LILRB4 shapes an immunosuppressive microenvironment to drive cervical cancer progression through tumor-infiltrating myeloid cell expansion and CD8+ T-cell suppression.

Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinical benefits for CC, highlighting the need to find more effective therapeutic targets. LILRB4, a member of the leukocyte immunoglobulin-like receptor superfamily, is considered a key mediator of cancer immunosuppression. However, its role in the CC immune microenvironment remains unclear. Here, LILRB4 expression was upregulated in CC tissues, and high expression levels were positively associated with advanced disease and immunosuppressive genes in tumors. In an immunocompetent mouse model, LILRB4 expression in CC tumors increased with tumor growth, whereas blocking LILRB4 reduced tumor growth. Flow cytometry analysis revealed that blockade of LILRB4 reduced CD8+ T-cell exhaustion within tumors. Additionally, blockade of LILRB4 decreased the number of tumor‑infiltrating myeloid cells (TIMs), including myeloid‑derived suppressor cells (MDSCs) and M2 tumor‑associated macrophages (M2‑TAMs). Cell coculture experiments demonstrated that blockade of LILRB4 prevented CD8+ T-cell exhaustion by reducing the numbers of MDSCs and TAMs. Furthermore, HPV16 upregulated ApoE expression through transcriptional regulation, and LILRB4 mediated the suppression of CD8+ T cells by ApoE. Overall, the HPV16/ApoE/LILRB4 axis induced TIM-mediated suppression of CD8+ T cells, creating an immunosuppressive microenvironment that promoted CC progression.