ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1600792

This article is part of the Research TopicImmune Predictive and Prognostic Biomarkers in Immuno-Oncology: Refining the Immunological Landscape of CancerView all 22 articles

Galectin-9 and Tim-3 in Gastric Cancer: A Checkpoint Axis Driving T Cell Exhaustion and Treg-Mediated Immunosuppression Independently of Anti-PD-1 Blockade

Provisionally accepted
Charlotte Nicole HillCharlotte Nicole Hill1,2,3,4*Gabriela MaitaGabriela Maita1,4Camille CabrolierCamille Cabrolier1,4Ana María Vega-LetterAna María Vega-Letter5Pamela GonzalezPamela Gonzalez1,4Alexis M KalergisAlexis M Kalergis1,4Patricia Luz CrawfordPatricia Luz Crawford1,2,3*Gareth I. OwenGareth I. Owen1,4*Constanza Aros-ValdiviaConstanza Aros-Valdivia3
  • 1Millennium Institute on Immunology and Immunotherapy, University of Chile, Santiago, Santiago Metropolitan Region (RM), Chile
  • 2Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
  • 3Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Universidad de Los Andes, Santiago, Santiago Metropolitan Region (RM), Chile
  • 4Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Santiago Metropolitan Region (RM), Chile
  • 5Escuela de ingeniería bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaiso, Chile

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The development of immune checkpoint inhibitors is transforming gastric cancer (GC) therapy. However, an immunosuppressive tumor microenvironment and redundancy among inhibitory checkpoints contribute to high rates of treatment failure. Tim-3 (HAVCR2), an emerging checkpoint target, enhances immunosuppression, yet the role of its ligand, Galectin-9 (Gal-9, LGALS9), in GC remains unclear. Bioinformatic analysis of stomach adenocarcinoma (STAD) from the TCGA database revealed upregulation of LGALS9 and HAVCR2 in gastric tumors, correlating with poor survival.HAVCR2 expression was significantly elevated in invasive adenocarcinomas. Further bioinformatic analysis showed a strong correlation between LGALS9 and molecular signatures of CD8+ T cell dysfunction and tumor-infiltrating Tregs, suggesting a role for Gal-9 in promoting CD8+ T cell exhaustion and Treg expansion in GC. Ex vivo, Gal-9 enhanced Treg suppressive activity and CD8+ T cell dysfunction via Tim-3 in a PD-1independent manner, potentially driving resistance to anti-PD-1 therapy. Based on these findings, we propose circulating Gal-9 as a candidate biomarker for anti-PD-1 resistance and suggest that combined blockade of PD-1 and Tim-3 may enhance therapeutic efficacy.

Keywords: gastric cancer, Immune checkpoint blockade, galectin-9, TIM-3, Anti-PD1

Received: 26 Mar 2025; Accepted: 22 May 2025.

Copyright: © 2025 Hill, Maita, Cabrolier, Vega-Letter, Gonzalez, Kalergis, Luz Crawford, Owen and Aros-Valdivia. 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:
Charlotte Nicole Hill, Millennium Institute on Immunology and Immunotherapy, University of Chile, Santiago, 8320000, Santiago Metropolitan Region (RM), Chile
Patricia Luz Crawford, Laboratorio de Inmunología Celular y Molecular, Centro de Investigación Biomédica, Universidad de Los Andes, Santiago, Santiago Metropolitan Region (RM), Chile
Gareth I. Owen, Millennium Institute on Immunology and Immunotherapy, University of Chile, Santiago, 8320000, Santiago Metropolitan Region (RM), Chile

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material