HSP90AA1 induces M2 macrophage polarization via stabilizing ITGB1 and promoting CCL2 secretion in nasopharyngeal carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) presents a major treatment challenge, largely due to immunotherapy resistance. The molecular mechanisms that drive the remodeling of the immunosuppressive tumor microenvironment (TME) in NPC are still not well understood. This study explored how heat shock protein 90 alpha family class A member 1 (HSP90AA1) regulated the NPC immune microenvironment. A total of 54 NPC patients receiving first-line immunotherapy were analyzed by immunohistochemistry (IHC). High HSP90AA1 expression predicted shorter progression-free survival (PFS). According to the TIMER database, HSP90AA1 expression positively correlated with M2 macrophage infiltration. Additionally, we established an indirect co-culture model containing NPC cells and THP-1-derived macrophages and found that HSP90AA1 facilitated macrophage M2 polarization. According to the results of co-immunoprecipitation (Co-IP) and cycloheximide (CHX) chase assays, HSP90AA1 associated with integrin β1 (ITGB1) and stabilized its protein expression, subsequently increasing C-C motif chemokine ligand 2 (CCL2) secretion. HSP90AA1 knockdown suppressed CCL2 secretion and M2 polarization, and ITGB1 overexpression partially reversed this effect. Taken together, our in vitro models and retrospective clinical correlation suggest that the HSP90AA1-ITGB1-CCL2 axis may drive immunosuppressive TME remodeling in NPC, highlighting HSP90AA1 as a promising predictive biomarker and therapeutic target against immunotherapy resistance.