ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
AGR2 promotes tumor progression by regulating macrophage polarization via the CD98hc-xCT/p-ERK pathway
Provisionally accepted
- Renmin Hospital of Wuhan University, Wuhan, China
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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. 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, recombinant AGR2 (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. Thus, 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.
Keywords: AGR2, CD98hc‑xCT, Macrophage polarization, p‑ERK/ERK pathway, Tumor Microenvironment
Received: 23 Dec 2025; Accepted: 16 Feb 2026.
Copyright: © 2026 Wu, Zhao and Jiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Liang Zhao
Shan Jiang
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