiltrated and margine areas correlated with PD-1 + CD8 + T cells density ( r = 0.545, P < 0.001), predicting unfavorable prognosis. Functional studies show that CD112 on tumor cells interacts with CD112R on CD8 + T cells, promoting abnormal numbers and functions of CD8 + T cells, while CD112 antibodies can reverse CD8 + T cell exhaustion and enhance the anti-tumor effects by synergized with PD-1 inhibitors. Mechanistically, the transcription factor Sp1 drives the overexpression of CD112 in CC cells. Additionally, CD112 confers resistance to ferroptosis in CC through the SLC7A11/GPX4 pathway. CD112 acts as a “dual-target” mediating immune suppression and ferroptosis resistance. Combining CD112 and PD-1 inhibition may enhance CC immunotherapy.