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Emerging knowledge in cancer biology reflects upon a critical understanding that cancer development, progression and prognosis is not merely dictated by alterations in oncogenic or tumor suppressor genes, but also by host tumor microenvironment (TME). TME reshapes tumor trajectory from progression to therapy response ultimately impacting patient survival [1]. Articles in the special issue, volume 2 of Frontiers in Endocrinology, provide a concise understanding of various tumor driven local and systemic parameters (altered inflammatory, nutritional and metabolic indices) as useful biomarkers of disease onset, progression and prognosis across colorectal, gastric and pancreatic malignancies. For instance, gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide [2]. Approximately 75% of the patients present advanced disease during diagnosis [3]. Pancreatic ductal adenocarcinoma (PDAC) is another major tumor type comprising 95% of the pancreatic cancer cases worldwide [4]. Colorectal cancer (CRC) is among the most prevalent cancers globally and continues to impose substantial burden [5,6], while developing from benign polyps to adenomas to ultimately invasive carcinoma [7,8].These deadly cancers urgently require strategically improved diagnostics and biomarkers to curtail disease burden (Figure 1).Here, a systemic review and meta-analysis by Wang et al, encompassing ~26000 patients from 35 studies highlighted the prognostic significance of system immune-inflammation index (SII) in CRC. Since elevated pre-treatment SII consistently predicts poor overall and progression-free survival; inflammatory TME, immune suppression and pro-thrombotic states mediate tumor progression and metastasis. Additionally, lymph node metastasis (LNM) [9] is one of the major reasons behind poor prognosis of GC and current LNM diagnostic modalities [10] offer limited reliability. Addressing this concern, Dai and group established the combined use of carcinoembryonic antigen (CEA), SII, and prognostic nutritional index (PNI), differentiation status, and tumor diameter in improving the diagnostic accuracy for LNM in GC patients versus either index alone [11]. Integration of inflammatory and nutritional indices highlights a broader concept of tumor progression being influenced by systemic immunity and metabolic reserves, further encouraging composite biomarkers over specific laboratory test parameters. Predominantly retrospective design with variable cut-offs indicates a translational gap further encouraging prospective, multicenter initiatives to facilitate standardization and obtain translationally meaningful data.Interestingly, metabolic markers may serve as powerful yet context dependent determinants of tumorigenesis. Recent study emphasized dysregulated lipid and glucose metabolism at the core of CRC carcinogenesis risk, and highlighted triglyceride-glucose index, (substitute of insulin resistance often associated with obesity, type2 diabetes etc) showing strong association with CRC incidence [12]. Based on a meta-analysis of nine robust pooled observational studies, Wang et al, proposed that individuals with higher TyG values possess greater likelihood of developing CRC. This finding aligned well with the long-lasting evidence mechanistically linking metabolic imbalance, chronic inflammation, and CRC tumorigenesis; and supporting the TyG index as a lowcost, accessible tool for identifying high-risk individuals and guiding early preventive strategies.Metabolic effects can exert variable repercussions across tumor types, whereby Yi et al, in a retrospective cohort study (n=172) identified the TyG index as a novel, reverse prognostic biomarker for pancreatic cancer liver metastasis. This study proposed a specific metabolic shift, i.e. transition from an insulin-resistant state to a catabolic equilibrium marked by reduced insulin secretion and cachexia-driven depletion of glucose and lipids. This was potentially intensified by cytokine-mediated inhibition of hepatic triglyceride synthesis within the metastatic niche. The study established TyG index as an accessible marker reflecting a distinct metabolic phenotype in advanced pancreatic cancer, necessitating further validation and mechanistic investigations.Tumor-directed local therapies, and a sequenced arsenal of systemic options, enabling personalized, precision-based treatment to optimize survival and quality of life are essentially required while managing aggressive metastatic tumor spread. From the viewpoint of managing liver metastasis in gastroenteropancreatic neuroendocrine tumors, Xue et al, systematically reviewed this subject and reported that surgical resection and cytoreductive therapy offer most favorable survival outcome, whereas liver directed therapies like ablation and embolization could address unresectable cases. A systemic approach could manage symptoms and control disease progression; however, the requirement of prospective comparative studies cannot be negated. Collectively studies infer that gastro-intestinal (GI) cancers evolve as systemic metabolic diseases, encompassing immune-inflammatory activation, insulin resistance, lipid dysregulation thus orchestrating tumor-intrinsic signaling.Tumor evolution, its burden, aggressiveness, heterogeneity and therapeutic responsiveness are key determinants for the choice of tumor-directed therapies (either combined/targeted), enabling optimal survival and quality of life. Computational analysis and systems biology basedcomprehensive, integrated approach combining multiomics, metabolomics, immune and molecular signatures may offer novel avenues for risk assessment, biomarker development and enabling personalized oncotherapeutic strategies with greater precision for holistic management of GI cancers. Together these studies could positively impact drug designing and efficient patient stratification, survival prediction and metastasis management based on above mentioned considerations with promising outcomes.