AGR2 promotes tumor progression by regulating macrophage polarization via the CD98hc-xCT/p-ERK pathway.

Introduction: Anterior gradient 2 (AGR2) contributes to tumorigenesis, yet its function within the tumor microenvironment (TME) and in macrophage polarization remains unclear. This study assessed the prognostic significance of AGR2 and investigated its mechanism in cancer progression. Methods: We used TCGA for pan-cancer AGR2 expression and survival analysis, examined macrophage infiltration in clinical specimens, and performed in vitro experiments with recombinant AGR2 (rAGR2) to assess macrophage polarization. We verified AGR2's interaction with the CD98hc-xCT receptor complex and explored related mechanisms via CD98hc knockdown. In vivo experiments were conducted in B16-F10 melanoma and Lewis lung carcinoma (LLC) models using flow cytometry. Results: Pan-cancer analyses showed that elevated AGR2 expression correlates with poor prognosis in multiple cancers and is associated with reduced immune infiltration. AGR2 is predominantly expressed in CD163+ M2-like tumor-associated macrophages (TAMs), with levels rising alongside tumor stage. In vitro, rAGR2 promoted M2 polarization while inhibiting M1 polarization of macrophages, and enhanced the pro-tumorigenic effects of M2-conditioned medium on cancer cell motility and proliferation. Mechanistically, AGR2 binds to the CD98hc-xCT receptor complex, activating the ERK pathway, an effect abrogated by CD98hc knockdown. In vivo, rAGR2 accelerated tumor growth in melanoma and lung cancer models, accompanied by increased TAM accumulation, a shift toward M2 polarization, and suppressed T-cell function. Discussion: AGR2 drives tumor progression by reprogramming TAMs toward an M2 phenotype and attenuating T-cell function via the CD98hc-xCT/p-ERK pathway, highlighting its potential as both a prognostic marker and a therapeutic target.