Secreted protein circuits in the gastrointestinal tumour microenvironment: determinants of immunotherapy response and resistance

Immune checkpoint blockade has transformed treatment in selected gastrointestinal (GI) cancers, yet primary resistance, incomplete responses and acquired resistance remain common. This heterogeneity is not explained by tumour-cell genomics alone; extracellular signalling programmes within the tumour microenvironment can determine immune recruitment, access and adaptation to therapy. The tumour secretome—including cytokines, chemokines, growth factors, complement components, matricellular proteins, soluble checkpoint molecules and extracellular-vesicle-associated cargo—regulates immune-cell recruitment, exclusion, suppression, tertiary lymphoid structure formation and exhaustion across anatomical and molecular contexts. Across gastric and esophageal cancers, colorectal cancer, pancreatic ductal adenocarcinoma, hepatocellular carcinoma and biliary tract cancers, recurrent suppressive circuits include TGF-β, VEGF, CXCL12-CXCR4, CXCL8/IL-8-CXCR1/2, CCL2-CCR2, CSF1-CSF1R, IL-6-family cytokines, SPP1/osteopontin, periostin, galectins, DKK1, MIF, complement and soluble or vesicular PD-L1. Conversely, CXCL9/10/11-CXCR3 signalling and CXCL13-associated tertiary lymphoid structures characterise immune-permissive states that can support checkpoint responsiveness. We organise these circuits into four overlapping functional modules—myeloid-enriched, fibroblast-driven exclusion, angiogenic-immunosuppressive and immune-permissive—and apply a four-level evidence hierarchy that separates clinical validation from mechanistic inference. Clinically useful secretome biomarkers will therefore need to integrate cellular source, spatial localisation, receptor context, temporal dynamics and linkage to actionable immune-state transitions. Secreted proteins constitute a dynamic extracellular layer of the GI tumour microenvironment and can strongly influence immunotherapy response even when genomic biomarkers appear favourable. Protein abundance alone is insufficient; source, spatial topology, receptor distribution, metastatic niche, host physiology, and treatment timing determine biological meaning. TGF-β, VEGF, CXCL12-CXCR4, CXCL8/IL-8-CXCR1/2, CCL2-CCR2, CSF1-CSF1R, IL-6-family cytokines, SPP1, DKK1, MIF, galectins, complement, and soluble or vesicular PD-L1 form recurrent suppressive modules. CXCL9/10/11-CXCR3 and CXCL13-associated tertiary lymphoid structures define immune-permissive secretome programmes that may amplify checkpoint blockade when stromal and myeloid barriers are relieved.