ANXA6 (annexin A6) is a calcium-dependent phospholipid-binding protein with multifaceted roles in cancer biology and immune regulation. Functionally, ANXA6 regulates intracellular calcium homeostasis and associates with membrane-proximal signaling complexes 1. Primary mechanisms involve ANXA6's ability to suppress EGFR-ERK1/2 phosphorylation through facilitation of EGFR-PKCα complex formation, a process enhanced by SUMOylation at lysine residues 12. In hepatocellular carcinoma, SUMOylation-dependent ANXA6 inhibits RHOU/AKT1-mediated epithelial-mesenchymal transition 3. Disease relevance is substantial across multiple cancer types. ANXA6 shows tumor-suppressive effects in nasopharyngeal carcinoma, where downregulation correlates with metastasis and poor survival 4. Similarly, ANXA6 upregulation enhances cisplatin sensitivity in bladder cancer and inhibits proliferation/migration in prostate cancer 25. Conversely, in breast cancer, chemotherapy-elicited extracellular vesicles enriched in ANXA6 promote metastasis through NF-κB-dependent endothelial activation and monocyte recruitment 6. Immunologically, ANXA6 modulates immune infiltration and macrophage polarization. ANXA6 overexpression in decidual macrophages drives pyroptosis and M1 polarization via NLRP3 and NF-κB pathways, impairing trophoblast function in recurrent spontaneous abortion 7. In prostate cancer, ANXA6 promotes CD4+ and CD8+ T cell chemotaxis and M1 macrophage polarization 5. These findings position ANXA6 as context-dependent prognostic biomarker with therapeutic potential.