TCTP regulates the infiltration of CXCR4+ immunosuppressive cells in cervical Cancer via the non-canonical NF-κB/ZEB1/CXCL12 Axis.

The immunomodulatory factor translationally controlled tumor protein (TCTP) drives tumor progression by inducing an immunosuppressive microenvironment; however, its specific role and underlying mechanisms in cervical cancer (CC) remain uncharacterized. To address this gap, in this study, we analyzed the expression of TCTP, non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), zinc finger E-box-binding homeobox 1 (ZEB1), C-X-C motif chemokine ligand 12 (CXCL12), and C-X-C chemokine receptor type 4 (CXCR4) in CC tissues from patients and compared them with that in paired no cervical epithelial lesion tissues. TCTP, ZEB1, non-canonical NF-κB pathway molecules, and CXCL12 exhibited marked upregulation at the mRNA and protein levels in CC tissues. TCTP knockdown reduced ZEB1, p100/p52, and CXCL12 expression in CC cells. Treating CC cells with non-canonical NF-κB activation cascade agonist CD40L and inhibitor B022 increased and decreased ZEB1 and CXCL12 expression, respectively. Dual luciferase reporter assays in both SiHa and HeLa cells confirmed that ZEB1 has a transcriptional activating effect on CXCL12 expression, suggesting that TCTP may interact with NF-κB/ZEB1 to regulate CXCL12 secretion. Additionally, CC tissues exhibited elevated infiltration of immunosuppressive cell populations, including M2-polarized tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, and exhausted CD4+PD-1+ T cells. Furthermore, these cells showed increased surface expression of CXCR4, the specific receptor for CXCL12. In summary, our findings indicate that high TCTP expression potentiates NF-κB/ZEB1-mediated signaling in CC, increases CXCL12 secretion, and recruits the infiltration of immunosuppressive cells in CC tissues, thereby providing a potential molecular target for improving the tumor-suppressive microenvironment.