Chemoradiotherapy facilitates siglec-10/siglec-9 macrophage-mediated impairment of CD24/MUC16 tumor cell elimination and enhances PD-L2 dependent immunosuppression in cervical cancer.

The post-treatment recurrence after chemoradiotherapy remains a major clinical challenge in cervical cancer, and the underlying mechanisms remain incompletely understood. In this study, single-cell RNA sequencing analysis of human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) revealed that cervical cancer tumor cells exhibited enhanced stemness along with upregulated expression of CD24 and MUC16 following CCRT. Meanwhile, tumor-associated macrophages exhibited upregulated expression of Siglec-10 and Siglec-9 after CCRT. Siglec-10/Siglec-9 macrophages could interact with CD24/MUC16 tumor cells, thereby potentially suppressing their ability to eliminate tumor cells. IL-4 strongly induces PD-L2 expression in Siglec-10/Siglec-9macrophages. Furthermore, these Siglec-10/Siglec-9 macrophages inhibited T cell function via PD-L2/PD-1 interactions, thereby facilitating tumor immune evasion. In summary, in cervical cancer following CCRT, CD24/MUC16 tumor cells might interact with Siglec-10/Siglec-9 macrophages to suppress tumor cell elimination and upregulate PD-L2 expression, thereby promoting T cell dysfunction, tumor immune evasion, disease recurrence, and ultimately poorer patient prognosis.