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Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review

  • Authors:
    • Jie Wen
    • Haiyan Yu
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Peking University First Hospital Taiyuan Branch (Taiyuan Central Hospital), Taiyuan, Shanxi 030032, P.R. China
    Copyright: © Wen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 54
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    Published online on: September 1, 2026
       https://doi.org/10.3892/mi.2026.338
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Abstract

The global rise in gastrointestinal (GI) cancer among adolescents and young adults (AYAs; aged 15‑39) represents a striking departure from traditional age‑dependent epidemiology. In the present systematic review, it is proposed that premature immunosenescence may be a contributing driver of this trend and introduces the metabolic‑inflammatory‑hormonal axis as a working framework to explore these observations. Findings from PubMed/MEDLINE (1990‑2024) were synthesized, focusing on high‑impact studies and systematic reviews from the last 5 years, using keywords related to young‑onset GI cancer, immunosenescence and metabolic inflammation. A PRISMA screening process was employed, with defined inclusion/exclusion criteria. The present systematic review identified several interconnected mechanisms that may drive premature immune aging in AYAs: i) T‑cell exhaustion and thymic involution; ii) chronic inflammation fueled by the senescence‑associated secretory phenotype and tumor‑derived vesicles; and iii) metabolic perturbations, such as cholesterol buildup and lactate‑mediated immunosuppression. Collectively, these changes may create an immunosuppressive microenvironment enriched with regulatory T cells, myeloid‑derived suppressor cells and M2 macrophages. The metabolic‑inflammatory‑hormonal (M‑I‑H) axis integrates these pathways, potentially driving immune dysfunction independent of chronological age. The present systematic review emphasizes that this framework remains largely hypothetical, with numerous proposed associations awaiting direct experimental validation in AYA populations. Biomarkers including polymerase ε/polymerase δ1 mutations, microsatellite instabilityhigh/deficient mismatch repair‑status, tumor mutational burden, circulating tumor DNA, and immune gene signatures may help guide precision therapy, although their specific relationship to premature immunosenescence requires further investigation. It was proposed in the present systematic review that targeting this axis, through metabolic modulation, anti‑inflammatory strategies, hormonal interventions, or microbiota engineering, holds promise for treating AYA GI cancer. Ultimately, validating plasma biomarkers for early detection and assessing these combinatorial approaches in prospective trials will be critical to addressing this growing clinical challenge.
View Figures

Figure 1

Divergent trends in gastrointestinal
cancer incidence between AYA (15-39 years) and elderly (≥40 years)
populations, SEER 1975-2015. (A) Colon and (B) rectal cancers
showed marked increases in AYA incidence (+143 and +111%,
respectively) vs. declines in elderly populations, with clear
divergence after 1995. (C) Gastric cancer decreased in both groups.
Shaded areas, 95% confidence intervals. This divergence supports
the need to consider age-specific biological mechanisms, including
premature immunosenescence, rather than attributing the trend
solely to enhanced detection. The birth-cohort pattern visible in
panels A and B is consistent with a generational shift in
environmental or biological risk factors converging on the M-I-H
axis. AYA, adolescents and young adults; SEER, Surveillance,
Epidemiology, and End Results program; M-I-H,
metabolic-inflammatory-hormonal.

Figure 2

PRISMA flow diagram of literature
screening. Records identified through PubMed/MEDLINE database
searching (n=6,493) were combined with citation-tracked records
(n=1) and screened by title and abstract (n=6,494), assessed for
full-text eligibility (n=652), and included in the thematic
synthesis (n=53). Embase was not searched due to institutional
access limitations. AYA, adolescents and young adults.

Figure 3

M-I-H axis as a working framework for
premature immunosenescence in AYA gastrointestinal cancers. The
schematic illustrates how metabolic factors (cholesterol
accumulation, lactate, insulin resistance, and leptin),
inflammatory factors (SASP, IL-1β/IL-6, and extracellular
vesicles), hormonal factors (cortisol, estrogen, and thyroid
hormones), and the gut microbiome interact through three key
feedback loops: i) The leptin-IL-6-Treg amplification loop; ii) the
cholesterol-PD-1 stabilization loop; and iii) the cortisol-thymic
atrophy-naïve T-cell depletion loop. These interconnected pathways
converge to create an immunosuppressive TME enriched with Tregs,
MDSCs, and M2 macrophages. It is emphasize that this model is a
working hypothesis; the dashed arrows indicate hypothesized
pathways requiring direct experimental validation in AYA
populations. M-I-H, metabolic-inflammatory-hormonal; AYA,
adolescents and young adults; HMGCR, 3-hydroxy-3-methylglutaryl-CoA
reductase; HCAR1, hydroxycarboxylic acid receptor 1; HIF-1α,
hypoxia-inducible factor-1α; MDSCs, myeloid-derived suppressor
cells; SASP, senescence-associated secretory phenotype; TME, tumor
microenvironment; Tregs, regulatory T cells; TSLP, thymic stromal
lymphopoietin.
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Wen J and Yu H: Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review. Med Int 6: 54, 2026.
APA
Wen, J., & Yu, H. (2026). Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review. Medicine International, 6, 54. https://doi.org/10.3892/mi.2026.338
MLA
Wen, J., Yu, H."Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review". Medicine International 6.6 (2026): 54.
Chicago
Wen, J., Yu, H."Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review". Medicine International 6, no. 6 (2026): 54. https://doi.org/10.3892/mi.2026.338
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Spandidos Publications style
Wen J and Yu H: Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review. Med Int 6: 54, 2026.
APA
Wen, J., & Yu, H. (2026). Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review. Medicine International, 6, 54. https://doi.org/10.3892/mi.2026.338
MLA
Wen, J., Yu, H."Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review". Medicine International 6.6 (2026): 54.
Chicago
Wen, J., Yu, H."Premature immunosenescence in AYA gastrointestinal cancer: The metabolic‑inflammatory‑hormonal axis as an integrative framework: A systematic review". Medicine International 6, no. 6 (2026): 54. https://doi.org/10.3892/mi.2026.338
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