Abstract Background: Aging is associated with a chronic low-grade inflammatory state that profoundly influences tumor development and progression, known as inflammaging. While this is due to increased myelopoiesis, the exact mechanisms leading to increased myeloid production and the effects on the gastric tumor microenvironment remain poorly understood. Methods: We conducted comprehensive analyses of young (3 months) and aged (18 months) Hdc-GFP mice, evaluating expression of the peptide trefoil factor family 2 (TFF2) and abundance of GFP+ MDSCs in the stomach, circulation and other sites. The ACKP orthotopic model and Mist1CreERT; RhoAY42CCDH1ff; Hdc-GFP mouse (GEM) model were used to test whether aging promotes gastric cancer progression and to explore the underlying mechanisms. TFF2-MSA was given by i.p. injection twice weekly for 2 weeks before ACKP tumor inoculation, to test whether pretreatment could reverse the aging-related pro-tumor effects. Results: Aging led to a significant reduction in TFF2 levels in both the stomach and circulation, as confirmed by IHC, ELISA, and qPCR. The decline in circulating TFF2 was accompanied by elevated IL-1β expression in bone marrow, peripheral blood, and gastric neutrophils, together with increased circulating IL-1β levels. Enhanced IL-1β signaling contributed to a myeloid-biased hematopoietic phenotype, leading to the increased GFP+ MDSCs in the stomach, spleen, and peripheral blood. Elevated IL-1β in the aged stomach induced fibroblast activation with a senescence-associated secretory phenotype (SASP)-like profile, including increased IL-6, CXCL1 and CXCL2 expression. In the ACKP orthotopic and model and GEM model, with tumorigenesis initiated at 3mo or 18mo, aging significantly accelerated tumor growth and shortened survival. Immunofluorescence analyses of aged ACKP tumor identified an increased subset of IL-1R1+ cancer-associated fibroblasts (CAFs) and CGRP+ sensory nerves. Functionally, pretreatment with TFF2-MSA prior to ACKP tumor implantation decreased IL-1R1+ CAF and sensory nerves, reduced MDSC accumulation and IL-1β expression, and suppressed gastric tumor growth in aged mice. Conclusion: Our findings uncover a systemic aging axis linking reduced gastric TFF2 production to myelopoiesis and thus to gastric cancer susceptibility. Aging-associated IL-1β signaling from expanded myeloid cells reprograms gastric fibroblasts toward a pro-inflammatory SASP phenotype, fostering immune suppression and tumor growth. Restoring youthful TFF2 levels may provide effective strategies to mitigate the aging-related tumor risk and other associated inflammaging syndromes. Citation Format: Shuang Li, Hualong Zheng, Jin Qian, Puran Zhang, Feijing Wu, Yi Zeng, Biyun Zheng, Juli Lin, Hiroki Kobayashi, Yosuke Ochiai, Mashahiro Hata, Arai Junya, Leah B. Zamechek, Bruce Daugherty, Seth Lederman, Timothy C. Wang. TFF2 deficiency amplifies IL-1β-driven inflammation and promotes aging-associated gastric tumor progression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6822.
Li et al. (Fri,) studied this question.