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

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.