PLA2G2A⁺ CAFs as a Key Driver of Lymph Node Metastasis in Penile Cancer and Its Underlying Mechanisms

Metastasis to lymph nodes in penile squamous cell carcinoma (PSCC) significantly impacts patient survival rates, and the challenge of accurately identifying patients who would genuinely benefit from inguinal lymph node dissection prior to surgery remains a pressing and unresolved issue in clinical practice. This research utilized single-cell RNA sequencing, bulk RNA sequencing, and various machine learning techniques (including LASSO, Random Forest, and XGBoost) to systematically identify PLA2G2A as a crucial molecular marker for lymph node metastasis in PSCC. In a separate clinical cohort of 69 patients, immunohistochemical studies demonstrated that PLA2G2A was markedly elevated in those with metastasis, and its high levels correlated with unfavorable clinical outcomes. Additionally, we pinpointed PLA2G2A expression to a distinct subpopulation of fibroblasts. Mechanistic investigations indicated that PLA2G2A-positive cancer-associated fibroblasts (CAFs) attract CXCR4-positive monocytes into the tumor microenvironment via CXCL12 secretion, subsequently driving their transformation from an M1-like to an M2-like immunosuppressive phenotype through the MDK–NCL/LRP1 signaling pathway, thus fostering a tumor microenvironment conducive to metastasis. Overall, this study clarifies the significant regulatory function of PLA2G2A-positive CAFs in PSCC metastasis and positions PLA2G2A as a valuable biomarker for evaluating the risk of lymph node metastasis before surgery.